Usage
This combination medication is prescribed for the management of moderate to severe pain, particularly acute musculoskeletal pain, postoperative pain, dental pain, and pain associated with osteoarthritis and rheumatoid arthritis flare-ups.
Pharmacological Classification:
- Analgesic (pain reliever)
- Nonsteroidal anti-inflammatory drug (NSAID) - Diclofenac
- Opioid analgesic - Tramadol
- Antipyretic (fever reducer) - Paracetamol
Mechanism of Action:
This combination targets different pain pathways for enhanced analgesia. Diclofenac inhibits cyclooxygenase (COX) enzymes, reducing prostaglandin production, thereby decreasing inflammation and pain. Paracetamol has central analgesic and antipyretic effects. Tramadol is a centrally acting opioid analgesic that binds to mu-opioid receptors in the brain and spinal cord, altering pain perception.
Alternate Names
There is no single international nonproprietary name (INN) for this specific combination. However, the individual components have their own established INNs. The combination is sometimes referred to as a “fixed-dose combination (FDC)” of Diclofenac, Paracetamol, and Tramadol.
Brand Names:
Brand names can vary significantly by region. Examples include:
- Some examples mentioned in studies: DURAPAIN®, RESYNC®, DIBOL®, and DIBOLS® (India)
How It Works
Pharmacodynamics:
Diclofenac exerts its analgesic and anti-inflammatory effects through COX enzyme inhibition, preventing the production of prostaglandins, which mediate pain and inflammation. Paracetamol’s exact mechanism is unclear, but it seems to involve inhibition of COX enzymes in the central nervous system, resulting in pain and fever reduction. Tramadol activates mu-opioid receptors, modulating the transmission of pain signals in the central nervous system.
Pharmacokinetics:
All three drugs are absorbed well orally. Diclofenac is highly protein-bound, metabolized in the liver, and excreted primarily through the kidneys. Paracetamol undergoes hepatic metabolism, with a small portion excreted unchanged in the urine. Tramadol also undergoes hepatic metabolism, with its active metabolite, O-desmethyltramadol, significantly contributing to the analgesic effect. Both Tramadol and its metabolite are excreted primarily by the kidneys.
Mode of Action:
- Diclofenac: Inhibits COX-1 and COX-2 enzymes.
- Paracetamol: Likely inhibits central COX enzymes, though the precise mechanism remains to be fully elucidated.
- Tramadol: Binds to mu-opioid receptors, inhibiting pain signal transmission and modulating noradrenaline and serotonin reuptake.
Elimination Pathways:
Primarily renal excretion for all three drugs, with varying degrees of hepatic metabolism. Tramadol metabolism involves CYP2D6 enzyme.
Dosage
Standard Dosage
Adults:
Studies mentioned dosages of Diclofenac 75 mg + Tramadol 50 mg, one tablet twice daily. Another study explored Diclofenac 50 mg + Paracetamol 500 mg. Tramadol/Paracetamol combinations typically involve 37.5 mg of Tramadol and 325 mg of Paracetamol, two tablets every 4–6 hours, up to a maximum of eight tablets daily. However, combining all three requires careful titration based on individual needs and pain severity. Dosages should aim to utilize the lowest effective doses of each component to minimize adverse effects.
Children:
The combined use of diclofenac, paracetamol, and tramadol is generally not recommended for children under 12. Safety and efficacy have not been established in this population. Individual components can be used in pediatrics with appropriate dosing adjustments based on age and weight. For instance, paracetamol is commonly dosed at 10-15 mg/kg/dose every 4-6 hours, with various formulations available.
Special Cases:
- Elderly Patients: Dose reduction and increased dosing intervals may be necessary due to age-related decline in renal and hepatic function. Start with lower doses and titrate cautiously.
- Patients with Renal Impairment: Dose adjustments are needed based on creatinine clearance.
- Patients with Hepatic Dysfunction: Reduced doses and careful monitoring are essential due to impaired drug metabolism.
- Patients with Comorbid Conditions: Individualized assessment and dosing adjustments should be considered for patients with diabetes, cardiovascular diseases, or other significant conditions.
Clinical Use Cases
There is limited information on the FDC’s specific use in clinical settings like intubation, surgery, mechanical ventilation, or ICU. Individual components may be employed, but the triple combination is typically reserved for post-operative pain management when moderate to severe pain necessitates multimodal analgesia. The use of tramadol for emergency situations is not indicated. Diclofenac can be administered intravenously for acute pain management in certain settings.
Dosage Adjustments
Dose adjustments must consider renal/hepatic function, metabolic disorders, age, and potential drug interactions. Genetic polymorphisms impacting CYP2D6 activity can affect tramadol metabolism.
Side Effects
Common Side Effects:
Nausea, vomiting, dizziness, drowsiness, constipation, dry mouth, indigestion, stomach pain, loss of appetite, headache, itching, and rash.
