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Codeine: Drug information

Codeine: Drug information
(For additional information see "Codeine: Patient drug information" and see "Codeine: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Special Alerts
FDA Requiring Updates to Opioid Prescribing Information April 2023

The FDA has issued a drug safety communication to announce safety-related updates to the prescribing information for immediate-release (IR) and extended-release (ER)/long-acting (LA) opioid analgesics, including updates to Boxed Warnings, Indications and Usage, Dosage and Administration, Warnings and Precautions, and the Medication Guide. These safety labeling changes are intended to provide clarity on appropriate patient populations for opioid treatment, appropriate dosage and administration, and updated information on the risks associated with opioid use. The required safety labeling changes include stating:

  • the risk of overdose increases as the dosage increases for all opioid pain medicines;

  • IR opioids should not be used for an extended period of time unless a patient's pain remains severe enough to require them and alternative treatment options continue to be inadequate;

  • many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine;

  • it is recommended to reserve ER/LA opioid pain medicines for severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine and for which alternative treatment options are inadequate; and

  • a warning about opioid-induced hyperalgesia (OIH), including information on differentiating OIH symptoms from those of opioid tolerance and withdrawal.

Further information may be found at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescribing-information-all-opioid-pain-medicines-provide-additional-guidance-safe-use.

ALERT: US Boxed Warning
Addiction, abuse, and misuse:

Codeine exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing codeine and monitor all patients regularly for the development of these behaviors and conditions.

Opioid analgesic risk evaluation and mitigation strategy (REMS):

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are strongly encouraged to complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist; and consider other tools to improve patient, household, and community safety.

Life-threatening respiratory depression:

Serious, life-threatening, or fatal respiratory depression may occur with use of codeine. Monitor for respiratory depression, especially during initiation of codeine or following a dose increase.

Accidental ingestion:

Accidental ingestion of even one dose of codeine, especially by children, can result in a fatal overdose of codeine.

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 who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy and many of the children had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism. Codeine is contraindicated in pediatric patients <12 years of age and in pediatric patients <18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of codeine in pediatric patients 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

Neonatal opioid withdrawal syndrome:

Prolonged use of codeine during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Interactions with drugs affecting cytochrome P450 isoenzymes:

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine requires careful consideration of the effects on the parent drug, codeine, and the active metabolite morphine.

Risks from concomitant use with benzodiazepines or other CNS depressants:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of codeine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Brand Names: Canada
  • Codeine 15 [DSC];
  • Codeine 30;
  • Codeine Contin;
  • Linctus Codeine Blanc;
  • TEVA-Codeine
Pharmacologic Category
  • Analgesic, Opioid;
  • Antitussive
Dosing: Adult
Pain management

Pain management (analgesic):

Note: For acute non–cancer-related pain severe enough to require an opioid, utilize multimodal pain control, maximize nonopioid analgesics, and limit the quantity prescribed to the expected duration of pain severe enough to require opioids. Do not use long-acting preparations for treatment of acute pain (CDC [Dowell 2022]).

Injection [Canadian product]:

Opioid-naive patients: IM, SUBQ: 30 to 60 mg every 4 to 6 hours as needed (use the lowest effective dose for the shortest period of time necessary)

Conversion from oral codeine or another opioid: IM, SUBQ: Refer to product labeling for dose conversions.

Oral: Note: These are guidelines and do not represent the maximum doses that may be required in all patients. Doses should be titrated to pain relief/prevention.

Immediate release ( tablet, oral solution [Canadian product]): Initial: 15 to 60 mg every 4 hours as needed; maximum total daily dose: 360 mg/day; patients with prior opioid exposure may require higher initial doses.

Controlled release: Codeine Contin [Canadian product]: Note: Titrate at intervals of ≥48 hours until adequate analgesia has been achieved. Daily doses >600 mg/day should not be used; patients requiring higher doses should be switched to an opioid approved for use in severe pain. In patients who receive both Codeine Contin and an immediate release or combination codeine product for breakthrough pain, the rescue dose of immediate release codeine product should be ≤12.5% of the total daily Codeine Contin dose.

Opioid-naive patients: Initial: 50 mg every 12 hours

Conversion from immediate release codeine preparations: Immediate release codeine preparations contain ~75% codeine base. Therefore, patients who are switching from immediate release codeine preparations may be transferred to a ~25% lower total daily dose of Codeine Contin, equally divided into 2 daily doses every 12 hours.

