Adult: Available preparations:
Tramadol 75 mg and dexketoprofen 25 mg tab
Tramadol 75 mg and dexketoprofen 25 mg granules for oral solution in sachet
For short-term treatment: 1 tab or sachet 8 hourly as needed. Max: 3 tabs or sachets daily (tramadol 225 mg and dexketoprofen 75 mg). Max duration: 5 days. Elderly: Available preparations:
Tramadol 75 mg and dexketoprofen 25 mg tab
Tramadol 75 mg and dexketoprofen 25 mg granules for oral solution in sachet
For short-term treatment: 1 tab or sachet 8 hourly as needed. Max: 2 tabs or sachets daily (tramadol 150 mg and dexketoprofen 50 mg), may be increased to 3 tabs or sachets daily if tolerated.
Special Patient Group
Pharmacogenomics:
Tramadol
Tramadol is metabolised in the liver by CY2D6 isoenzyme to form the active metabolite, O-desmethyltramadol (M1), which has a significantly higher affinity for opioid receptors. CYP2D6 is a highly polymorphic gene which may be associated with the clinical effect and safety of tramadol. Genetic testing may be considered prior to therapy.
According to studies, CYP2D6 ultrarapid metabolisers have 1.1-5.9-fold higher M1 concentrations than normal metabolisers. On the other hand, an approximate 2-4-fold higher nonresponse rate to tramadol was reported among CYP2D6 poor metabolisers than normal metabolisers or intermediate metabolisers. Variations in CYP2D6 polymorphism occur at different frequencies among subpopulations of different ethnic or racial origins. Some individuals may be ultrarapid metabolisers of CYP2D6. The prevalence of CYP2D6 ultrarapid metabolisers varies widely and has been estimated to be 29% in African/Ethiopian, 3.4-6.5% in African American, 1.2-2% in Asian, 3.6-6.5% in Caucasian, 6% in Greek, 1.9% in Hungarian, and 1-2% in Northern European population; while up to 7% of the Caucasian population has a deficiency or is completely lacking functional CYP2D6 activity.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of December 2020:
Phenotype
Implications
Recommendations
CYP2D6 ultrarapid metabolisers
Increased formation of O-desmethyltramadol, resulting in increased risk of toxicity.
Avoid tramadol use due to the potential for toxicity. If opioid use is needed, may consider a non-codeine opioid.
CYP2D6 intermediate metabolisers
Decreased O-desmethyltramadol formation.
No dose adjustments needed; however, if there is no response and opioid use is warranted, may consider using a non-codeine opioid.
CYP2D6 poor metabolisers
Greatly reduced O-desmethyltramadol formation resulting in diminished therapeutic effect.
Avoid tramadol use due to the possibility of diminished analgesic effect. If opioid use is needed, may consider a non-codeine opioid.
Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of November 2018:
Phenotype
Implications
Recommendations
CYP2D6 ultrarapid metabolisers
Increased conversion of tramadol into the active metabolite which may result in increased risk of potentially life-threatening adverse effects.
Choose an alternative agent that is not metabolised by CYP2D6 (e.g. morphine). If an alternative is not possible, may use 40% of the usual dose and advise patient to monitor for adverse effects (e.g. drowsiness, confusion, respiratory depression).
CYP2D6 intermediate metabolisers
Reduced conversion of tramadol into the active metabolite which may result in reduced analgesic effect.
Be vigilant of the reduced effect. In case of inadequate response, a dose increase may be considered and if there is still no response, an alternative agent that is not metabolised by CYP2D6 (e.g. morphine) may be given. If no alternative agent is selected, advise patient to report inadequate analgesic effect.
CYP2D6 poor metabolisers
Reduced conversion of tramadol into the active metabolite which may result in reduced analgesic effect.
Be vigilant of the reduced effect. In case of inadequate response, a dose increase may be considered and if there is no response, an alternative agent that is not metabolised by CYP2D6 (e.g. morphine) may be given. If no alternative agent is selected, advise patient to report inadequate analgesic effect.
Additionally, the Annotation of FDA label for tramadol recommends that CYP2D6 ultrarapid metabolisers must not use tramadol due to the risk of life-threatening or fatal respiratory depression even at labelled dosage regimens.
Treatment recommendations may vary among local treatment guidelines. Refer to country-specific guidelines.
Renal Impairment
CrCl (mL/min)
Dosage
≤59
Contraindicated.
60-89
Reduce initial total daily dose to 2 tabs or sachets (tramadol 150 mg and dexketoprofen 50 mg).
Hepatic Impairment
Mild to moderate: Initiate therapy at reduced number of doses. Total daily dose: 2 tabs or sachets (tramadol 150 mg and dexketoprofen 50 mg). Severe: Contraindicated.
