codeine

Absorption: 50% absorbed from the GI tract.

Distribution: Widely distributed to tissues.

Metabolism/Excretion: Mostly metabolized by the liver via the CYP2D6 isoenzyme; 10% converted to morphine;the CYP2D6 isoenzyme exhibits genetic polymorphism (some patients [1–10% Whites, 3% African Americans, 16–28% North Africans/Ethiopians/Arabs] may be ultra-rapid metabolizers and may have ↑ morphine concentrations and an ↑ risk of adverse effects); 5–15% excreted unchanged in urine.

Half-Life: 2.5–4 hr.

Time/Action Profile ⬆ ⬇

(analgesia)

ROUTE	ONSET	PEAK	DURATION
PO	30–45 min	60–120 min	4 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
Significant respiratory depression;
Acute or severe bronchial asthma (in unmonitored setting or in absence of resuscitative equipment);
Known or suspected GI obstruction (including paralytic ileus);
Concurrent use of MAO inhibitors (or use within the past 14 days);
Ultra-rapid CYP2D6 metabolizers of codeine;
Lactation: Lactation;
Pedi: Children 12 yr, children 18 yr following tonsillectomy and/or adenoidectomy, and children 12–18 yr who are postoperative; have obstructive sleep apnea, obesity, severe pulmonary disease, or neuromuscular disease; or are taking other medications that cause respiratory depression ( risk of respiratory depression and death).

Use Cautiously in:

Personal or family history of substance use disorder or mental illness;
Head trauma;
↑intracranial pressure;
Severe renal impairment;
Severe hepatic impairment;
Severe pulmonary disease;
Hypothyroidism;
Adrenal insufficiency;
Prostatic hyperplasia;
Undiagnosed abdominal pain;
OB: Has been used during labor; respiratory depression may occur in the newborn;
Geri: Older adults may be more susceptible to CNS depression and constipation (dose required).

Adv. Reactions/Side Effects ⬆ ⬇

CV: hypotension, bradycardia

Derm: flushing, sweating

EENT: blurred vision, diplopia, miosis

GI: constipation, nausea, vomiting

GU: urinary retention

Neuro: confusion, sedation, dysphoria, euphoria, floating feeling, hallucinations, headache, unusual dreams

Resp: RESPIRATORY DEPRESSION (INCLUDING CENTRAL SLEEP APNEA AND SLEEP-RELATED HYPOXEMIA)

Misc: allodynia, opioid-induced hyperalgesia, physical dependence, psychological dependence, tolerance

Interactions ⬆ ⬇

Drug-drug:

MAO inhibitors↑ risk of adverse reactions; concurrent use or use within previous 14 days contraindicated.
Additive CNS depression with alcohol, antidepressants, antihistamines, benzodiazepines, and sedative/hypnotics.
CYP3A4 inhibitors, including erythromycin, clarithromycin, ketoconazole, itraconazole, and protease inhibitors, may ↑ levels and risk of respiratory depression.
CYP3A4 inducers may ↓ levels and effectiveness.
CYP2D6 inhibitors, including amiodarone and quinidine, may ↓ analgesic effects.
Mixed agonist/antagonist analgesics, including nalbuphine or butorphanol, and partial agonist analgesics, including buprenorphine, may ↓ meperidine's analgesic effects and/or precipitate opioid withdrawal in physically dependent patients.
Drugs that affect serotonergic neurotransmitter systems, including tricyclic antidepressants, SSRIs, SNRIs, MAO inhibitors, TCAs, tramadol, trazodone, mirtazapine, 5HT3 receptor antagonists, linezolid, methylene blue, and triptans, ↑ risk of serotonin syndrome.

Drug-Natural Products:

Concomitant use of kava-kava, valerian, skullcap, chamomile, or hops can ↑ CNS depression.

Route/Dosage ⬆ ⬇

PO (Adults ): Analgesic: 15–60 mg every 4 hr as needed (not to exceed 360 mg/day). Antitussive: 10–20 mg every 4–6 hr as needed (not to exceed 120 mg/day).

Renal Impairment

(Adults ): CCr 10–50 mL/min: Administer 75% of the dose; CCr <10 mL/min: Administer 50% of the dose.

Availability ⬆ ⬇

(Generic available)