Conversion from a combination codeine product (eg, codeine with acetaminophen or aspirin): See table:

Number of 30 mg Codeine Combination Tablets Daily

Initial Dose of Codeine Contin

Maintenance Dose of Codeine Contina

a Titrate at intervals of ≥48 hours until adequate analgesia has been achieved.

≤6

50 mg every 12 hours

100 mg every 12 hours

7 to 9

100 mg every 12 hours

150 mg every 12 hours

10 to 12

150 mg every 12 hours

200 mg every 12 hours

>12

200 mg every 12 hours

200 to 300 mg every 12 hours (maximum: 300 mg every 12 hours)

Conversion from another opioid analgesic: Using the patient's current opioid dose, calculate an equivalent daily dose of immediate release codeine. A ~25% lower dose of Codeine Contin should then be initiated, equally divided into 2 daily doses.

Discontinuation of therapy: When reducing the dose, discontinuing, or tapering long-term opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established. Individualize tapering based on discussions with patient to minimize withdrawal, while considering patient-specific goals and concerns and the opioid’s pharmacokinetics. Proposed initial schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days) (CDC 2015; CDC [Dowell 2022]). Slower tapers may be appropriate after long-term use (eg, >1 year), whereas more rapid tapers may be appropriate in patients experiencing severe adverse effects. During tapering, patients may be at an increased risk of overdose if they return to their original (or higher) opioid dose or use illicit opioids, due to rapid loss of tolerance; consider prescribing naloxone. Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt autonomic withdrawal symptoms and other adjunctive agents to treat GI symptoms and muscle spasms, as needed. Continue to offer nonopioid analgesics as needed for pain management during the taper (CDC [Dowell 2022]).

Cough in select patients

Cough in select patients (off-label use):

Note: In most cases, nonspecific antitussives such as codeine should be used for short-term symptomatic relief of cough that is not associated with an upper respiratory infection or acute bronchitis (ACCP [Bolser 2006]; Smith 2020).

Oral: Reported doses vary with a range of 7.5 to 120 mg/day as a single dose or in divided doses; however, evidence is of low quality (ACCP [Bolser 2006]; Smith 2010; Yancy 2013). Some experts recommend 30 to 60 mg 4 times daily in specific patient populations (eg, lung cancer) (ACCP [Molassiotis 2017]).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function:

Oral, Injection [Canadian product]:

eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary (expert opinion).

eGFR 30 to <60 mL/minute/1.73 m2: Avoid use; use of alternative analgesics preferred (Coluzzi 2020; Davison 2014; Koncicki 2017; Owsiany 2019; expert opinion). Codeine and its metabolites (including morphine-3-glucuronide and morphine-6-glucuronide) are eliminated by the kidneys. Patients with chronic kidney disease who are ultra-rapid metabolizers of codeine are at greatest risk of neurotoxic effects (Coluzzi 2020; Molanaei 2010). If necessary, administer 50% to 75% of the usual dose initially; titrate gradually based on tolerability and response with frequent monitoring for adverse effects.

eGFR <30 mL/minute/1.73 m2: Avoid use (Coluzzi 2020; Davison 2014; Koncicki 2017; Owsiany 2019; expert opinion).

Hemodialysis, intermittent (thrice weekly): Oral, Injection [Canadian product]: Avoid use (Coluzzi 2020; Owsiany 2019). Codeine and its metabolites (including morphine-3-glucuronide and morphine-6-glucuronide) are eliminated by the kidneys and accumulation is likely (Guay 1988). Serious adverse effects, including oversedation and seizures, have been reported in dialysis patients (Kuo 2004; Matzke 1986).

Peritoneal dialysis: Oral, Injection [Canadian product]: Avoid use (Coluzzi 2020; Owsiany 2019). Codeine and its metabolites (including morphine-3-glucuronide and morphine-6-glucuronide) are eliminated by the kidneys and accumulation is likely (Guay 1988). Serious adverse effects, including oversedation and seizures, have been reported in dialysis patients (Kuo 2004; Matzke 1986).

CRRT: Oral, Injection [Canadian product]: Avoid use (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): O ral, Injection [Canadian product]: Avoid use (expert opinion).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, lower initial doses or longer dosing intervals followed by careful titration are recommended.

Dosing: Older Adult

Refer to adult dosing. Use with caution and consider initiation at the low end of the dosing range; reduced initial dosages may be necessary.

