DRUG INTERACTIONS
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
Abiraterone: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with abiraterone is necessary; also monitor for tramadol-related adverse reactions, including seizures and serotonin syndrome. Consider increasing the dose of tramadol if clinically appropriate. If abiraterone is discontinued, consider a dose reduction of tramadol and frequently monitor for signs or respiratory depression and sedation. Tramadol is metabolized by CYP2D6 to its active metabolite, M1; M1 is critical to the activity of tramadol. Abiraterone is a moderate CYP2D6 inhibitor. Concomitant use with CYP2D6 inhibitors may result in an increase in tramadol plasma levels and a decrease in the levels of the active metabolite, M1. In patients who have developed physical dependence to tramadol, decreased M1 levels may result in opioid withdrawal or reduced efficacy while increased tramadol levels may cause serotonin syndrome or seizures.
Acetaminophen; Aspirin; Diphenhydramine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists; avoid concurrent use whenever possible. If used together, extreme caution is needed, and a reduced tramadol dose is recommended.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Acetaminophen; Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Acetaminophen; Codeine: (Major) Concomitant use of codeine with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of codeine with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Acetaminophen; Dextromethorphan; Doxylamine: (Major) Reserve concomitant use of opioids and doxylamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Acetaminophen; Diphenhydramine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Acetaminophen; Hydrocodone: (Major) Concomitant use of hydrocodone with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of hydrocodone with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Acetaminophen; Oxycodone: (Major) Concomitant use of tramadol with oxycodone may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Acetaminophen; Pentazocine: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as tramadol. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. There is also a potential increased risk of seizures if tramadol and pentazocine are given concurrently. Concurrent use of pentazocine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
Acrivastine; Pseudoephedrine: (Major) Avoid coadministration of opioid agonists with acrivastine due to the risk of additive CNS depression.
Adagrasib: (Moderate) Concurrent use of tramadol with adagrasib may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A; adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psychotropic activity such as opiate agonists. In addition, aldesleukin, IL-2, is a CYP3A4 inhibitor and may increase oxycodone plasma concentrations and related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patients for an extended period and adjust oxycodone dosage as necessary.
Alfentanil: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists; avoid concurrent use whenever possible. If used together, extreme caution is needed, and a reduced tramadol dose is recommended.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Almotriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tramadol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Alosetron: (Major) Patients taking medications that decrease GI motility may be at greater risk for serious complications from alosetron, like constipation, via a pharmacodynamic interaction. Constipation is the most frequently reported adverse effect with alosetron. Alosetron, if used with drugs such as opiate agonists, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
Alprazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Alvimopan: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
Amifampridine: (Major) Carefully consider concomitant use of amifampridine with tramadol due to increased seizure risk. The concomitant use of amifampridine and other drugs that lower the seizure threshold, such as tramadol, may lead to an increased risk of seizures.
Amiloride: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when amiloride is administered with tramadol. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when amiloride is administered with tramadol. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Amiodarone: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with amiodarone is necessary. If amiodarone is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and amiodarone is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Amlodipine: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with amlodipine is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of amlodipine, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Amlodipine; Atorvastatin: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with amlodipine is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of amlodipine, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Amlodipine; Benazepril: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with amlodipine is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of amlodipine, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Amlodipine; Celecoxib: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with amlodipine is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of amlodipine, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with celecoxib is necessary. If celecoxib is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and celecoxib is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Amlodipine; Olmesartan: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with amlodipine is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of amlodipine, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Amlodipine; Valsartan: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with amlodipine is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of amlodipine, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with amlodipine is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of amlodipine, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Amobarbital: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Amoxapine: (Major) Concomitant use of tramadol with amoxapine may cause excessive sedation and somnolence and increase the risk for seizures. Limit the use of tramadol with amoxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and the potential increased risk for seizures.
Amphetamine; Dextroamphetamine Salts: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering amphetamines with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and tramadol. Patients receiving tramadol and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The amphetamine and tramadol should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. In addition, the risk of seizures from the use of tramadol may be increased with concomitant use of CNS stimulants that may induce seizures, including the amphetamines. Extreme caution and close clinical monitoring is recommended if these agents must be used together.
Antacids: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
Apalutamide: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with apalutamide is necessary; consider increasing the dose of tramadol as needed. If apalutamide is discontinued, consider a dose reduction of tramadol and frequently monitor for signs or respiratory depression and sedation. Tramadol is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Apomorphine: (Major) Concomitant use of opioid agonists with apomorphine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with apomorphine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents like apomorphine have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Apraclonidine: (Minor) Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as opiate agonists. Although no specific drug interactions were identified with systemic agents and apraclonidine during clinical trials, apraclonidine can cause dizziness and somnolence.
Aprepitant, Fosaprepitant: (Moderate) Use caution if tramadol and aprepitant, fosaprepitant are used concurrently and monitor for an increase in tramadol-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tramadol is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of tramadol. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. (Minor) Use caution if acetaminophen and aprepitant are used concurrently and monitor for an increase in acetaminophen-related adverse effects for several days after administration of a multi-day aprepitant regimen. Acetaminophen is a minor (10 to 15%) substrate of CYP3A4. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of acetaminophen. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Major) Reserve concomitant use of tramadol and aripiprazole for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation as well as seizures. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, seizures, and death.
