Codeine + Diclofenac

Usage

Codeine + Diclofenac is prescribed for the short-term management of moderate to severe acute pain, particularly when a single analgesic is insufficient. It combines the analgesic effects of codeine, an opioid, with the anti-inflammatory and analgesic properties of diclofenac, a nonsteroidal anti-inflammatory drug (NSAID). Pharmacologically, this drug is classified as a combination analgesic. The codeine component works centrally, binding to opioid receptors in the brain and spinal cord to reduce pain perception. Diclofenac inhibits cyclooxygenase (COX) enzymes, decreasing prostaglandin synthesis, thereby reducing inflammation and pain at the peripheral site of injury.

Alternate Names

No internationally recognized alternate generic name exists. However, some regional variations may occur. Brand names vary depending on the manufacturer and country. Some examples include: Codeine Phosphate/Diclofenac Sodium, and some country-specific brand names were mentioned in source [10].

How It Works

Pharmacodynamics: Codeine acts centrally, binding to mu-opioid receptors in the central nervous system. It has weak opioid activity on its own, relying partially on conversion to morphine via CYP2D6 enzyme for enhanced analgesia. Inter-individual variability in CYP2D6 activity can influence efficacy and risk of side effects. Diclofenac is a nonselective COX inhibitor, reducing the synthesis of prostaglandins, which play a key role in inflammation and pain sensitization.

Pharmacokinetics: Codeine is well-absorbed orally. Hepatic metabolism produces several metabolites, including morphine (the primary active metabolite), norcodeine, and codeine-6-glucuronide. Excretion is primarily renal. Diclofenac is also well-absorbed orally, with extensive protein binding. Hepatic metabolism occurs primarily via CYP2C9. Excretion is through both renal and biliary routes.

Mode of Action/Receptor Binding, Enzyme Inhibition: As stated previously, codeine acts through mu-opioid receptor agonism and diclofenac through COX enzyme inhibition.

Elimination Pathways: Codeine is eliminated mostly as metabolites via renal excretion. Diclofenac is primarily eliminated through hepatic metabolism and both renal and biliary excretion.

Dosage

Standard Dosage

Adults:

Diclofenac: 50 mg three times daily or 75 mg twice daily, combined with Codeine: 15-60 mg every 4-6 hours as needed, not exceeding 360mg/day ([20]) . It is crucial to utilize the lowest effective dose for the shortest possible duration.

Children:

Codeine is contraindicated in children under 12. ([1,3]) It should only be given after 12 years of age for short-term management of moderate pain and is not advised for children below 18 years of age. 0.5 - 1 mg/kg every 4-6 hours for children 12 years or older, max dose 60 mg. Diclofenac dosing in children must be determined by a doctor, adjusted for age and weight. ([20,29]) Extreme caution and close monitoring are crucial when using codeine in children due to potential respiratory depression. ([1])

Special Cases:

• Elderly Patients: Dose reductions are advisable for both codeine and diclofenac due to age-related declines in renal and hepatic function. Start with a lower dose and titrate based on response and tolerability.
• Patients with Renal Impairment: Dose reductions are often necessary, especially for diclofenac. Monitor renal function closely.
• Patients with Hepatic Dysfunction: Caution is advised, particularly with codeine due to its metabolic pathway. Dose adjustments may be necessary.
• Patients with Comorbid Conditions: Consider the patient’s overall health status, including cardiovascular disease and diabetes. Use cautiously in patients with respiratory conditions.

Clinical Use Cases

Codeine + Diclofenac is not typically recommended for use in the following clinical settings:

• Intubation
• Surgical Procedures
• Mechanical Ventilation
• Intensive Care Unit (ICU) Use
• Emergency Situations

Other analgesics tailored to these settings are preferred.

Dosage Adjustments

Dosage adjustments are required in elderly patients, those with renal or hepatic impairment, and based on individual response and tolerability. Genetic variations influencing CYP2D6 activity significantly impact codeine metabolism.

Side Effects

Common Side Effects:

• Drowsiness, dizziness, nausea, vomiting, constipation, dry mouth, lightheadedness, headache, stomach upset, indigestion, and decreased appetite.

Rare but Serious Side Effects:

• Allergic reactions (rash, itching, swelling), difficulty breathing, severe dizziness, respiratory depression, seizures, hepatotoxicity, gastrointestinal bleeding or ulcers.

Long-Term Effects:

• Potential for opioid dependence with prolonged codeine use. Chronic NSAID use can contribute to cardiovascular issues and renal dysfunction.

Adverse Drug Reactions (ADR):

• Respiratory depression (codeine), anaphylaxis, Stevens-Johnson syndrome (diclofenac), gastrointestinal perforation.