Dosing: Pediatric

(For additional information see "Codeine: Pediatric drug information")

Note: Codeine 30 mg/5 mL oral solution has been discontinued in the US for more than 1 year. Doses should be titrated to appropriate analgesic effect; use the lowest effective dose for the shortest period of time:

Pain management; analgesia

Pain management; analgesia: Limited data available: Note: Use is contraindicated in pediatric patients <12 years of age and for postoperative management in pediatric patients 12 to 18 years of age who have undergone tonsillectomy and/or adenoidectomy. Avoid codeine use in all pediatric patient populations in which it is contraindicated and in pediatric patients 12 to 18 years of age who have other risk factors that increase risk for respiratory depression associated with codeine (eg, conditions associated with hypoventilation like postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, use of other medications known to depress respiratory drive); in rare cases in which codeine-containing product is the only option, consider genotype testing prior to use; use extra precaution; monitor closely for adverse effects. Codeine has been associated with reports of life-threatening or fatal respiratory depression in children and adolescents; multifactorial causes have been identified; of primary concern are unrecognized ultrarapid metabolizers of CYP2D6 who may have extensive conversion of codeine (prodrug) to morphine and thus increased opioid-mediated effects. Avoid codeine use in pediatric patient populations in which it is contraindicated; in rare cases in which codeine-containing product is the only option, consider genotype testing prior to use; use extra precaution; monitor closely for adverse effects (AAP [Tobias 2016]; Dancel 2017; Gammal 2016; Goldschneider 2017; Poonai 2015).

Children and Adolescents: Oral: 0.5 to 1 mg/kg/dose every 4 to 6 hours as needed; maximum single dose: 60 mg/dose (APS 2016)

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no specific dosage adjustments provided in the manufacturer’s labeling; however, clearance may be reduced; active metabolites may accumulate. Use with caution; initiate at lower doses or longer dosing intervals followed by careful titration.

The following guidelines have been used by some clinicians (Aronoff 2007):

Children and Adolescents:

GFR >50 mL/minute/1.73 m2: No adjustment needed

GFR 10 to 50 mL/minute/1.73 m2: Administer 75% of normal dose

GFR <10 mL/minute/1.73 m2: Administer 50% of normal dose

Hemodialysis: Administer 50% of normal dose

Peritoneal dialysis (PD): Administer 50% of normal dose

CRRT: Administer 75% of normal dose

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, initial lower doses or longer dosing intervals followed by careful titration are recommended in adult patients.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Frequency not defined.

Cardiovascular: Bradycardia, cardiac arrest, circulatory depression, flushing, hypertension, hypotension, palpitations, shock, syncope, tachycardia

Central nervous system: Abnormal dreams, agitation, anxiety, apprehension, ataxia, chills, depression, disorientation, dizziness, drowsiness, dysphoria, euphoria, fatigue, hallucination, headache, increased intracranial pressure, insomnia, nervousness, paresthesia, sedation, shakiness, taste disorder, vertigo

Dermatologic: Diaphoresis, pruritus, skin rash, urticaria

Gastrointestinal: Abdominal cramps, abdominal pain, anorexia, biliary tract spasm, constipation, diarrhea, nausea, pancreatitis, vomiting, xerostomia

Genitourinary: Urinary hesitancy, urinary retention

Hypersensitivity: Hypersensitivity reaction

Neuromuscular & skeletal: Laryngospasm, muscle rigidity, tremor, weakness

Ophthalmic: Blurred vision, diplopia, miosis, nystagmus, visual disturbance

Respiratory: Bronchospasm, dyspnea, respiratory arrest, respiratory depression

<1%, postmarketing, and/or case reports: Allodynia (opioid-induced hyperalgesia) (FDA Safety Communication 2023), hypogonadism (Brennan 2013; Debono 2011)

Contraindications

Hypersensitivity (eg, anaphylaxis) to codeine or any component of the formulation; pediatric patients <12 years of age; postoperative management in pediatric patients <18 years of age who have undergone tonsillectomy and/or adenoidectomy; significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; GI obstruction, including paralytic ileus (known or suspected); concurrent use with monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days.

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Canadian labeling: Additional contraindications (not in US labeling): Cor pulmonale; hypercarbia; acute alcoholism; delirium tremens; severe CNS depression; convulsive disorders; increased cerebrospinal or intracranial pressure; head injury; chronic obstructive airway disease; status asthmaticus; mechanical GI obstruction or any disease that affects bowel transit (known or suspected); suspected surgical abdomen (eg, acute appendicitis, pancreatitis); pregnancy and during labor and delivery.

Additional product specific contraindications:

Codeine Contin: Acute or mild pain that can be managed with immediate release pain medication; intermittent or short duration pain that can be managed with alternative pain medication; CYP2D6 ultra-rapid metabolizers; breastfeeding.