Artemether; Lumefantrine: (Moderate) Lumefantrine is an inhibitor and tramadol is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased tramadol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Asciminib: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with asciminib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of asciminib, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Asenapine: (Moderate) Concomitant use of tramadol with asenapine may cause excessive sedation, somnolence, and increased risk of seizure. Limit the use of tramadol with asenapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and seizures.
Aspirin, ASA; Butalbital; Caffeine: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of codeine with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of codeine with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Concomitant use of tramadol with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Aspirin, ASA; Carisoprodol: (Major) Concomitant use of tramadol with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of codeine with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of codeine with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Major) Concomitant use of tramadol with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of tramadol with oxycodone may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Atazanavir; Cobicistat: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Atenolol; Chlorthalidone: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Atropine: (Major) Reserve concomitant use of tramadol and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) Tramadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol. (Major) Reserve concomitant use of tramadol and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Atropine; Difenoxin: (Major) Reserve concomitant use of tramadol and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events.
Atropine; Edrophonium: (Major) Reserve concomitant use of tramadol and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Avacopan: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with avacopan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of avacopan, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Azelastine: (Major) Concomitant use of opioid agonists with azelastine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with azelastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Azelastine; Fluticasone: (Major) Concomitant use of opioid agonists with azelastine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with azelastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Azilsartan; Chlorthalidone: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Baclofen: (Major) Concomitant use of tramadol with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Barbiturates: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Belladonna; Opium: (Major) Concomitant use of tramadol with opium may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Belumosudil: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with belumosudil is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of belumosudil, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Belzutifan: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of tramadol as needed. If belzutifan is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Bendroflumethiazide; Nadolol: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of other opiate agonists with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of other opiate pain medications with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking tramadol, reduce the initial dosage and titrate to clinical response. If tramadol is prescribed in a patient taking benzhydrocodone, use a lower initial dose of tramadol and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and tramadol because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Concomitant use of tramadol increases the seizure risk in patients taking other opiate agonists.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) Tramadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Benzphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and tramadol. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. An additive risk of seizures is also possible. Inform patients taking this combination of the possible increased risk of serotonin syndrome and seizures and monitor for adverse effects particularly after a dose increase or the addition of interacting medications. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Benztropine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and benztropine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Berotralstat: (Moderate) Concurrent use of tramadol with berotralstat may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A4; berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Bethanechol: (Moderate) Bethanechol facilitates intestinal and bladder function via parasympathomimetic actions. Opiate agonists impair the peristaltic activity of the intestine. Thus, these drugs can antagonize the beneficial actions of bethanechol on GI motility.
Bicalutamide: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with bicalutamide is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of bicalutamide, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Bismuth Subsalicylate: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Brexanolone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Brexpiprazole: (Major) Concomitant use of tramadol with brexpiprazole may cause excessive sedation, somnolence, and increased risk of seizures. Limit the use of opioid pain medications with brexpiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and seizures.
Brigatinib: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of tramadol as needed. If brigatinib is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
Brompheniramine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Brompheniramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Brompheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and glycopyrrolate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Bumetanide: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and tramadol; increase the dosage of the loop diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Epinephrine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Meloxicam: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Buprenorphine: (Major) Avoid concomitant use of tramadol and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of tramadol and/or precipitation of withdrawal symptoms.
Buprenorphine; Naloxone: (Major) Avoid concomitant use of tramadol and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of tramadol and/or precipitation of withdrawal symptoms.
Bupropion: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with bupropion is necessary. If bupropion is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and bupropion is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Bupropion; Naltrexone: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with bupropion is necessary. If bupropion is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and bupropion is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Buspirone: (Moderate) Tramadol can cause additive CNS depression when used with other agents that are CNS depressants including buspirone.
Busulfan: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Butabarbital: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen; Caffeine: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of codeine with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of codeine with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butorphanol: (Major) Avoid the concomitant use of butorphanol and opiate agonists, such as tramadol. Butorphanol is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Butorphanol may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of butorphanol with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. There is also a potential increased risk of seizures if tramadol is given with other opiates.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) Concomitant use of opioid agonists with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with sodium oxybate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Cannabidiol: (Moderate) Concomitant use of opioid agonists with cannabidiol may cause excessive sedation and somnolence. Limit the use of opioid pain medications with cannabidiol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Capsaicin; Metaxalone: (Major) Concomitant use of opioid agonists with metaxalone may cause respiratory depression, profound sedation, and death. Limit the use of opioid pain medication with metaxalone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use of metaxalone and opioid agonists increases the risk for serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Carbamazepine: (Major) Reserve concomitant use of tramadol and carbamazepine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required, and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal; consider increasing the dose of tramadol as needed. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death and/or decrease tramadol concentrations, which may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If carbamazepine is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and carbamazepine is a strong CYP3A inducer. (Minor) Carbamazepine may potentially accelerate the hepatic metabolism of acetaminophen. In addition, due to enzyme induction, carbamazepine may increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Clinicians should be alert to decreased effect of acetaminophen. Dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted.
