Codeine

Codeine is an Opiate agonist belonging to Analgesic /Antitussive agent.

Codeine is an opioid analgesic used to treat moderate to severe pain when the use of an opioid is indicated.

Codeine is absorbed from the gastrointestinal tract. The maximum plasma concentration occurs 60 minutes after administration. Apparent volume of distribution: about 3-6 L/kg, showing an extensive distribution of the drug into tissues. Approximately 70 to 80% of the ingested dose of codeine is metabolized in the liver by conjugation with glucuronic acid to codeine-6 glucuronide (C6G) and by O-demethylation to morphine (about 5-10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major metabolic enzymes mediating the Glucouronidation of codeine to the metabolite, codeine 6 glucuronide. About 90% of the total dose of codeine is excreted by the kidneys. Approximately 10% of the drug excreted by the kidneys is unchanged codeine.

Codeine shows side effects like Headache, Tiredness, Loss of appetite, Stomach pain, Constipation, Nausea and Vomiting.

Codeine is available in the form of Oral tablets, Oral suspension, and injectable solution.

Codeine is available in India, US, Canada, China, Japan, France, Italy, Singapore, and Australia.

Codeine belongs to the Analgesic /Antitussive agent acts as an Opiate agonist.

Codeine is a selective agonist for the mu opioid receptor, but with a much weaker affinity to this receptor than morphine, a more potent opioid drug. Codeine binds to mu-opioid receptors, which are involved in the transmission of pain throughout the body and central nervous system. The analgesic properties of codeine are thought to arise from its conversion to Morphine, although the exact mechanism of analgesic action is unknown at this time.

The Onset of Codeine is about 0.5-1 hour (oral) and 10-30mins (injectable).

The duration of action of Codeine is approximately 4-6 hours (oral) and 4-6hours (injectable).

The Tmax of Codeine is approximately 1-1.5 hours (oral route) and 30-60min (injectable route).

Codeine is approved for use in the following clinical indications

• Pain management (analgesic)
• Cough in select patients (off-label)

Adult Dose

• Pain management (analgesic)

IM, subcutaneously: 30 to 60 mg every 4 to 6 hours as needed.

Oral

Immediate release (tablet, oral solution): 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:

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.

• Cough in select patients (off-label)

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 low. Some experts recommend 30 to 60 mg 4 times daily in specific patient populations (eg, lung cancer).

Pediatric Dose

• Pain management (analgesic)

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

Codeine is available in various strengths as 30 mg; 60 mg; 30 mg/mL; 60 mg/mL; 15 mg/mL; 15 mg; 15 mg/5 mL; 30 mg/5 mL.

Codeine is contraindicated in patients with

• Codeine sulfate is contraindicated for postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy.
• Codeine sulfate is contraindicated in patients with known hypersensitivity to codeine or any components of the product. Persons known to be hypersensitive to certain other opioids may exhibit cross-sensitivity to codeine.
• Codeine sulfate is contraindicated in patients with respiratory depression in the absence of resuscitative equipment.
• Codeine sulfate is contraindicated in patients with acute or severe bronchial asthma or hypercarbia.
• Codeine sulfate is contraindicated in any patient who has or is suspected of having paralytic ileus.

• Death Related to Ultra-Rapid Metabolism Of Codeine To Morphine

Respiratory depression and death have occurred in children who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 [CYP2D6] or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine. Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher-than-expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing).Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy. When prescribing codeine, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose.

• Respiratory Depression

Respiratory depression is the primary risk of codeine sulfate. Respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation. Codeine produces dose-related respiratory depression. Caution should be exercised when codeine sulfate is used postoperatively, in patients with pulmonary disease or shortness of breath, or whenever ventilatory function is depressed. Opioid related respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation. Opioids, including codeine sulfate, should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale and in patients having a substantially decreased respiratory reserve (e.g., severe kyphoscoliosis), hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of codeine sulfate may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative non-opioid analgesics should be considered, and codeine sulfate should be employed only under careful medical supervision at the lowest effective dose in such patients.