Codeine injection: Breastfeeding; mild pain that can be managed with alternative pain medications.

Oral solution, tablet (immediate release): Mild pain that can be managed with other pain medications; CYP2D6 ultra-rapid metabolizers; breastfeeding.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery, driving).

• Constipation: May cause or aggravate constipation; chronic use may result in obstructive bowel disease, particularly in those with underlying intestinal motility disorders. May also be problematic in patients with unstable angina and patients post-myocardial infarction (MI). Consider preventative measures (eg, stool softener, increased fiber) to reduce the potential for constipation.

• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Avoid use in patients with circulatory shock.

• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).

• Respiratory depression: Fatal respiratory depression may occur. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Patients and caregivers should be educated on how to recognize respiratory depression and the importance of getting emergency assistance immediately (eg, calling 911) in the event of known or suspected overdose.

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).

• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; may cause constriction of sphincter of Oddi.

• CNS depression/coma: Avoid use in patients with impaired consciousness or coma, as these patients are susceptible to intracranial effects of CO2 retention.

• Delirium tremens: Use with caution in patients with delirium tremens.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

• Hepatic impairment: Use with caution in patients with severe hepatic impairment.

• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2022]).

• Obesity: Use with caution in patients who are morbidly obese.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: Use should generally be avoided in patients with impaired kidney function (Coluzzi 2020; Davison 2014; Koncicki 2017; Owsiany 2019).

• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale and those having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or preexisting respiratory depression, particularly when initiating therapy and titrating therapy. Critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Sleep-related disorders: Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and central nervous system depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2022]).

• Seizure disorders: Use with caution in patients with a history of seizure disorders; may cause or exacerbate seizures.

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Special populations:

• CYP2D6 "poor metabolizers": Poor metabolizers have decreased metabolism of codeine to its active metabolite, which may diminish analgesia; avoid the use of codeine and consider alternatives that are not metabolized by CYP2D6 (CPIC [Crews 2021]).

• CYP2D6 “ultrarapid metabolizers”: Ultrarapid metabolizers have increased metabolism of codeine to its active metabolite, which may increase the risk of serious adverse effects; avoid the use of codeine and consider alternatives that are not metabolized by CYP2D6 (CPIC [Crews 2021]). The prevalence of this phenotype is estimated to be 1% to 10% for White (European and North American) patients; 3% to 4% for Black patients; 1% to 2% for Chinese, Japanese, and Korean patients; and >10% in certain ethnic groups such as Oceanian, Northern African, Middle Eastern, Ashkenazi Jew, and Puerto Rican patients.

• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Older adult: Use opioids with caution in older adults; may be more sensitive to adverse effects. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increased adverse effects. Monitor closely for adverse effects associated with opioid therapy (eg, respiratory and central nervous system depression, falls, cognitive impairment, constipation) (CDC [Dowell 2022]). Consider the use of alternative nonopioid analgesics in these patients when possible.

• Neonates: Neonatal withdrawal syndrome: Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

• Pediatric: Respiratory depression: 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. Deaths have also occurred in breastfeeding infants after being exposed to high concentrations of morphine because the mothers were ultra-rapid metabolizers. Additionally, Health Canada recommends to avoid the use of nonprescription codeine-containing pain relief products in pediatric patients <18 years of age (Health Canada 2020).

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid. Benzoic acid (benzoate) is a metabolite of benzyl alcohol. Large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997], CDC 1982). Some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

• Oral solution: Risk of medication errors: Ensure accuracy when prescribing, dispensing, and administering codeine oral solution. Dosing errors due to confusion between mg and mL and other codeine solutions of different concentrations can result in accidental overdose and death.

• Sulfites: Some preparations may contain sulfites, which may cause allergic reactions.

Other warnings/precautions:

• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent on opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances; provide care as needed. Concurrent use of mixed agonist/antagonist (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists.

• Abuse/misuse/diversion: Use with caution in patients with a history of substance abuse; potential for drug dependency exists. Other factors associated with increased risk for misuse include concomitant depression or other mental health conditions, higher opioid dosages, or taking other central nervous system depressants. Consider offering naloxone prescriptions in patients with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), concomitant benzodiazepine use, and patients at risk for returning to a high dose after losing tolerance (CDC [Dowell 2022]).