Tablets: 15 mg; 30 mg; 60 mg

Assessment ⬆ ⬇

Assess BP, pulse, and respirations before and periodically during administration. If respiratory rate <10/min, assess level of sedation. Physical stimulation may be sufficient to prevent significant hypoventilation. Dose may need to be decreased by 25–50%. Initial drowsiness will diminish with continued use. Monitor for respiratory depression, especially during initiation or following dose ↑; serious, life-threatening, or fatal respiratory depression may occur. May cause sleep-related breathing disorders (central sleep apnea, sleep-related hypoxemia).
- Assess bowel function routinely. Prevention of constipation should be instituted with increased intake of fluids, bulk, and laxatives to minimize constipating effects. Stimulant laxatives should be administered routinely if opioid use exceeds 2–3 days, unless contraindicated. Consider drugs for opioid induced constipation.
Assess risk for opioid addiction, abuse, or misuse prior to administration.
Pain: Assess type, location, and intensity of pain before and 1 hr (peak) after administration. When titrating opioid doses, ↑ of 25–50% should be administered until there is either a 50% ↓ in the patient’s pain rating on a numerical or visual analogue scale or the patient reports satisfactory pain relief. A repeat dose can be safely administered at the time of the peak if previous dose is ineffective and side effects are minimal.
- An equianalgesic chart (see Equianalgesic Dosing Guidelines) should be used when changing routes or when changing from one opioid to another.
- Monitor patients for opioid-induced hyperalgesia occurs when an opioid paradoxically causes an ↑ in pain, or an ↑ in sensitivity to pain. Opioid-induced hyperalgesia differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect. Symptoms of opioid-induced hyperalgesia include ↑ levels of pain upon opioid dosage ↑, ↓ levels of pain upon opioid dosage ↓, or pain from ordinarily nonpainful stimuli. If opioid-induced hyperalgesia suspected, consider ↓ codeine dose.
- Prolonged use may lead to physical and psychological dependence and tolerance, which should not prevent patient from receiving adequate analgesia. Most patients who receive codeine for pain do not develop psychological dependence. If progressively higher doses are required, consider conversion to a stronger opioid.
Cough: Assess cough and lung sounds during antitussive use.

Lab Test Considerations:

May cause ↑ plasma amylase and lipase concentrations.

Toxicity and Overdose:

If an opioid antagonist is required to reverse respiratory depression or coma, naloxone is the antidote. Dilute the 0.4-mg ampule of naloxone in 10 mL of 0.9% NaCl and administer 0.5 mL (0.02 mg) by IV push every 2 min. For children and patients weighing <40 kg, dilute 0.1 mg of naloxone in 10 mL of 0.9% NaCl for a concentration of 10 mcg/mL and administer 0.5 mcg/kg every 2 min. Titrate dose to avoid withdrawal, seizures, and severe pain.

Implementation ⬆ ⬇

Accidental overdosage of opioid analgesics has resulted in fatalities. Before administering, clarify all ambiguous orders.
Explain therapeutic value of medication before administration to enhance the analgesic effect.
- Regularly administered doses may be more effective than prn administration. Analgesic is more effective if given before pain becomes severe.
- Coadministration with nonopioid analgesics may have additive analgesic effects and permit lower doses.
- FDA strongly encourages health care professionals to complete a REMS-compliant education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain, available at www.fda.gov/OpioidAnalgesicREMSBlueprint. Information on programs can be found at 1-800-503-0784 or www.opioidanalgesicrems.com
  .
- Discuss availability of naloxone for emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing therapy, especially if patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any patient.
- When combined with nonopioid analgesics (aspirin, acetaminophen) #2 = 15 mg, #3 = 30 mg, #4 = 60 mg codeine. Codeine as an individual drug is a Schedule II substance. In combination with other drugs, tablet form is Schedule III, and elixir or cough suppressant is Schedule V (see Controlled Substances Schedules).
PO: Oral doses may be administered with food or milk to minimize GI irritation.
If administered regularly for ≥1 wk, discontinue by tapering dose gradually by a small enough increment (not >10%–25% of total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2–4 wk or longer. Monitor for withdrawal symptoms (restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, ↑ blood pressure, respiratory rate, or heart rate) during taper. If withdrawal symptoms occur, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. Monitor for changes in mood, emergence of suicidal thoughts, or use of other substances.

Patient/Family Teaching ⬆ ⬇

Instruct patient on how and when to ask for and take pain medication. Do not stop abruptly without consulting health care professional.
Instruct patient on risk of addiction, abuse, and misuse, which could lead to death. Discuss safe use, risks, and proper storage and disposal of opioid analgesics with patients and caregivers with each Rx. The Patient Counseling Guide is available at www.fda.gov/OpioidAnalgesicREMSPCG. Advise patient not to share codeine with others and to protect from theft or misuse.
Advise patient that codeine is a drug with known abuse potential. Protect it from theft, and never give to anyone other than the individual for whom it was prescribed. Store out of sight and reach of children, and in a location not accessible by others.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Inform patients and caregivers about various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (by prescription, directly from a pharmacist, or as part of a community-based program).
May cause drowsiness or dizziness. Advise patient to call for assistance when ambulating or smoking. Caution ambulatory patient to avoid driving or other activities requiring alertness until response to medication is known.
Advise patient to change positions slowly to minimize orthostatic hypotension.
Caution patient to avoid concurrent use of alcohol or other CNS depressants with this medication.
Encourage patient to turn, cough, and breathe deeply every 2 hr to prevent atelectasis.
Advise patient that good oral hygiene, frequent mouth rinses, and sugarless gum or candy may decrease dry mouth.
Rep: Advise patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Inform patient of potential for neonatal opioid withdrawal syndrome with prolonged use during pregnancy. Monitor neonate for signs and symptoms of withdrawal symptoms (irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight); usually occur the first days after birth. Monitor infants exposed to codeine through breast milk for excess sedation and respiratory depression.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