• Misuse And Abuse of Opioids

Codeine sulfate is an opioid agonist of the morphine-type and a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty. Codeine can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing codeine sulfate in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Misuse and abuse of codeine sulfate poses a significant risk to the abuser that could result in overdose and death. Codeine may be abused by crushing, chewing, snorting or injecting the product. Concerns about abuse and addiction should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

• Interaction With Alcohol And Drugs Of Abuse

Codeine sulfate may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression, because respiratory depression, hypotension, profound sedation, coma or death may result.

• Head Injury And Increased Intracranial Pressure

Respiratory depressant effects of opioids and their capacity to elevate cerebrospinal fluid pressure resulting from vasodilation following CO2 retention may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids including codeine sulfate, produce adverse reactions which may obscure the clinical course of patients with head injuries.

• Hypotensive Effect

Codeine sulfate may cause severe hypotension in an individual whose ability to maintain blood pressure has already been compromised by a depleted blood volume or concurrent administration of drugs such as phenothiazines or general anesthetics. Codeine sulfate may produce orthostatic hypotension and syncope in ambulatory patients.

Codeine sulfate should be administered with caution to patients in circulatory shock, as vasodilation produced by the drug may further reduce cardiac output and blood pressure.

• Gastrointestinal Effects

Codeine sulfate should not be administered to patients with gastrointestinal obstruction, especially paralytic ileus because codeine sulfate diminishes propulsive peristaltic waves in the gastrointestinal tract and may prolong the obstruction. Chronic use of opioids, including codeine sulfate, may result in obstructive bowel disease especially in patients with underlying intestinal motility disorder. Codeine sulfate may cause or aggravate constipation. Administration of codeine sulfate may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

• Use In Pancreatic/Biliary Tract Disease

Codeine sulfate should be used in caution in patients with biliary tract disease, including acute pancreatitis, as codeine sulfate may cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions.

• Special Risk Patients

As with other opioids, codeine sulfate should be used with caution in elderly or debilitated patients and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, or urethral Stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind. Caution should be exercised in the administration of codeine sulfate to patients with CNS depression, acute alcoholism, and delirium tremens. All opioids may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

• Driving And Operating Machinery

Patients should be cautioned that codeine sulfate could impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.

Patients should also be cautioned about the potential combined effects of codeine sulfate with other CNS depressants, including opioids, phenothiazines, sedative/hypnotics, and alcohol

Consumption of alcohol is not recommended during treatment with this medicine due to the increased risk of side effects such as dizziness, lightheadedness, and fainting.

The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and the baby. Caution should be exercised when codeine is administered to a nursing woman.

There are no adequate and well-controlled studies in pregnant women. Codeine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Common

● Bradycardia, cardiac arrest, circulatory depression, flushing, hypertension, hypotension, palpitations, shock, syncope, tachycardia, 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, Diaphoresis, pruritus, skin rash, urticaria, Abdominal cramps, abdominal pain, anorexia, biliary tract spasm, constipation, diarrhea, nausea, pancreatitis, vomiting, xerostomia, Urinary hesitancy, urinary retention, Hypersensitivity reaction, Laryngospasm, muscle rigidity, tremor, weakness, Blurred vision, diplopia, miosis, nystagmus, visual disturbance, Bronchospasm, dyspnea, respiratory arrest, respiratory depression, Hypogonadism.

• CNS Depressants

Concurrent use of other opioids, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants (including sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, or other tranquilizers or alcohol) concomitantly with codeine sulfate tablets may result in additive CNS depression, respiratory depression, hypotension, profound sedation, or coma. Use codeine sulfate with caution and in reduced dosages in patients taking these agents.

