Codeine

Dosage Forms

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

Tablet, Oral, as sulfate:

Generic: 15 mg, 30 mg, 60 mg

Pharmacology

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/Pharmacodynamics

Absorption

Oral: Adequate

Distribution

~3 to 6 L/kg

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).

Excretion

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

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

Time to Peak

Plasma: Immediate release: 1 hour; Controlled release [Canadian product]: 3.3 hours

Duration of Action

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

Half-Life Elimination

~3 hours

Protein Binding

~7% to 25%

Use: Labeled Indications

Pain management: Management of mild- to moderately-severe 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

Cough in select patientscyes

In a metaanalysis of trials evaluating the treatment of chronic cough, the use of codeine demonstrated efficacy in patients with this condition Yancy 2013. In a systematic review of the evidence, it was found that there is no good evidence for or against this use and determined that higher quality evidence is needed (Smith 2010). Additional data may be necessary to further define the role of codeine for the treatment of chronic cough.

Based on the American College of Chest Physicians (ACCP) guidelines on the diagnosis and management of cough, the use of codeine (among other central cough suppressants such as dextromethorphan) in patients with chronic bronchitis is recommended for the short-term symptomatic relief of coughing. Routine use of codeine as an antitussive in patients with upper respiratory infections is not recommended. The ACCP guidelines on symptomatic treatment of cough among adult patients with lung cancer recommends the use of codeine to help suppress non-specific cough in patients with lung cancer in the palliative stage of their illness. Note: In palliative medicine, codeine is less preferred compared to other opioids due to its greater side effect profile.

Persistent diarrhea (palliative care)c

Clinical experience suggests the utility of codeine in managing persistent and bothersome diarrhea in palliative care patients von Guten 2013. Additional data may be necessary to further define the role of codeine in this condition.

Restless legs syndromecyes

Evidence from noncontrolled trials suggests that the use of opioids, including codeine, may be of benefit in the treatment of RLS in adults, particularly in those who do not respond to dopaminergics or other therapies. Guideline recommendations are conflicting. American Academy of Sleep Medicine guidelines note that low-level evidences supports use of opioids, including codeine, in the management of RLS AASM [Aurora 2012]. The Willis-Ekbom Disease Foundation suggests the use of low-potency opioids (eg, codeine or tramadol) may be helpful Silber 2013.

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.

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.

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosage and Administration

Dosing: Adult

Pain management (analgesic):

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. Note: The American Pain Society recommends an initial dose of 30 to 60 mg for adults with moderate pain (American Pain Society 2016).

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:

Table has been converted to the following text.

Number of 30 mg codeine combination tablets daily: ≤6 tablets/day

Initial dose of Codeine Contin: 50 mg every 12 hours

Maintenance dose of Codeine Contin: 100 mg every 12 hours

Number of 30 mg codeine combination tablets daily: 7 to 9 tablets/day

Initial dose of Codeine Contin: 100 mg every 12 hours

Maintenance dose of Codeine Contin: 150 mg every 12 hours

Number of 30 mg codeine combination tablets daily: 10 to 12 tablets/day

Initial dose of Codeine Contin: 150 mg every 12 hours

Maintenance dose of Codeine Contin: 200 mg every 12 hours

Number of 30 mg codeine combination tablets daily: >12 tablets/day

Initial dose of Codeine Contin: 200 mg every 12 hours

Maintenance dose of Codeine Contin: 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 discontinuing chronic opioid therapy, the dose should be gradually tapered down. An optimal universal tapering schedule for all patients has not been established (CDC [Dowell 2016]). Proposed schedules range from slow (eg, 10% reductions per week) to rapid (eg, 25% to 50% reduction every few days) (CDC 2015). Tapering schedules should be individualized to minimize opioid withdrawal while considering patient-specific goals and concerns as well as the pharmacokinetics of the opioid being tapered. An even slower taper may be appropriate in patients who have been receiving opioids for a long duration (eg, years), particularly in the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse events (CDC [Dowell 2016]). 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 withdrawal symptoms (Berna 2015; CDC [Dowell 2016]). Continue to offer nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasm) as needed (Berna 2015; Sevarino 2018).

Cough in select patients (off-label use): 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). Some experts recommend 30 to 60 mg 4 times daily in specific patient populations (eg, lung cancer) (ACCP [Molassiotis 2017]). Additional data may be necessary to further define the role of codeine in this condition.

Diarrhea (persistent) (palliative care) (off-label use): Oral: 15 to 30 mg every 4 hours as needed (von Gunten 2013). Additional data may be necessary to further define the role of codeine in this condition.

Restless leg syndrome (off-label use): Oral: Initial: 30 mg once daily at bedtime or during the night; may increase to 60 mg if needed; maximum dose: 180 mg in 2 to 3 divided doses. May be used alone or in combination with other medications used to treat RLS (Earley 2003; Sandyk 1987; Silbers 2013; Walters 2001).

Dosing: Geriatric

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

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: 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)

Extemporaneously Prepared

A 3 mg/mL oral suspension may be made with codeine phosphate powder, USP. Add 600 mg of powder to a 400 mL beaker. Add 2.5 mL of Sterile Water for Irrigation, USP, and stir to dissolve the powder. Mix for 10 minutes while adding Ora-Sweet to make 200 mL; transfer to a calibrated bottle. Stable 98 days at room temperature.

Dentinger PJ and Swenson CF, "Stability of Codeine Phosphate in an Extemporaneously Compounded Syrup," Am J Health Syst Pharm, 2007, 64(24):2569-73.18056945

Administration

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.

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

Storage

Immediate release tablet: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from moisture and light.