• Appropriate use: Outpatient setting: Opioids should not be used as first-line therapy for acute (<1-month duration), subacute (1- to 3-month duration), or chronic pain (>3-month duration [outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment]). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, nonsteroidal anti-inflammatory drugs, acetaminophen, certain antiseizure medications and antidepressants) as appropriate for the specific condition. If opioid therapy is initiated, it should be combined with nonpharmacologic and non-opioid therapy, as appropriate. Prior to initiation, known risks and realistic benefits of opioid therapy should be discussed with the patient. Therapy should be initiated at the lowest effective dosage using IR opioids (instead of ER/long-acting opioids). For the treatment of acute pain, therapy should only be given for the expected duration of pain severe enough to require opioids and prescribed as needed (not scheduled). For the treatment of subacute and chronic pain, realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Risk to patients increases with higher opioid dosages. Dosages ≥50 MME/day are likely to not have increased benefit to pain relief or function relative to overall risk to patients; before increasing dosage to ≥50 MME/day, readdress pain and reassess evidence of individual benefits and risks (CDC [Dowell 2022]).

• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of), or have experienced a previous opioid-induced respiratory depression/opioid overdose. Additionally, health care providers should consider prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.

• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

• Surgery: Opioids decrease bowel motility; monitor for decreased bowel motility in postoperative patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

Warnings: Additional Pediatric Considerations

Use is contraindicated in pediatric patients <12 years of age and for postoperative management in pediatric patients 12 to 18 years of age who have undergone tonsillectomy and/or adenoidectomy. Avoid codeine use in all pediatric patient populations in which it is contraindicated and in pediatric patients 12 to 18 years of age who have other risk factors that increase risk for respiratory depression associated with codeine (eg, conditions associated with hypoventilation like postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, use of other medications known to depress respiratory drive); in rare cases in which codeine-containing product is the only option, consider genotype testing prior to use; use extra precaution; monitor closely for adverse effects. Prior to 2017, acetaminophen/codeine was approved for use in children as young as 3 years of age. Codeine has also been removed from the WHO List of Essential Medications in Children since 2011. Codeine has been associated with reports of life-threatening or fatal respiratory depression in children and adolescents; a review of FDA adverse events data and the literature includes reports of at least 21 deaths in infants or children (1965-2015). Multifactorial causes for the respiratory depression have been identified; of primary concern are unrecognized ultrarapid metabolizers of CYP2D6 who may have extensive conversion of codeine (prodrug) to morphine and thus increased opioid-mediated effects (ie, respiratory depression). Other oral opioid and nonopioid analgesics are alternate options depending upon severity of pain and other patient specific factors (eg, age, route of administration, etc); however, each also has unique therapeutic challenges and concerns; refer to individual monographs for detailed information. Avoid codeine use in pediatric patient populations in which it is contraindicated; in rare cases where codeine-containing product is the only option, consider genotype testing prior to use; use extra precaution; monitor closely for adverse effects (AAP [Tobias 2016]; Dancel 2017; Gammal 2016; Goldschneider 2017; Poonai 2015).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as sulfate:

Generic: 15 mg, 30 mg, 60 mg

Generic Equivalent Available: US

Yes

Pricing: US

Tablets (Codeine Sulfate Oral)

15 mg (per each): $0.86

30 mg (per each): $0.93 - $1.86

60 mg (per each): $1.70

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Liquid, Oral:

Generic: 0.2% (500 mL, 2000 mL)

Solution, Injection:

Generic: 30 mg/mL (1 mL)

Syrup, Oral:

Generic: 5 mg/mL (8 mL, 500 mL, 2000 mL)

Tablet, Oral:

Generic: 15 mg, 30 mg

Tablet Extended Release, Oral:

Codeine Contin: 50 mg [contains fd&c blue #2 (indigo carm) aluminum lake]

Codeine Contin: 100 mg [contains fd&c yellow #5 (tartrazine)aluminum lake, quinoline (d&c yellow #10) aluminum lake]

Codeine Contin: 150 mg, 200 mg

Controlled Substance

C-II

Administration: Adult

Oral:

Oral solution [Canadian product]: Administer with an accurate measuring device (calibrated oral syringe or measuring cup); do not use a household teaspoon or tablespoon to measure dose (overdosage may occur).

Controlled-release tablets: Codeine Contin [Canadian product]: Tablets should be swallowed whole; do not chew, dissolve, or crush. All strengths may be halved, except the 50 mg tablets; half tablets should also be swallowed intact.

Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Switch to IR formulation (tablet or oral suspension).

Injection [Canadian product]: May be administered by IM or SubQ injection.

Administration: Pediatric

Oral: Administer with food or water to decrease nausea and GI upset; administer oral liquid doses with an accurate measuring device (calibrated oral syringe or measuring cup); do not use a household teaspoon or tablespoon to measure dose (overdosage may occur)

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Codeine sulfate oral solution: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202245s009lbl.pdf#page=29

Codeine sulfate tablets: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022402s014lbl.pdf#page=29

Use: Labeled Indications

Pain management: Management of mild to moderate pain.

