Chemical formula: C₁₆H₂₅NO₂ Molecular mass: 263.381 g/mol PubChem compound: 33741
Tramadol interacts in the following cases:
Concomitant administration of tramadol with other centrally acting drugs including alcohol may potentiate CNS depressant effect.
Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure threshold-lowering medicinal products (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions.
Concomitant therapeutic use of tramadol and serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors, tricyclic antidepressants and mirtazapine may cause serotonin toxicity.
Serotonin syndrome is likely when one of the following is observed:
Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.
Alcohol is not permitted during treatment with tramadol.
Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased INR and ecchymoses in some patients.
Tetracyclines can increase the toxicity of tramadol by reducing its metabolism and clearance.
Protease inhibitors can increase the toxicity of tramadol by reducing its metabolism and clearance.
The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited.
Other active substances known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied.
In patients with hepatic insufficiency the elimination of tramadol is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient’s requirements.
In patients with renal insufficiency the elimination of tramadol is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient’s requirements.
Aminoglutethimide can reduce tramadol’s activity by increasing its metabolism and clearance.
Amiodarone can increase the toxicity of Tramadol by reducing the metabolism and clearance of Tramadol. Amiodarone can also reduce the activity of Tramadol by reducing the production of Tramadol active metabolites.
The combination with mixed agonist/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not advisable, because the analgesic effect of a pure agonist may be theoretically reduced in such circumstances.
Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect of tramadol and shorten the duration of action.
Cyclosporin can increase the toxicity of tramadol by reducing its metabolism and clearance.
With the concomitant or previous administration of cimetidine clinically relevant interactions are unlikely to occur. Therefore no alteration of the tramadol dosage regimen is recommended for patients receiving chronic cimetidine therapy.
Cinacalcet can reduce the activity of tramadol by reducing the production of its active metabolites.
Clotrimazole can increase the toxicity of tramadol by reducing its metabolism and clearance.
Clozapine can reduce the activity of tramadol by reducing the production of its active metabolites.
Cocaine can reduce the activity of tramadol by reducing the production of its active metabolites.
Conivaptan can increase the toxicity of tramadol by reducing its metabolism and clearance.
Darifenacin can reduce the activity of tramadol by reducing the production of its active metabolites.
Delavirdine can reduce the activity of tramadol by reducing the production of its active metabolites.
Dexamethasone can reduce the activity of tramadol by increasing its metabolism and clearance.
Diltiazem can increase the toxicity of tramadol by reducing its metabolism and clearance.
Diphenhydramine may reduce the activity of tramadol by reducing the production of its active metabolites.
Duloxetine can reduce the activity of tramadol by reducing the production of its active metabolites.
Erythromycin can increase the toxicity of tramadol by reducing its metabolism and clearance.
Etravirine can reduce the activity of tramadol by increasing its metabolism and clearance.
Fluconazole can increase the toxicity of tramadol by reducing its metabolism and clearance.
Fosamprenavir can increase the toxicity of tramadol by reducing its metabolism and clearance.
Phosphenytoin can reduce the activity of tramadol by increasing its metabolism and clearance.
Haloperidol can reduce the activity of tramadol by reducing the production of its active metabolites.
Imatinib can increase the toxicity of tramadol by reducing its metabolism and clearance.
Isoniazid can reduce the activity of tramadol by reducing the production of its active metabolites.
Itraconazole can increase the toxicity of tramadol by reducing its metabolism and clearance.
Ketoconazole can increase the toxicity of tramadol by reducing its metabolism and clearance.
Lapatinib can increase the toxicity of tramadol by reducing its metabolism and clearance.
Lidocaine can increase the toxicity of tramadol by reducing its metabolism and clearance.
Methadone can reduce the activity of tramadol by reducing the production of its active metabolites.
Metronidazole can increase the toxicity of tramadol by reducing its metabolism and clearance.
Miconazole can increase the toxicity of tramadol by reducing its metabolism and clearance.
Nefazodone can increase the toxicity of tramadol by reducing its metabolism and clearance.
Nevirapine can reduce the activity of tramadol by increasing its metabolism and clearance.
Nicardipine can increase the toxicity of tramadol by reducing its metabolism and clearance.
Nilotinib can reduce the activity of tramadol by reducing the production of its active metabolites.
There is a theoretical possibility that tramadol could interact with noradrenaline, 5HT or lithium due to their respective mechanisms of action, thus potentiate their anti-depressant effect. However there have been no reports of such interactions.
Norfloxacin can increase the toxicity of tramadol by reducing its metabolism and clearance.
In a limited number of studies the pre- or post-operative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.
Oxcarbazepine can reduce the activity of tramadol by increasing its metabolism and clearance.
Pentobarbital may reduce the activity of tramadol by increasing its metabolism and clearance.
Phenobarbital may reduce the activity of tramadol by increasing its metabolism and clearance.
Phenytoin can reduce the activity of tramadol by increasing its metabolism and clearance.
Pioglitazone can reduce the activity of tramadol by reducing the production of its active metabolites.
Posaconazole can increase the toxicity of tramadol by reducing its metabolism and clearance.
Primidone can reduce the activity of tramadol by increasing its metabolism and clearance.
Pyrimethamine can reduce the activity of tramadol by reducing the production of its active metabolites.
A study in 12 healthy volunteers has shown that quinidine causes an approximate 25% increase in the tramadol Cmax and AUC; Tmax is unaffected. However, the increases in Cmax and AUC fall within the normal therapeutic range for tramadol, and no dosage adjustment is required.