Rare but Serious Side Effects:
Allergic reactions (anaphylaxis), seizures, respiratory depression, serotonin syndrome (with concomitant serotonergic drugs), Stevens-Johnson syndrome, gastrointestinal bleeding, and liver damage.
Long-Term Effects:
Potential for opioid tolerance and dependence with prolonged tramadol use. NSAIDs like diclofenac can contribute to renal impairment with chronic use.
Adverse Drug Reactions (ADR):
Serious ADRs include severe hypotension, cardiac arrhythmias, angioedema, and anaphylaxis. Immediate medical intervention is required.
Contraindications
- Hypersensitivity to any of the components.
- Active peptic ulcer or gastrointestinal bleeding.
- Severe hepatic impairment.
- Severe renal impairment.
- Epilepsy not controlled by treatment.
- Concurrent use of monoamine oxidase inhibitors (MAOIs).
- Pregnancy (especially the third trimester due to diclofenac).
- Respiratory depression.
- Acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids, or psychotropic drugs.
Drug Interactions
- Other NSAIDs, anticoagulants (warfarin, heparin), antidepressants (SSRIs, SNRIs), antihypertensives, alcohol, opioid analgesics (morphine, codeine), benzodiazepines, and CYP2D6 inhibitors or inducers.
- Avoid grapefruit juice.
Pregnancy and Breastfeeding
- Pregnancy: This combination is generally contraindicated in pregnancy, particularly the third trimester due to diclofenac’s potential for premature ductus arteriosus closure. Tramadol’s safety in pregnancy is not well-established. Paracetamol is generally considered safe at recommended doses.
- Breastfeeding: Tramadol and its metabolites are present in breast milk. Diclofenac is present in small amounts. Although paracetamol is considered safe during breastfeeding, caution is advised with this combination. Monitor the infant for drowsiness, feeding difficulties, and other adverse effects.
Drug Profile Summary
- Mechanism of Action: Multimodal analgesia through COX inhibition (diclofenac), central analgesia (paracetamol), and mu-opioid receptor activation (tramadol).
- Side Effects: Nausea, vomiting, dizziness, drowsiness, constipation, GI upset, respiratory depression (severe).
- Contraindications: Hypersensitivity, peptic ulcers, severe hepatic/renal impairment, epilepsy, MAOI use, pregnancy.
- Drug Interactions: NSAIDs, anticoagulants, antidepressants, antihypertensives, alcohol, opioids, benzodiazepines.
- Pregnancy & Breastfeeding: Contraindicated, particularly in the third trimester. Use with caution during breastfeeding.
- Dosage: Adult dosages vary based on the specific combination and formulation. Not recommended for children under 12.
- Monitoring Parameters: Respiratory rate, blood pressure, liver function tests, renal function tests, pain scores.
Popular Combinations
This specific triple combination isn’t routinely used in clinical practice. More common are combinations of two of the drugs. For example, tramadol/paracetamol combinations are commonly used.
Precautions
- Assess for allergies, renal/hepatic function, drug interactions, and contraindications.
- Caution in elderly patients.
- Avoid alcohol.
- Monitor for respiratory depression and other adverse effects.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Diclofenac + Paracetamol + Tramadol?
A: There’s no fixed FDC for this triple combination with an established recommended dosage. If combining the three, it would necessitate careful titration based on individual patient response and pain severity. Consult a pain specialist.
Q2: Can this combination be used in children?
A: Generally not recommended for children under 12 due to limited safety and efficacy data.
Q3: What are the key drug interactions to watch for?
A: Interactions with other NSAIDs, anticoagulants, antidepressants, antihypertensives, alcohol, opioids, and benzodiazepines are clinically significant.
Q4: Is this combination safe during pregnancy and breastfeeding?
A: Generally contraindicated, especially in the third trimester. Tramadol and diclofenac are present in breast milk. Consult a specialist if analgesic medication is needed during pregnancy or breastfeeding.
Q5: What are the common side effects?
A: Nausea, vomiting, dizziness, drowsiness, constipation, and gastrointestinal upset are frequently reported.
Q6: What are the serious side effects?
A: Respiratory depression, seizures, serotonin syndrome (with concomitant serotonergic medications), allergic reactions, and cardiovascular events are serious potential adverse effects.
Q7: What precautions should be taken when prescribing this medication?
A: Assess for allergies, renal and hepatic function, drug interactions, and contraindications. Monitor closely for adverse reactions, especially respiratory depression. Caution is advised in elderly patients. Advise patients to avoid alcohol.
Q8: Are there any long-term risks associated with this combination?
A: Chronic tramadol use carries a risk of opioid tolerance and dependence. Long-term use of diclofenac can increase the risk of renal impairment.
Q9: What should be done in case of overdose?
A: Immediately contact a poison control center or seek emergency medical assistance. Supportive care and symptomatic treatment may be required. Naloxone can be administered to reverse opioid-induced respiratory depression.
