Codeine

Intramuscular
Mild to moderate pain

Oral
Acute diarrhoea

Oral
Mild to moderate pain

Oral
Cough suppressant

CYP2D6 is the major enzyme responsible for the conversion of codeine to morphine (higher potency). Genetic testing for CYP2D6 is recommended prior to initiation of codeine therapy, especially in young children and lactating mothers. CYP2D6 testing may also be considered in patients who does not respond to codeine therapy (possible poor metabolisers) or who have unexpected adverse effects (possible ultra-rapid metabolisers).

Ultra-rapid metabolisers (carriers of >2 copies of functional alleles e.g. *1/*1xN, *1/*2xN)
Avoid use of codeine due to increased morphine formation which may lead to higher risk of toxicity (e.g. respiratory depression). Analgesics which are not affected by CYP2D6 polymorphism (e.g. morphine, non-opioid analgesics) may be given as alternative. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5-1% in Chinese, Japanese, and Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians, and Arabs.

Extensive metabolisers (carriers of 2 alleles encoding full or reduced function; or 1 full-function allele together with either 1 nonfunctional or 1 reduced-function allele e.g. *1/*1, *1/*2, *2/*2, *1/*41, *1/*4, *2/*5, *1/*10)
No dose adjustment needed.

Intermediate metabolisers (carriers of 1 reduced-function and 1 nonfunctional allele e.g. *4/*10, *5/*41)
No dose adjustment needed. If there is no response, may consider use of alternative analgesics (e.g. morphine, non-opioid analgesics).

Poor metabolisers (individuals not carrying any functional alleles e.g. *4/*4, *4/*5, *5/*5, *4/*6)
Avoid use of codeine due to reduced morphine formation, resulting in lack of efficacy. Analgesics which are not affected by CYP2D6 polymorphism (e.g. morphine, non-opioid analgesics) may be given as alternative.

Oral
Mild to moderate pain: Dose adjustment may be needed.

Intramuscular
Mild to moderate pain:

CrCl (mL/min)	Dosage
<10	50% of normal dose.
10-<20	75% of normal dose.

Oral
Mild to moderate pain: Severe: Dose reduction or careful titration may be needed.

Intramuscular
Mild to moderate pain: Contraindicated.

May be taken with or without food.

Acute respiratory depression, comatose states, liver failure, acute or severe bronchial asthma, GI obstruction, paralytic ileus, abdominal distension, acute alcoholism, head injuries, increased intracranial pressure, diarrhoea caused by pseudomembranous colitis or poisoning. CYPD26 ultrarapid metabolisers. Hepatic impairment (IM inj). Children <12 years old; <18 years of age who undergo tonsillectomy and/or adenoidectomy; 12-18 years old who have other risk factors for respiratory depression; <18 years old (when used in the management of cough). Lactation. Concomitant or within 14 days of MAOI use.

Patient with hypotension, hypothyroidism, prostatic hypertrophy, urethral stricture, adrenocortical insufficiency, acute abdominal conditions, biliary tract dysfunction (e.g. acute pancreatitis), inflammatory or obstructive bowel disorders, shock, convulsive disorders, myasthenia gravis, mental health conditions, toxic psychosis, history of drug abuse or acute alcoholism. Morbidly obese patients. CYP2D6 extensive, intermediate, and poor metabolisers. Renal and hepatic impairment. Children and elderly. Pregnancy.

Significant: CNS depression, hypotension, constipation.
Blood and lymphatic system disorders: Lymphadenopathy, splenomegaly.
Cardiac disorders: Tachycardia, bradycardia, palpitations.
Endocrine disorders: Hyperglycaemia.
Eye disorders: Miosis, blurred or double vision.
Gastrointestinal disorders: Nausea, vomiting, dry mouth, pancreatitis, stomach cramps.
General disorders and administration site conditions: Fever, malaise, tiredness.
Hepatobiliary disorders: Biliary spasm.
Immune system disorders: Maculopapular rash.
Metabolism and nutrition disorders: Anorexia.
Musculoskeletal and connective tissue disorders: Muscular rigidity, uncontrolled muscle movements.
Nervous system disorders: Dizziness, headache, vertigo, raised intracranial pressure, convulsions.
Psychiatric disorders: Confusion, restlessness, mood disorder, mental depression, hallucinations, nightmares.
Renal and urinary disorders: Urinary retention, difficulty in micturition, dysuria.
Reproductive system and breast disorders: Sexual dysfunction, decreased libido.
Respiratory, thoracic and mediastinal disorders: Dyspnoea.
Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria, sweating.
Vascular disorders: Hypotension.
Potentially Fatal: Respiratory depression.

Parenteral/PO: C

This drug may cause drowsiness or visual disturbances (e.g. blurred or double vision), if affected, do not drive or operate machinery.

Monitor pain relief, blood pressure, heart rate, respiratory and mental status; development of addiction, abuse or misuse.

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.

Increased risk of CNS or respiratory depression with benzodiazepines (e.g. anxiolytics, sedatives), anaesthetics, antihistamines, and sodium oxybate. Increased risk of severe constipation with anticholinergics and antidiarrhoeals. Quinidine may impair codeine metabolism. Cimetidine may increase plasma concentration of codeine. Delays the absorption of mexiletine. Antagonises the effect of domperidone, metoclopramide, cisapride.
Potentially Fatal: Severe CNS excitation or depression with MAOIs.

Enhances the hypotensive, sedative, and respiratory depressive effects of alcohol.

May interfere with gastric emptying studies and with hepatobiliary imaging using technetium Tc 99m disofenin.

Description:
Mechanism of Action: Codeine is a phenantrene derivative opiate agonist which alters the perception of and response to pain by binding to opiate receptors in the CNS, blocking the ascending pain pathways. It also helps suppress cough by direct action in the medulla and appears to exert a drying effect on the respiratory tract mucosa, thus increasing the viscosity of bronchial secretions.
Onset: Analgesia: 0.5-1 hour (oral, immediate-release); 10-30 minutes (inj).
Duration: 4-6 hours.
Pharmacokinetics:
Absorption: Well absorbed from the gastrointestinal tract. Bioavailability: 53%. Time to peak plasma concentration: 1-1.5 hours.
Distribution: Crosses placenta and enters breast milk. Volume of distribution: Approx 3-6 L/kg. Plasma protein binding: Approx 7-25%.
Metabolism: Metabolised in the liver via O-demethylation by CYPD26 to morphine (active), N-demethylation by CYP3A4, and partial conjugation with glucuronic acid.
Excretion: Via urine (approx 90%, 10% as unchanged drug); faeces. Plasma half-life: 3-4 hours (oral/IM).

Store between 15-30°C. Protect from light.

Analgesics (Opioid) / Cough & Cold Preparations

R05DA04 - codeine ; Belongs to the class of opium alkaloids and derivatives. Used as cough suppressant.

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