Controlled release tablet [Canadian product]: Store at 15°C to 30°C (59°F to 86°F).

Injection [Canadian product]: Store at 15°C to 30°C (59°F to 86°F). Protect from light. Do not use if more than slightly discolored or contains a precipitate.

Oral solution [Canadian product]: Store at 15°C to 30°C (59°F to 86°F).

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

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

Alizapride: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

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

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

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

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

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

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. 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. Consider therapy modification

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

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. 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. Consider therapy modification

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

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

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

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

Dacomitinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of dacomitinib with CYP2D6 subtrates that have a narrow therapeutic index. Consider therapy modification

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

Desmopressin: Opioid Agonists may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

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

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

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. 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. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

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

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

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

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone 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. Consider therapy modification

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

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

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. Consider therapy modification

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

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

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. 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 adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

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

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

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

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

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. 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. Avoid combination

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

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

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. Consider therapy modification

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

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. 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). Monitor therapy

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

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Perhexiline: CYP2D6 Substrates (High risk with Inhibitors) may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). 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. Consider therapy modification

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

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. 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. Consider therapy modification

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

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

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

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

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

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonergic Agents (High Risk): Opioid Agonists 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. 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. Consider therapy modification

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Somatostatin Analogs: May decrease the metabolism of Codeine. The formation of two major codeine metabolites (morphine and norcodeine) may be impaired by somatostatin analogs. Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. 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. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol 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. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

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. Consider therapy modification

Test Interactions

Some quinolones may produce a false-positive urine screening result for opioids using commercially-available immunoassay kits. This has been demonstrated most consistently for levofloxacin and ofloxacin, but other quinolones have shown cross-reactivity in certain assay kits. Confirmation of positive opioid screens by more specific methods should be considered.

Adverse Reactions

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: Hypogonadism (Brennan 2013; Debono 2011)

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). Monitor for symptoms of hypotension following initiation or dose titration. 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: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely for respiratory depression, especially during initiation or dose escalation. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

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 sexual dysfunction, infertility, 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 increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]).
• 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 with caution in patients with renal failure.
• 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: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).
• 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.

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: [US Boxed Warning]: 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 dosage and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.
• CYP 3A4 interactions: [US Boxed Warning]: The effects of concomitant use or discontinuation of CYP-450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of CYP-450 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.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• CYP2D6 “ultrarapid metabolizers”: Use caution in patients with two or more copies of the variant CYP2D6*2 allele; may have extensive conversion to morphine and thus increased opioid-mediated effects. Avoid the use of codeine in these patients; consider alternative analgesics such as morphine or a nonopioid agent (Crews 2012). The occurrence of this phenotype is seen in 0.5% to 1% of Chinese and Japanese, 0.5% to 1% of Hispanics, 1% to 10% of Caucasians, 3% of African-Americans, and 16% to 28% of North Africans, Ethiopians, and Arabs.
• 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.
• Elderly: Use with caution in the elderly; may be more sensitive to adverse effects. Use opioids for chronic pain with caution in this age group; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (Dowell [CDC 2016]).
• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged use during pregnancy can cause neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated 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. 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: [US Boxed Warning]: 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 CYP-450 2D6 polymorphism. Codeine is contraindicated in pediatric patients <12 years of age and 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. 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.

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: [US Boxed Warning]: Use 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 or conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk for misuse include younger age, concomitant depression (major), and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]).
• Accidental ingestion: [US Boxed Warning]: Accidental ingestion of even one dose of codeine, especially by children, can result in a fatal overdose of codeine.
• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, nonsteroidal anti-inflammatory drugs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and 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. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (Dowell [CDC 2016]).
• 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.
• REMS program: [US Boxed Warning]: To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, a REMS is required. Drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are 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.
• Surgery: Opioids decrease bowel motility; monitor for decreased bowel motility in postop patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

Monitoring Parameters

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

Alternate recommendations: Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC 2016]).

Pregnancy

Pregnancy Considerations

Opioids cross the placenta.

According to some studies, maternal use of opioids may be associated with birth defects (including neural tube defects, congenital heart defects, and gastroschisis), poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2016]).

[US Boxed Warning]: 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. If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur (Chou 2009). Symptoms of neonatal abstinence syndrome (NAS) following opioid exposure may be autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, hyperactivity, increased muscle tone, increased wakefulness/abnormal sleep pattern, irritability, sneezing, seizure, tremor, yawning) (Dow 2012; Hudak 2012). Mothers who are physically dependent on opioids may give birth to infants who are also physically dependent. Opioids may cause respiratory depression and psycho-physiologic effects in the neonate; newborns of mothers receiving opioids during labor should be monitored.

Codeine is not commonly used to treat pain during labor and immediately postpartum (ACOG 209 2019) or chronic noncancer pain in pregnant women or those who may become pregnant (CDC [Dowell 2016]; Chou 2009).

Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility in men and women (Brennan 2013).

Patient Education

What is this drug used for?

• It is used to ease pain.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Sweating a lot

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Severe dizziness
• Passing out
• Chest pain
• Fast heartbeat
• Difficulty breathing
• Slow breathing
• Shallow breathing
• Noisy breathing
• Confusion
• Severe fatigue
• Abnormal heartbeat
• Sensing things that seem real but are not
• Mood changes
• Seizures
• Severe abdominal pain
• Severe headache
• Difficult urination
• Tremors
• Vision changes
• Severe nausea
• Severe vomiting
• Severe constipation
• Severe loss of strength and energy
• Sexual dysfunction (males)
• No menstrual periods
• Decreased sex drive
• Trouble getting pregnant
• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea.
• Adrenal gland problems like severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.