Limitations of use: Reserve codeine for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate.

Use: Off-Label: Adult

Cough in select patients

Medication Safety Issues
Sound-alike/look-alike issues:

Codeine may be confused with Cardene, Cordran, iodine, Lodine

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Pediatric patients: High-risk medication:

KIDs List: Codeine, when used in pediatric patients <18 years of age, is identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list and should be avoided due to risk of respiratory depression and death unless pharmacogenetic testing completed (strong recommendation; high quality of evidence) (PPA [Meyers 2020]).

Metabolism/Transport Effects

Substrate of CYP2D6 (major), CYP3A4 (major), UGT2B4, UGT2B7; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy

Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

CYP2D6 Inhibitors (Moderate): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease serum concentrations of the active metabolite(s) of Codeine. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of Codeine. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase serum concentrations of the active metabolite(s) of Codeine. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Codeine. Risk C: Monitor therapy

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Desmopressin: Opioid Agonists may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy

DroPERidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Codeine. Risk X: Avoid combination

Nalfurafine: Opioid Agonists may enhance the adverse/toxic effect of Nalfurafine. Opioid Agonists may diminish the therapeutic effect of Nalfurafine. Risk C: Monitor therapy

Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination

Nefazodone: Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of Opioid Agonists (metabolized by CYP3A4 and CYP2D6). Management: Monitor for increased opioid effects, including fatal respiratory depression, when these agents are combined and consider opioid dose reductions until stable drug effects are achieved. Additionally, monitor for serotonin syndrome/serotonin toxicity. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

PHENobarbital: May enhance the CNS depressant effect of Codeine. PHENobarbital may decrease the serum concentration of Codeine. Management: Avoid use of codeine and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased codeine efficacy and withdrawal if combined. Risk D: Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Primidone: May enhance the CNS depressant effect of Codeine. Primidone may decrease the serum concentration of Codeine. Management: Avoid use of codeine and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased codeine efficacy and withdrawal if combined. Risk D: Consider therapy modification

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination

Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may diminish the therapeutic effect of Opioid Agonists (metabolized by CYP3A4 and CYP2D6). Management: Monitor for decreased therapeutic response (eg, analgesia) and opioid withdrawal when coadministered with SSRIs that strongly inhibit CYP2D6. Additionally, monitor for serotonin syndrome/serotonin toxicity if these drugs are combined. Risk C: Monitor therapy

Serotonergic Agents (High Risk): Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification

Somatostatin Analogs: May decrease serum concentrations of the active metabolite(s) of Codeine. Specifically, the concentrations of the active metabolite morphine may be reduced. Risk C: Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification

Reproductive Considerations

Chronic opioid use may cause hypogonadism and hyperprolactinemia which may decrease fertility in patients of reproductive potential. Menstrual cycle disorders (including amenorrhea), erectile dysfunction, and impotence have been reported. The incidence of hypogonadism may be increased with the use of opioids in high doses or long-acting opioid formulations. It is not known if the effects on fertility are reversible. Monitor patients on long-term therapy (de Vries 2020; Gadelha 2022).

Consider family planning, contraception, and the effects on fertility prior to prescribing opioids for chronic pain to patients who could become pregnant (ACOG 2017; CDC [Dowell 2022]).

Pregnancy Considerations

Opioids cross the placenta.

Maternal use of opioids may be associated with poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2022]). Opioids used as part of obstetric analgesia/anesthesia during labor and delivery may temporarily affect the fetal heart rate (ACOG 2019).

Neonatal abstinence syndrome (NAS)/neonatal opioid withdrawal syndrome (NOWS) may occur following prolonged in utero exposure to opioids (CDC [Dowell 2022]). NAS/NOWS may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. Presentation of symptoms varies by opioid characteristics (eg, immediate release, sustained release), time of last dose prior to delivery, drug metabolism (maternal, placental, and infant), net placental transfer, as well as other factors (AAP [Hudak 2012]; AAP [Patrick 2020]). Clinical signs characteristic of withdrawal following in utero opioid exposure include excessive crying or easily irritable, fragmented sleep (<2 to 3 hours after feeding), tremors, increased muscle tone, or GI dysfunction (hyperphagia, poor feeding, feeding intolerance, watery or loose stools) (Jilani 2022). NAS/NOWS occurs following chronic opioid exposure and would not be expected following the use of opioids at delivery (AAP [Patrick 2020]).

