Tramadol Interactions
Anxiolytics, Sedatives, and Hypnotics
General Anesthetics
- Haloperidol
- Imatinib, STI-571
- Linezolid
- Maprotiline
- Meperidine
- Mirtazapine
Mixed opiate agonists/antagonists
Monoamine oxidase inhibitors (MAOIs)
- Naloxone
- Nefazodone
- Ondansetron
Opiate agonists
Phenothiazines
- Pramipexole
- Pregabalin
- Procarbazine
- Propafenone
- Propoxyphene
- Quinacrine
- Quinidine
- Quinine
Radiopaque Contrast Agents
Sedating H1-blockers
Selective serotonin reuptake inhibitors (SSRIs)
Serotonin norepinephrine reuptake inhibitors
Skeletal Muscle Relaxants
- St. John’s Wort, Hypericum perforatum
- Terbinafine
- Tolcapone
Tricyclic antidepressants
Tramadol Interactions
As the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 may affect the analgesic effect of tramadol (see Mechanism of Action). Increased serum concentrations of tramadol and reduced serum concentrations of M1 would be expected from concurrent use of tramadol and a CYP2D6 inhibitor (see Pharmacokinetics). Agents that inhibit CPY2D6 include amiodarone , chloroquine, haloperidol , imatinib, STI-571 , gefitinib, ritonavir, terbinafine, propoxyphene, quinacrine, quinine, quinidine, and propafenone. The list of drugs that inhibit CYP2D6 is not all inclusive. Reduced analgesic effects of tramadol are possible when a concurrent CYP2D6 inhibitor is used.
The analgesic effect of tramadol may be reduced when used with carbamazepine. Carbamazepine induces the metabolism of tramadol, which may reduce the analgesic effect. Also, carbamazepine may contribute to the CNS depressant effects of tramadol. Furthermore, tramadol may decrease the seizure threshold in some patients and thus, interfere with the ability of carbamazepine to control seizures. Concomitant usage of tramadol and carbamazepine is not recommended.
The risk of seizures and serotonin syndrome may be enhanced by concurrent use of tramadol and monoamine oxidase inhibitors (MAOIs). Use tramadol cautiously, if at all, in patients also receiving a MAOI or a drug with MAO-inhibiting activity, such as furazolidone, linezolid and procarbazine. International recommendations contraindicate the concurrent use of tramadol and MAOIs or the use of tramadol within 14 days of discontinuing MAOI therapy.
Administration of tramadol may enhance the seizure risk in patients taking other medications that decrease the seizure threshold. Tricyclic antidepressants and other tricyclic compounds (e.g., cyclobenzaprine) that decrease the seizure threshold have been associated with increased risk of seizures when given concurrently with tramadol. Other agents that may decrease the seizure threshold include neuroleptics (e.g., phenothiazines), amoxapine, maprotiline, bupropion, clozapine, meperidine, and cocaine. Additive CNS depression may also occur when some of these agents are given concurrently with tramadol. A reduced dose of tramadol is recommended when used in patients who take a phenothiazine. Also, as the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 by amitriptyline or bupropion may affect the analgesic effect of tramadol (see Mechanism of Action). Increased serum concentrations of tramadol and reduced serum concentrations of M1 would be expected from concurrent use of tramadol and a CYP2D6 inhibitor (see Pharmacokinetics).
Tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists. Concomitant use of tramadol and opiate agonists may also increase the risk of seizures; avoid concurrent use whenever possible. If used together, a reduced tramadol dose is recommended.
Tramadol can cause additive CNS depression and respiratory depression when used with other agents that are CNS depressants, such as general anesthetics or anxiolytics, sedatives, and hypnotics. Other agents that may contribute to CNS depression when used with tramadol include mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, pentazocine), droperidol, dronabinol, THC, entacapone, sedating H1-blockers, pramipexole, pregabalin, ropinirole, skeletal muscle relaxants, and tolcapone. In addition, chlorpheniramine and diphenhydramine inhibit CYP2D6, an enzyme responsible for the metabolism of tramadol. Close monitoring for side effects in patients receiving tramadol-containing products and chlorpheniramine or diphenhydramine is recommended. Extreme caution is needed in using tramadol at the same time as other CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant.
Ethanol should not be consumed while taking tramadol. Acute intoxication with alcohol is a contraindication for tramadol usage. Tramadol may worsen CNS and respiratory depression. Also, alcohol withdrawal is associated with a seizure risk, and tramadol appears to increase the risk of seizure development.
Naloxone should be used cautiously in situations of tramadol overdose. Naloxone administration may increase the risk of seizures in these patients. Furthermore, naloxone will reverse some but not all symptoms caused by tramadol overdosage (see Mechanism of Action).
An increased incidence of digoxin toxicity has been reported during post-marketing reports with the concurrent use of tramadol and digoxin. If concurrently used, monitor serum digoxin concentrations, especially after the initiation and cessation of tramadol.
The risk of seizures and serotonin syndrome may be enhanced by concurrent use of tramadol and selective serotonin reuptake inhibitors (SSRIs). Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. Several cases of serotonin syndrome have been reported following the administration of tramadol with a SSRI. Citalopram, escitalopram, fluoxetine, paroxetine, and sertraline inhibit the formation of the active M1 metabolite of tramadol by inhibiting cytochrome P450 2D6. The inhibition of M1 formation may decrease the analgesic effectiveness of tramadol but increase the serum concentration of the parent compound (see Mechanism of Action).
Medications that decrease the reuptake of serotonin, such as serotonin norepinephrine reuptake inhibitors (e.g., duloxetine or venlafaxine), nefazodone or St. John’s wort, Hypericum perforatum, may cause serotonin syndrome in patients taking tramadol. Also, additive CNS depression may occur when tramadol is used with a mirtazapine or nefazodone. The addition of tramadol to extended-release venlafaxine 300 mg/day and mirtazapine 30 mg/day likely caused serotonin syndrome. A patient developed agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, mydriasis, tachycardia, and fever within 7 weeks of taking tramadol 400 mg daily. He had taken 300 mg tramadol without difficulty. Discontinuation of the 3 drugs and rehydration led to symptom resolution over 36 hours. Reinstitution of the antidepressants 3 days after patient presentation was uneventful.
Elevation of prothrombin times during concurrent tramadol and warfarin usage has been reported rarely during the post-marketing period. Increased INRs have been reported in patients previously stabilized on warfarin who start taking tramadol. For example, a patient stabilized on warfarin 5 mg/daily had an increased INR from 3.5 to 7.1. He had begun tramadol 50 mg three times daily 1 month earlier. In another case, addition of tramadol 50 mg every 6 hours to a stable dose of warfarin 45 mg/week resulted in an INR of 10.6. The patient begun tramadol about 2 weeks before presentation and stopped tramadol 2 - 3 days earlier. Cessation of warfarin and slow reinstitution of 45 mg/week led to a therapeutic INR. The mechanism of the interaction is unknown; tramadol is not highly protein bound and is not known to affect enzymes associated with the metabolism of warfarin. Closely monitor patients who require the combination of tramadol and warfarin for changes in INR and bleeding. Another alternative analgesic agent may be warranted in patients receiving warfarin.
Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Tramadol should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from a few small studies indicate that ondansetron may reduce the analgesic effects of tramadol. Since adverse effects may occur when tramadol is administered in excessive dosage as patients try to obtain pain relief, clinicians should be alert to increases in the patient reported frequency of tramadol administration during concurrent use.
[ Last revised: 3/1/2005 9:09:00 AM ]
References
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