Quinidine can increase the toxicity of tramadol by reducing its metabolism and clearance.
Quinine can reduce the activity of tramadol by reducing the production of its active metabolites.
Ranolazine can reduce the activity of tramadol by reducing the production of its active metabolites.
Ranolazine can reduce the activity of tramadol by reducing the production of its active metabolites.
Rifabutin can reduce tramadol’s activity by increasing its metabolism and clearance.
Rifampicin can reduce the activity of tramadol by increasing its metabolism and clearance.
Rifapentine can reduce the activity of tramadol by increasing its metabolism and clearance.
Sitaxentan can increase the toxicity of tramadol by reducing its metabolism and clearance.
Telithromycin may reduce the metabolism and clearance of tramadol.
Terbinafine can reduce tramadol’s activity by reducing the production of its active metabolites.
Terbinafine can reduce the activity of tramadol by reducing the production of its active metabolites.
Thioridazine can reduce tramadol’s activity by reducing the production of its active metabolites.
Thioridazine can reduce the activity of tramadol by reducing the production of its active metabolites.
Ticlopidine can reduce tramadol’s activity by reducing the production of its active metabolites.
Verapamil can increase the toxicity of Tramadol by reducing its metabolism and clearance.
Tramadol is metabolised by the liver enzyme CYP2D6. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect may not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency.
If the patient is an ultra-rapid metaboliser of CYP2D6 there is a risk of developing side effects of opioid toxicity even at commonly prescribed doses.
General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life threatening and very rarely fatal.
Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised below:
| Population | Prevalence % |
|---|---|
| African/Ethiopian | 29% |
| African American | 3.4% to 6.5% |
| Asian | 1.2% to 2% |
| Caucasian | 3.6% to 6.5% |
| Greek | 6.0% |
| Hungarian | 1.9% |
| Northern European | 1% to 2% |
Nafcillin can reduce the activity of tramadol by increasing its metabolism and clearance.
Sitaxentan can increase the toxicity of tramadol by reducing its metabolism and clearance.
Animal studies with tramadol revealed at very high doses effects on organ development, ossification and neonatal mortality. Tramadol crosses the placenta. There is inadequate evidence available on the safety of tramadol in human pregnancy, therefore tramadol should not be used in pregnant women.
Tramadol – administered before or during birth – does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant. Chronic use during pregnancy may lead to neonatal withdrawal symptoms.
Approximately 0.1% of the maternal dose of tramadol is excreted in breast milk. In the immediate post-partum period, for maternal oral daily dosage up to 400 mg, this corresponds to a mean amount of tramadol ingested by breast-fed infants of 3% of the maternal weight-adjusted dosage. For this reason tramadol should not be used during lactation or alternatively, breast-feeding should be discontinued during treatment with tramadol. Discontinuation of breast-feeding is generally not necessary following a single dose of tramadol.
Post marketing surveillance does not suggest an effect of tramadol on fertility. Animal studies did not show an effect of tramadol on fertility.
Even when taken according to instructions, tramadol may cause drowsiness and dizziness and this effect may be potentiated by alcohol and other central nervous system (CNS) depressants or psychotropic substances. Ambulant patients should be warned not to drive or operate machinery if affected.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
Rapid intravenous administration may be associated with a higher incidence of adverse effects and therefore should be avoided.
The most commonly reported adverse drug reactions are nausea and dizziness, both occurring in more than 10% of patients.
The frequencies are defined as follows: Very common ≥1/10, Common ≥1/100, <1/10, Uncommon ≥1/1000, <1/100, Rare ≥1/10 000, <1/1000, Very rare <1/10 000, Not known cannot be estimated from the available data.
Uncommon: cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). These adverse effects may occur especially after intravenous administration and in patients who are physically stressed.
Rare: bradycardia, hypertension (increase in blood pressure).
Very common: dizziness.
Common: headache, somnolence.
Rare: changes in appetite, paraesthesia, tremor, epileptiform convulsions, involuntary muscle contractions, abnormal coordination, syncope, speech disorders.
Epileptiform convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with medicinal products which can lower the seizure threshold or themselves induce cerebral convulsions (e.g. anti-depressants or anti-psychotics), syncope.
If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly, respiratory depression may occur.
Rare: hallucinations, confusion, sleep disturbance, delirium, anxiety and nightmares. Psychic side effects may occur following administration of tramadol, which vary individually in intensity and nature (depending on personality and duration of medication). These include changes in mood (usually elation, occasionally dysphoria), changes in activity (usually suppression, occasionally increase) and changes in cognitive and sensorial ability (e.g. decision behaviour, perception disorders). Dependence may occur.
Rare: blurred vision, miosis, mydriasis.
Rare: respiratory depression, dyspnoea
If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly, respiratory depression may occur.
Worsening of asthma has been reported, though a causal relationship has not been established.
Very common: nausea
Common: vomiting, constipation, dry mouth
Uncommon: retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea
Common: sweating.
Uncommon: dermal reactions (e.g. pruritus, rash, urticaria).
Rare: muscle weakness
In a few isolated cases, increases in liver enzyme values have been reported in a temporal connection with the therapeutic use of tramadol.
Rare: micturition disorders (difficulty in passing urine, dysuria and urinary retention)
Common: fatigue
Rare: hypersensitivity/allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.
Not known: hypoglycaemia
Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms.
Other symptoms that have very rarely been seen with tramadol discontinuation include: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, personalisation, derealisation, paranoia).
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