Contraindications
Hypersensitivity to tramadol, dexketoprofen, or other NSAIDs. History of asthma attacks, bronchospasm, acute rhinitis, nasal polyps, urticaria or angioneurotic oedema that were precipitated or caused by aspirin or other NSAIDs; known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates; active peptic ulcer or gastrointestinal haemorrhage, history of gastrointestinal bleeding, ulceration or perforation, including cases related to previous NSAID therapy; chronic dyspepsia, Crohn’s disease or ulcerative colitis, severe heart failure, haemorrhagic diathesis and other coagulation disorders, other active bleeding or bleeding disorders; severe dehydration due to vomiting, diarrhoea, or insufficient fluid intake; inadequately controlled epilepsy, severe respiratory depression, varicella infection. Acute intoxication with alcohol, hypnotics, analgesics, opioids, or psychotropic agents. CYP2D6 ultrarapid and poor metabolisers. Moderate to severe renal (CrCl ≤59 mL/min) and severe hepatic (Child-Pugh class C) impairment. Pregnancy and lactation. Concomitant use with or within 14 days after MAOI therapy; concomitant use with other NSAIDs (including cyclooxygenase-2 selective inhibitors).
Special Precautions
Patient with history of oesophagitis, gastritis, peptic ulcer, or other gastrointestinal disease (e.g. ulcerative colitis, Crohn's disease); predisposition to hypovolaemia; history of cardiac disease (particularly previous episodes of heart failure); hypertension, CHF, established ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, risk factors for CV disease (e.g. hyperlipidaemia, diabetes mellitus, smoking); congenital disorder of porphyrin metabolism (e.g. acute intermittent porphyria), recent major surgery; asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyposis; haematopoietic disorders, SLE, mixed connective tissue disease; history of seizures, head injury, increased intracranial pressure, shock, reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, sensitivity to opiates, history of drug abuse or acute alcoholism, tendency for drug abuse or dependence. Patient susceptible to seizures; pre-existing or risk factors for respiratory depression (e.g. substantial decreased respiratory reserve, hypoxia, hypercapnia). Dehydrated and debilitated patients. Patients taking benzodiazepines or other CNS depressants. CYP2D6 intermediate metabolisers. Mild renal and mild to moderate hepatic impairment. Elderly. Concomitant use with sedative agents (e.g. benzodiazepines).
Adverse Reactions
Significant: Increased plasma urea nitrogen, creatinine, AST, ALT; fluid retention and oedema, inhibition of platelet aggregation, prolonged bleeding time; risk for asthma attacks or bronchospasm; may mask symptoms of infectious disease; seizures, hyperkalaemia, new-onset or worsening of hypertension, increased risk of arterial thrombotic events (e.g. MI, stroke); drug tolerance, psychic and physical addiction (particularly during prolonged use). Cardiac disorders: Tachycardia. Ear and labyrinth disorders: Vertigo. Eye disorders: Periorbital oedema. Gastrointestinal disorders: Abdominal distension or pain, constipation, diarrhoea, dry mouth, dyspepsia, nausea, vomiting. General disorders and administration site conditions: Face oedema, asthenia, chills, discomfort, feeling abnormal. Investigations: Increased blood pressure, blood alkaline phosphatase, blood lactate dehydrogenase. Nervous system disorders: Dizziness, headache, somnolence. Psychiatric disorders: Psychotic disorder. Renal and urinary disorders: Haematuria. Respiratory, thoracic and mediastinal disorders: Laryngeal oedema. Skin and subcutaneous tissue disorders: Hyperhidrosis, pruritus, rash, urticaria. Vascular disorders: Hypertensive crisis, hypotension. Potentially Fatal: Gastrointestinal bleeding, ulceration or perforation; respiratory depression. Rarely, severe acute hypersensitivity reactions (e.g. anaphylactic shock). Very rarely, serious skin reactions (e.g. Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis).
Patient Counseling Information
This drug may cause dizziness or somnolence, if affected, do not drive or operate machinery.
Overdosage
Symptoms: Vomiting, anorexia, abdominal pain, somnolence, vertigo, disorientation, headache, miosis, CV collapse, consciousness disorders, coma, convulsions, respiratory depression up to respiratory arrest. Management: Symptomatic treatment. Administer activated charcoal within the 1st hour of ingestion of >5 mg dexketoprofen/kg or within 2 hours following tramadol intake. Maintain the respiratory tract open and avoid aspiration; maintain respiration and circulation according to the symptoms. In case of respiratory depression due to tramadol intake, naloxone may be used as an antidote. Administer IV diazepam for convulsions. Both dexketoprofen and tramadol may be removed by dialysis; however, tramadol is minimally eliminated from the serum by haemofiltration or haemodialysis.
