codeine (Rx)

>10%

Constipation

Drowsiness

1-10%

Hypotension

Tachycardia or bradycardia

Confusion

Dizziness

False feeling of well-being

Headache

Lightheadedness

Malaise

Paradoxical CNS stimulation

Restlessness

Rash, urticaria

Anorexia

Nausea, vomiting

Xerostomia

Ureteral spasm, urination decreased

LFTs increased

Burning at injection site

Weakness

Blurred vision

Dyspnea

Histamine release

<1%

Hypotension, with IV use

Anaphylactoid reaction (rare)

Seizure, with excessive doses

Respiratory depression

Postmarketing Reports

Severe hypotension

Life-threatening respiratory depression

Neonatal opioid withdrawal syndrome

Death related to ultra-rapid metabolizers of codeine

Adrenal insufficiency

Gastrointestinal adverse reactions

Seizures

Euphoria

Dysphoria

Abdominal pain

Pruritus

Sweating

Serotonin syndrome

Anaphylaxis

Androgen deficiency

Contraindications

Hypersensitivity to codeine

Significant respiratory depression

Children younger than 12 years

Postoperative pain management in children (<18 years) who have undergone tonsillectomy and/or adenoidectomy

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within last 14 days

Known or suspected gastrointestinal obstruction, including paralytic ileus

Cautions

Codeine sulfate tablets contain codeine, a schedule II controlled substance; as an opioid, codeine sulfate tablets exposes users to risks of addiction, abuse, and misuse; addiction can occur at recommended dosages and if drug is misused or abused; assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing codeine sulfate tablets, and monitor; risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression); potential for these risks should not prevent proper management of pain in any given patient; patients at increased risk may be prescribed opioids such as codeine sulfate tablets, but use in such patients necessitates intensive counseling about risks and proper use of codeine sulfate along with intensive monitoring for signs of addiction, abuse, and misuse; prescribe the drug in smallest appropriate quantity and advise patient on proper disposal of unused drug

Therapy may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients; there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics); monitor patients for signs of hypotension after initiating or titrating dosage; in patients with circulatory shock, therapy may cause vasodilation that can further reduce cardiac output and blood pressure; avoid therapy in patients with circulatory shock

In patients who may be susceptible to intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), therapy may reduce respiratory drive, and resultant CO2 retention can further increase intracranial pressure; monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy; opioids may obscure clinical course in a patient with a head injury; avoid the use in patients with impaired consciousness or coma

Contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus; may cause spasm of sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms

Therapy may increase frequency of seizures in patients with seizure disorders, and may increase risk of seizures occurring in other clinical settings associated with seizures; monitor patients with history of seizure disorders for worsened seizure control during therapy

Avoid use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic; mixed agonist/antagonist and partial agonist analgesics may reduce analgesic effect and/or precipitate withdrawal symptoms; when discontinuing therapy in physically-dependent patient, gradually taper dosage; do not abruptly discontinue therapy in these patients

Warn patients not to drive or operate dangerous machinery unless they are tolerant to effects of drug and know how they will react to medication

While serious, life-threatening, or fatal respiratory depression can occur at any time during therapy, risk is greatest during initiation of therapy or following dosage increase; monitor patients closely for respiratory depression, especially within first 24 to 72 hr of initiating therapy with and following dosage increases; accidental ingestion of even one dose, especially by children, can result in respiratory depression and death due to overdose of codeine

Deaths have occurred in nursing infants exposed to high levels of morphine in breast milk because mothers were ultra-rapid metabolizers of codeine

Profound sedation, respiratory depression, coma, and death may result from concomitant administration with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol); because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate

Use in patients with acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment is contraindicated; patients with significant chronic obstructive pulmonary disease or cor pulmonale, and with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients; monitor closely

Monoamine oxidase inhibitors (MAOIs) may potentiate effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion; therapy should not be administered within 14 days of taking MAOIs

Cases of adrenal insufficiency reported with opioid use, more often following greater than one month of use; symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids; wean patient off of opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers; other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible

Use caution when selecting dosage for an elderly patient, usually starting at low end of dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy; because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and may be useful to monitor renal function

Codeine pharmacokinetics may be altered in patients with renal failure; clearance may be decreased and metabolites may accumulate much higher plasma levels in patients with renal failure as compared to patients with normal renal function; start with a lower than normal dosage or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension

Use caution in cardiac arrhythmias, drug abuse/dependence, emotional lability, gallbladder disease, head injury, hepatic impairment, hypothyroidism, increased ICP, prostatic hypertrophy, renal impairment, seizures with epilepsy, urethral stricture, urinary tract surgeryLife-threatening respiratory depression and death reported in children who received codeine; codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to active metabolite morphine; based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression; children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to respiratory depressant effect

When prescribing codeine for adolescents, healthcare providers should choose lowest effective dose for shortest period of time and inform patients and caregivers about risks and signs of morphine overdose

At least one death reported in a nursing infant exposed to high levels of morphine in breast milk because mother was an ultra-rapid metabolizer of codeine; breastfeeding is not recommended during treatment with codeine sulfate oral solution

Risk of life-threatening side effects in nursing infants, especially if mother is an ultra-rapid metabolizer of codeine

Mechanism of Action

Narcotic agonist analgesic with antitussive activity, mu receptor agonist

Absorption

Onset: 30-60 min (PO); 10-30 min (IM)

Duration: 4-6 hr

Peak plasma time: 0.5-1 hr

Distribution

Protein bound: 25%

Vd: 3.5 L/kg (PO); 2.6 L/kg (IM)

Metabolism

Prodrug metabolized to morphine by CYP2D6; demethylated/conjugated in liver (undergoes O-demethylation, N-demethylation, and partial conjugation with glucuronic acid)

Elimination

Half-life: 3-4 hr

Excretion: Urine, feces

Pharmacogenomics

10% of codeine is metabolized to morphine by CYP2D6; the active morphine metabolite has a higher affinity for opioid receptors

CYP2D6 poor metabolizers may not achieve adequate analgesia

Ultra-rapid metabolizers (up to 7% of Caucasians and up to 30% of Asian and African populations) may have increased toxicity due to rapid conversion