• Mixed Agonist/Antagonist Opioid Analgesics

Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should NOT be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic such as codeine sulfate. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

• Anticholinergics

Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics including codeine sulfate, may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

• Antidepressants

Use of MAO inhibitors or tricyclic antidepressants with codeine sulfate may increase the effect of either the antidepressant or codeine. MAOIs markedly potentiate the action of morphine sulfate, the major metabolite of codeine. Codeine should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

• Metabolic Enzymes

Patients taking cytochrome P-450 enzyme inducers or inhibitors may demonstrate an altered response to codeine, therefore analgesic activity should be monitored. Codeine sulfate is metabolized by the cytochrome P-450 3A4 and 2D6 isoenzymes. The concurrent use of drugs that preferentially induce codeine Ndemethylation (cytochrome P-450 3A4) may increase the plasma concentrations of codeine's inactive metabolite norcodeine. Drugs that are strong inhibitors of codeine O-demethylation (cytochrome P-450 2D6) may decrease the plasma concentrations of codeine's active metabolites, morphine and morphine-6-glucuronide. The contribution of these active metabolites to the overall analgesic effect of codeine is not fully understood, but should be considered.

The common side effects of Codeine include the following

Common side effects

• Headache, Tiredness, Loss of appetite, Stomach pain, Constipation, Nausea and Vomiting.

Rare side effects

• Dizziness and Drowsiness, Increased heartbeat, Confusion, Difficulty urination, Rash, inability to get or keep an erection, irregular menstruation, decreased sexual desire, itching, hives, changes in vision, seizures.

• Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Codeine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Codeine has been shown to have embryolethal and fetotoxic effects (reduced fetal body weights and delayed or incomplete ossification) in the hamster, rat and mouse models at approximately 2-4 times the maximum recommended human dose of 360 mg/day based on a body surface area comparison. Maternally toxic doses that were approximately 7 times the maximum recommended human dose of 360 mg/day, were associated with evidence of resorptions and incomplete ossification, including meningoencephalocele and cranioschisis. In contrast, codeine did not demonstrate evidence of embryotoxicity or fetotoxicity in the rabbit model at doses up to 2 times the maximum recommended human dose of 360 mg/day based on a body surface area comparison.

• Nursing Mothers

Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.

• Pediatric Use

The safety and effectiveness and the pharmacokinetics of codeine sulfate in pediatric patients below the age of 18 have not been established. FDA has not required pediatric studies in ages birth to one month because there is evidence strongly suggesting that codeine would be ineffective in this pediatric group since the metabolic pathways to metabolize codeine are not mature.

• Geriatric Use

Codeine may cause confusion and over-sedation in the elderly. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Symptoms: CNS or respiratory depression, pinpoint-sized pupil, nausea, vomiting, dry mouth, sweating, facial flushing, circulatory failure, muscle rigidity, nightmares, coma or excitement, and in children, convulsions.

Management: Symptomatic and supportive treatment including airway clearing and monitoring of vital signs. Activated charcoal may be given within 1 hour of ingestion to reduce absorption. Administer naloxone if clinically significant respiratory or cardiac depression is present.

Pharmacodynamic

Codeine is a weak narcotic pain reliever and cough suppressant that is similar to morphine and hydrocodone. A small amount of ingested codeine is converted to morphine in the body. Codeine increases tolerance to pain, reducing existing discomfort. In addition to decreasing pain, codeine also causes sedation, drowsiness, and respiratory depression

Pharmacokinetics

• Absorption

Codeine is absorbed from the gastrointestinal tract. The maximum plasma concentration occurs 60 minutes after administration.

• Distribution

Apparent volume of distribution: about 3-6 L/kg, showing an extensive distribution of the drug into tissues

• Metabolism and Excretion

Approximately 70 to 80% of the ingested dose of codeine is metabolized in the liver by conjugation with glucuronic acid to codeine-6 glucuronide (C6G) and by O-demethylation to morphine (about 5-10%) and N-demethylation to nor codeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major metabolic enzymes mediating the glucurodination of codeine to the metabolite, codeine 6 glucuronide. About 90% of the total dose of codeine is excreted by the kidneys. Approximately 10% of the drug excreted by the kidneys is unchanged codeine.

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