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 depressant medicinal products including alcohol may potentiate the CNS effects.
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.
Medicinal products known to inhibit CYP3A4, such as ketoconazole, ritonavir and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) and probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied.
In patients with renal and/or 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.
Tramadol can induce convulsions and increase the potential for selective serotonin re-uptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic anti-depressants, anti-psychotics 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 serotonin syndrome, a potentially life-threatening condition.
Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased INR with major bleeding and ecchymoses in some patients.
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 and shorten the duration of action.
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.
In patients sensitive to opiates the product should only be used with caution.
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. However, if the patient is an ultra-rapid metaboliser 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% |
Tramadol may only be used with particular caution in opioid-dependent patients, patients with head injury, shock, a reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, increased intracranial pressure.
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.
Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Tramadol – administered before or during birth – does not affect uterine contractility. Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.
Administration to nursing women is not recommended as tramadol may be secreted in breast milk and may cause respiratory depression in the infant.
Approximately 0.1% of the maternal dose is excreted into the 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.
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 effects such as somnolence and dizziness and therefore may impair the reactions of drivers and machine operators. This applies particularly in conjunction with other psychotropic substances, particularly alcohol.
The undesirable effects are classified into system organ classes and their frequency is classified as follows: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
The most commonly reported adverse reactions are nausea and dizziness, both occurring in more than 10% of patients.
Not known: hypoglycaemia
Rare: changes in appetite
Rare: Hallucinations, confusion, sleep disturbance, 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 (mostly reduced, occasionally increased) and changes in cognitive and sensorial ability (e.g. decision behaviour, perception disorders). Dependence may occur.
Very common: Dizziness.
Common: Headache, somnolence.
Rare: Changes in appetite, paraesthesia, tremor, respiratory depression, epileptiform convulsions, abnormal coordination, involuntary muscle contractions, syncope.
If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly, respiratory depression may occur.
Epileptiform convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with medicinal products which can lower the seizure threshold.
Not known: speech disorders, serotonin syndrome
Rare: Blurred vision, miosis, mydriasis.
Uncommon: Cardiovascular regulation (palpitations, tachycardia, postural hypotension or cardiovascular collapse). These adverse effects may occur especially in connection with intravenous administration and if the patient is experiencing physical stress.
Rare: Bradycardia, increased blood pressure.
Uncommon: cardiovascular regulation (postural hypotension or cardiovascular collapse). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.
Rare: Dyspnoea
Frequency not known: Worsening of asthma has been reported, though a causal relationship has not been established, Hiccups.
Very common: Nausea.
Common: Vomiting, constipation, dry mouth.
Uncommon: Retching; gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea.
Frequency not known: In a few isolated cases an increase in liver enzyme values has been reported in a temporal connection with the therapeutic use of tramadol.
Common: Sweating.
Uncommon: Dermal reactions (e.g. pruritus, rash, urticaria).
Rare: Motorial weakness.
Rare: Micturition disorders (difficulty in passing urine and urinary retention).
Common: fatigue
Rare: Allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis; 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, depersonalization, derealization, paranoia).
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