Monitor infants of mothers on long-term/chronic opioid therapy for symptoms of withdrawal. Symptom onset reflects the half-life of the opioid used. Monitor infants for at least 3 days following exposure to immediate-release opioids; monitor for at least 4 to 7 days following exposure to sustained-release opioids (AAP [Patrick 2020]; CDC [Dowell 2022]). Monitor newborns for excess sedation and respiratory depression when opioids are used during labor.

When opioids are needed to treat acute pain in pregnant patients, the lowest effective dose for only the expected duration of pain should be prescribed (CDC [Dowell 2022]).

Codeine is not commonly used to treat pain during labor and immediately postpartum (ACOG 2019). Opioid use for pain following vaginal or cesarean delivery should be made as part of a shared decision-making process. A stepwise, multimodal approach to managing postpartum pain is recommended. A low-dose, low-potency, short-acting opioid can be used to treat acute pain associated with delivery when needed. If a codeine-containing medication is needed for postpartum pain, review the signs of NAS/NOWS with the patient and their caregivers (ACOG 2021).

Opioids are not preferred for the treatment of chronic noncancer pain during pregnancy; consider strategies to minimize or avoid opioid use. Advise pregnant patients requiring long-term opioid use of the risk of NAS/NOWS and provide appropriate treatment for the neonate after delivery. NAS/NOWS is an expected and treatable condition following chronic opioid use during pregnancy and should not be the only reason to avoid treating pain with an opioid in pregnant patients (ACOG 2017; CDC [Dowell 2022]). Do not abruptly discontinue opioids during pregnancy; taper prior to discontinuation when appropriate, considering the risks to the pregnant patient and fetus if maternal withdrawal occurs (CDC [Dowell 2022])

Breastfeeding Considerations

Codeine and its active metabolite morphine are present in breast milk and can be detected in the serum of breastfeeding infants (Meny 1993).

Concentrations of codeine and morphine in breast milk are dependent upon the mother's CYP2D6 metabolism. In patients with normal CYP2D6 metabolism, the amount detected in breast milk is expected to be dose-dependent; however, deaths have occurred in breastfeeding infants exposed to high concentrations of morphine when the mothers were ultrarapid metabolizers. Genetic testing for CYP2D6 is recommended for patients requiring codeine for postpartum pain and who will be breastfeeding (Madadi 2013).

Adverse events in the infant may include excessive sedation and respiratory depression.

Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer. Nonopioid analgesics are preferred for lactating patients who require pain control peripartum or for surgery outside of the postpartum period. When opioids are needed for lactating patients, use the lowest effective dose for the shortest duration of time to limit adverse events in the mother and breastfeeding infant. Codeine is not preferred when an opioid is needed (AAP [Sachs 2013]; ABM [Martin 2018]; ABM [Reece-Stremtan 2017]; WHO 2002).

When chronic opioids are prescribed prenatally and continued postpartum, breastfeeding may be initiated to help mitigate potential newborn withdrawal; monitor both the mother and the infant (AAP [Meek 2022]; AAP [Patrick 2020]).

Monitor infants exposed to opioids via breast milk for drowsiness, sedation, feeding difficulties, or limpness (ACOG 2019). Withdrawal symptoms may occur when maternal use is discontinued, or breastfeeding is stopped.

If a codeine-containing medication is used for postpartum pain, review the signs and symptoms of NAS/NOWS with the patient and their caregivers (ACOG 2021).

Monitoring Parameters

Pain relief, respiratory and mental status, blood pressure, heart rate; bowel function; signs/symptoms of substance use disorder, abuse, or misuse; signs/symptoms of hypogonadism or hypoadrenalism (Brennan 2013).

Alternate recommendations: Subacute or chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. In patients with subacute pain initially treated for acute pain, reassess pain and function after 30 days to address potentially reversible causes of pain and prevent unintentional long-term opioid therapy. In patients on long-term therapy, re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Toxicology testing is recommended prior to initiation and at least yearly (includes controlled prescription medications, illicit drugs of abuse, and benzodiazepines). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (CDC [Dowell 2022]).