Drug Interactions
Tramadol: Concomitant use with coumarin derivatives (e.g. warfarin) resulted in elevated INR with major bleeding and ecchymoses. May increase the risk of convulsions with SSRIs, serotonin-norepinephrine reuptake inhibitors, TCAs, antipsychotics, and other seizure threshold-lowering agents (e.g. mirtazapine, bupropion). Concomitant or previous use with carbamazepine may lead to reduced analgesic effect and shortened duration of action. May result in serotonin syndrome with serotonergic agents (e.g. triptans, SSRIs, TCAs), lithium, inhibitors of CYP2D6 and 3A4.
Dexketoprofen: Increased risk of ulceration or bleeding with oral corticosteroids, anticoagulants (e.g. warfarin), SSRIs, or antiplatelet agents (e.g. aspirin). Decreased renal excretion of lithium thus increasing blood lithium levels and risk of lithium toxicity. Increased haematologic toxicity of methotrexate. May increase the toxic effects of hydantoins (including phenytoin) and sulfonamides. May reduce the effect of diuretics and antihypertensive agents (e.g. β-blockers). Concomitant use with K-sparing diuretic may result in hyperkalaemia. Increased risk of bleeding with pentoxifylline and thrombolytics. Risk of increased red cell line toxicity with zidovudine. May enhance the hypoglycaemic effect of sulfonylureas. May enhance the nephrotoxicity of ciclosporin and tacrolimus. Probenecid may increase the plasma concentrations of dexketoprofen. May increase the plasma concentration of cardiac glycosides. Concomitant use with tenofovir may result in increased plasma urea nitrogen and creatinine. May increase the risk of gastrointestinal toxicity with deferasirox. Dexketoprofen may decrease pemetrexed elimination. Potentially Fatal:
Tramadol: Concomitant use with or within 14 days of MAOIs may increase the risk of serotonin syndrome. Increased risk of sedation, respiratory depression and coma with benzodiazepines or other CNS depressants.
Dexketoprofen: Increased risk of gastrointestinal bleeding and ulcers with other NSAIDs including cyclooxygenase-2 inhibitors.
Food Interaction
Delayed absorption with food.
Tramadol: May result in serotonin syndrome with St. John's wort. May potentiate CNS effects with alcohol.
Action
Description: Mechanism of Action: Tramadol, a centrally acting synthetic opioid analgesic, binds to μ-opiate receptors in the CNS resulting in inhibition of ascending pain pathways and altering the perception of and response to pain. It also has serotonergic and noradrenergic properties through inhibition of the reuptake of norepinephrine and serotonin neurotransmitters, which are involved in the descending inhibitory pain pathway responsible for relief of pain.
Dexketoprofen, the S-(+) enantiomer of ketoprofen, is an analgesic, anti-inflammatory and antipyretic agent. It reduces the synthesis of prostaglandin by inhibiting the cyclooxygenase pathway which also affects other inflammation mediators (e.g. kinins), causing a further increase in anti-inflammatory activity. Onset: Tramadol: Within 1 hour. Duration: Dexketoprofen: 4-6 hours. Pharmacokinetics: Absorption: Tramadol: Readily absorbed. Bioavailability: Approx 70-75%. Time to peak plasma concentrations: 1.6-2 hours (tramadol); 3 hours (active metabolite).
Dexketoprofen: Rapidly absorbed. Delayed absorption with food. Time to peak plasma concentrations: Approx 30 mins (range: 15-60 minutes). Distribution: Tramadol: Widely distributed in the body. Crosses the placenta and blood-brain barrier; enters breast milk (very small amounts). Plasma protein binding: Approx 20%.
Dexketoprofen: Volume of distribution: <0.25 L/kg. Plasma protein binding: 99%. Metabolism: Tramadol: Extensively metabolised in the liver via N- and O-demethylation (by CYP3A4 and CYP2D6), glucuronidation and sulfation; O-desmethyltramadol (active metabolite formed by CYP2D6). Undergoes some first-pass metabolism.
Dexketoprofen: Metabolised in the liver via glucuronidation. Excretion: Tramadol: Via urine (approx 30% as unchanged drug, 60% as metabolites). Elimination half-life: Approx 6 hours (tramadol); 7.4 ± 1.4 hours (active metabolite).
Dexketoprofen: Via urine (primarily as metabolites). Elimination half-life: 1-2.7 hours.
Chemical Structure
Tramadol Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 33741, Tramadol. https://pubchem.ncbi.nlm.nih.gov/compound/33741. Accessed Sept. 28, 2021.
Dexketoprofen_01 Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 667550, Dexketoprofen. https://pubchem.ncbi.nlm.nih.gov/compound/Dexketoprofen. Accessed Apr. 27, 2023.
Sign Out