Contraindications

• Hypersensitivity to codeine or diclofenac; severe asthma; respiratory depression; paralytic ileus; acute or severe bronchial asthma; suspected surgical acute abdomen; head injuries or increased intracranial pressure; severe liver, kidney or heart failure; history of heart attack or stroke; breastfeeding ([1,5,10]). Use with caution in pregnancy (diclofenac use in 3rd trimester is contraindicated), ([1,6,7]) elderly patients, and those with impaired respiratory function.

Drug Interactions

• Alcohol, other opioids, CNS depressants (additive sedative effects), anticoagulants (increased bleeding risk), antihypertensives (reduced effectiveness), other NSAIDs (additive gastrointestinal risks), antidepressants, methotrexate, lithium, quinolones ([1,2]). CYP2D6 inhibitors may reduce codeine efficacy, and inducers may increase the risk of side effects. ([21])

Pregnancy and Breastfeeding

Codeine + Diclofenac is generally contraindicated in both pregnancy (especially 3rd trimester) and breastfeeding. ([1, 6, 15]) Codeine can be transferred to the fetus and through breastmilk, potentially causing neonatal respiratory depression and other adverse effects. Diclofenac should also be avoided, particularly in the third trimester.

Drug Profile Summary

• Mechanism of Action: Codeine: Mu-opioid receptor agonist. Diclofenac: Nonselective COX inhibitor.
• Side Effects: Drowsiness, dizziness, nausea, vomiting, constipation, respiratory depression, gastrointestinal upset, allergic reactions.
• Contraindications: Hypersensitivity, respiratory depression, severe asthma, paralytic ileus, severe hepatic/renal/cardiac disease, breastfeeding.
• Drug Interactions: Alcohol, other opioids, CNS depressants, anticoagulants, antihypertensives, other NSAIDs, antidepressants.
• Pregnancy & Breastfeeding: Contraindicated, especially in the third trimester and during breastfeeding.
• Dosage: Adult: Diclofenac (50 mg TID or 75mg BID) + Codeine (15-60 mg every 4-6 hours, not exceeding 360 mg/day). Pediatric: codeine contraindicated <12 years, 0.5 - 1 mg/kg every 4-6 hours for children 12 years or older, max dose 60 mg, diclofenac dosage must be determined by doctor based on age and weight. Geriatric dose: Reduced due to decreased hepatic/renal function.
• Monitoring Parameters: Respiratory rate, oxygen saturation, pain scores, liver and renal function tests, blood pressure, signs of gastrointestinal bleeding.

Popular Combinations

Codeine may be used with paracetamol (acetaminophen). Diclofenac may be used with paracetamol.

Precautions

• Pre-existing respiratory disease, renal or hepatic impairment, gastrointestinal conditions, pregnancy, and breastfeeding.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Codeine + Diclofenac?

A: Adult: Diclofenac (50 mg TID or 75mg BID) + Codeine (15-60 mg every 4-6 hours, not exceeding 360 mg/day). Pediatric: codeine contraindicated <12 years, 0.5 - 1 mg/kg every 4-6 hours for children 12 years or older, max dose 60 mg, diclofenac dosage must be determined by doctor based on age and weight. Geriatric dose: Reduced due to decreased hepatic/renal function.

Q2: Can Codeine + Diclofenac be used during pregnancy or breastfeeding?

A: No, it’s contraindicated. Codeine and diclofenac can have adverse effects on the fetus/neonate.

Q3: What are the most concerning side effects of this combination?

A: Respiratory depression (codeine), gastrointestinal bleeding (diclofenac), allergic reactions, and the potential for codeine dependence.

Q4: Are there any drug interactions I should be aware of?

A: Yes, numerous. Avoid alcohol, other opioids, CNS depressants, anticoagulants, and other NSAIDs. Be mindful of potential interactions with antihypertensives and antidepressants.

Q5: How does CYP2D6 influence the use of this medication?

A: CYP2D6 metabolizes codeine into morphine. Variations in CYP2D6 activity affect efficacy and side effects. Ultra-rapid metabolizers are at higher risk for opioid toxicity.

Q6: Can this combination be used long-term for chronic pain?

A: It is intended for short-term management of acute pain only. Long-term codeine use carries the risk of dependence, and chronic NSAID use can lead to cardiovascular and renal problems.

Q7: Can this medication be used in patients with renal or hepatic impairment?

A: Use with caution and dose adjustments are usually necessary. Close monitoring is required.

Q8: Is there a risk of addiction with this medication?

A: Yes, prolonged codeine use carries the risk of dependence.

Q9: What are the key patient counseling points?

A: Avoid alcohol. Take with food to reduce GI upset. Do not drive or operate machinery if experiencing drowsiness. Report any signs of allergic reaction or breathing difficulties immediately. Do not exceed the prescribed dose or duration of treatment.