Mechanism of Action

Binds to opioid receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; causes cough suppression by direct central action in the medulla; produces generalized CNS depression

Pharmacokinetics (Adult Data Unless Noted)

Onset of action: Oral: Immediate release: 0.5 to 1 hour; Injection [Canadian product]: 10 to 30 minutes

Peak effect: Oral: Immediate release: 1 to 1.5 hours; Injection [Canadian product]: 30 to 60 minutes

Duration: Oral: Immediate release: 4 to 6 hours; Injection [Canadian product]: 4 to 6 hours

Absorption: Oral: Adequate

Distribution: ~3 to 6 L/kg

Protein binding: ~7% to 25%

Metabolism: Hepatic via UGT2B7 and UGT2B4 to codeine-6-glucuronide, via CYP2D6 to morphine (active), and via CYP3A4 to norcodeine. Morphine is further metabolized via glucuronidation to morphine-3-glucuronide and morphine-6-glucuronide (active).

Bioavailability: 53%

Half-life elimination: ~3 hours

Time to peak, plasma: Immediate release: 1 hour; Controlled release [Canadian product]: 3.3 hours

Excretion: Urine (~90%, ~10% of the total dose as unchanged drug); feces

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AT) Austria: Codein hydrochloride | Codein kwizda | Tricodein solco;
  • (BD) Bangladesh: Codinol;
  • (BE) Belgium: Bronchodine | Bronchosedal codeine | Glottyl | Toularynx codeini | Toux San Codeine | Toux-san | Tussosaintbois;
  • (BR) Brazil: Cod | Codein;
  • (CH) Switzerland: Codein knoll | Tricodein Solco;
  • (CI) Côte d'Ivoire: Calmatux;
  • (CN) China: Codeine | Ni ke kang;
  • (CZ) Czech Republic: Codein slovakofarma | Kodein Xantis;
  • (DE) Germany: Antitussivum buerger | Codeinphosphat | Codeinum phosphoricum forte compren | Codeinum phosporicum | Codi opt | Codicaps neo | Codicompren | Codipertussin | Tryasol codein;
  • (DK) Denmark: Kodein sad;
  • (EC) Ecuador: Pulmocodeina;
  • (ES) Spain: Codeisan | Histaverin | Perduretas codeina | Toseina nf;
  • (FI) Finland: Codein phosphas;
  • (FR) France: Codenfan | Neo codion adultes | Paderyl | Pneumogenol;
  • (GB) United Kingdom: Bepro | Codeine phos kent | Codeine Phosphate | Codeine phosphate arrow | Codeine phosphate astec | Codeine phosphate cox;
  • (HK) Hong Kong: Cough C;
  • (HR) Croatia: Codeini phosphatis Alkaloid | Kodeinfosfat Alkaloid;
  • (HU) Hungary: Codinep;
  • (ID) Indonesia: Codein;
  • (IE) Ireland: Codant;
  • (IL) Israel: Codical | Rekod;
  • (IN) India: Codeine Sulphate | Codine linctus | Kodex | Lincotuss | Montokuf;
  • (JP) Japan: Codeine phosphate dainippon | Codeine phosphate merck hoei | Codeine phosphate sankyo | Codeine phosphate shionogi | Codeine phosphate takeda | Codeine phosphate tanabe;
  • (KR) Korea, Republic of: Bc codeine phosphate | Codeine | Codeine guju | Decoin | Hana codeine phosphate;
  • (LT) Lithuania: Codein;
  • (LU) Luxembourg: Bromophar | Glottyl | Toularynx codeini;
  • (LV) Latvia: Codein | Tryasol codein;
  • (MA) Morocco: Codenfan;
  • (MY) Malaysia: Benatussil codeine | Cophos;
  • (NL) Netherlands: Codeinefosfaat | Codeinefosfaat expharma | Natterman bronchicum extra sterk stroop;
  • (NO) Norway: Kodein;
  • (NZ) New Zealand: Alpha-codeine phosphate;
  • (PE) Peru: Codilusa | Seditos;
  • (PL) Poland: Codeinum phosphoricum;
  • (PT) Portugal: Codeina | Codeisan;
  • (RO) Romania: Codein slovakofarm | Codeina fosfat | Codeina fosforica | Farmacod | Fosfat de codeina;
  • (RU) Russian Federation: Codeine;
  • (SE) Sweden: Kodein alternova | Kodein Recip;
  • (SG) Singapore: Codeine | L.t.r. | L.t.r. cough;
  • (SI) Slovenia: Codeine | Kodeinijev fosfat;
  • (SK) Slovakia: Codein;
  • (TH) Thailand: Codeine;
  • (TN) Tunisia: Codenfan | Paderyl | Pectoral adulte;
  • (TR) Turkey: Neocodin;
  • (TW) Taiwan: Codeine | Cotaine | Coutan | Enodone;
  • (UA) Ukraine: Codeini phosphas;
  • (UY) Uruguay: Codein;
  • (VE) Venezuela, Bolivarian Republic of: Codeina
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