Carbinoxamine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Carbinoxamine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Carbinoxamine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Cariprazine: (Moderate) Concomitant use of opioid agonists with cariprazine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cariprazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Also, concomitant use of tramadol increases the seizure risk in patients taking cariprazine.
Carisoprodol: (Major) Concomitant use of tramadol with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Celecoxib: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with celecoxib is necessary. If celecoxib is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and celecoxib is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with celecoxib is necessary. If celecoxib is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and celecoxib is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Cenobamate: (Moderate) Concomitant use of tramadol with cenobamate may cause excessive sedation and somnolence. Limit the use of tramadol with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with cenobamate is necessary; consider increasing the dose of tramadol as needed. If cenobamate is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ceritinib: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with ceritinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of ceritinib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Cetirizine: (Major) Reserve concomitant use of opioids and cetirizine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Cetirizine; Pseudoephedrine: (Major) Reserve concomitant use of opioids and cetirizine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Charcoal: (Minor) Activated charcoal binds many drugs within the gut. Administering charcoal dietary supplements at the same time as a routine acetaminophen dosage would be expected to interfere with the analgesic and antipyretic efficacy of acetaminophen. Charcoal is mostly used in the setting of acetaminophen overdose; however, patients should never try to treat an acetaminophen overdose with charcoal dietary supplements. Advise patients to get immediate medical attention for an acetaminophen overdose.
Chlophedianol; Dexbrompheniramine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Chlorcyclizine: (Moderate) Concomitant use of opioid agonists with chlorcyclizine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorcyclizine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Chlordiazepoxide: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Chlordiazepoxide; Amitriptyline: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Chlordiazepoxide; Clidinium: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Chlorothiazide: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Chlorpheniramine; Codeine: (Major) Concomitant use of codeine with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of codeine with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists; avoid concurrent use whenever possible. If used together, extreme caution is needed, and a reduced tramadol dose is recommended. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Chlorpheniramine; Hydrocodone: (Major) Concomitant use of hydrocodone with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of hydrocodone with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Chlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Chlorpromazine: (Moderate) Concurrent use of tramadol and chlorpromazine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that chlorpromazine has CYP2D6 inhibitory effects and has the potential to decrease the metabolism of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, hyperreflexia, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by chlorpromazine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and chlorpromazine.
Chlorthalidone: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Chlorthalidone; Clonidine: (Major) Concomitant use of opioid agonists with clonidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clonidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Chlorzoxazone: (Major) Concomitant use of tramadol with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Cholestyramine: (Moderate) Cholestyramine has been shown to decrease the absorption of acetaminophen by roughly 60%. Experts have recommended that cholestyramine not be given within 1 hour of acetaminophen if analgesic or antipyretic effect is to be achieved.
Choline Salicylate; Magnesium Salicylate: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. Although salicylates are rarely associated with nephrotoxicity, high-dose, chronic administration of salicylates combined other analgesics, including acetaminophen, significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Additive hepatic toxicity may occur, especially in combined overdose situations. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
Cinacalcet: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with cinacalcet is necessary. If cinacalcet is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Citalopram: (Moderate) Monitor patients for the emergence of serotonin syndrome if concomitant use of tramadol and citalopram is warranted. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Clemastine: (Moderate) Concomitant use of opioid agonists with clemastine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clemastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Clobazam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, in vivo data suggest clobazam is a CYP2D6 inhibitor. Because the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 by clobazam may affect the analgesic response to tramadol. Reduced analgesic effects of tramadol are possible, and the risk for serious adverse effects such as seizures may be increased.
Clonazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Clonidine: (Major) Concomitant use of opioid agonists with clonidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clonidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Clopidogrel: (Moderate) Coadministration of opioid agonists, such as tramadol, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
Clorazepate: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Clozapine: (Moderate) Concurrent use of tramadol and clozapine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that clozapine has CYP2D6 inhibitory effects and may increase plasma concentrations of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, hyperreflexia, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by clozapine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and clozapine.
Cobicistat: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Cocaine: (Major) Cocaine use has been associated with precipitating seizures. Since tramadol decreases the seizure threshold, an increased risk of seizures may be seen with concomitant use of these two drugs.
Codeine: (Major) Concomitant use of codeine with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of codeine with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Codeine; Guaifenesin: (Major) Concomitant use of codeine with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of codeine with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of codeine with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of codeine with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of codeine with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of codeine with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Major) Reserve concomitant prescribing of tramadol and promethazine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, seizures, coma, and death.
Codeine; Promethazine: (Major) Concomitant use of codeine with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of codeine with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Major) Reserve concomitant prescribing of tramadol and promethazine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, seizures, coma, and death.
COMT inhibitors: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Conivaptan: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with conivaptan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of conivaptan, a moderate CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Crizotinib: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with crizotinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of crizotinib, a moderate CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Crofelemer: (Moderate) Pharmacodynamic interactions between crofelemer and opiate agonists are theoretically possible. Crofelemer does not affect GI motility mechanisms, but does have antidiarrheal effects. Patients taking medications that decrease GI motility, such as opiate agonists, may be at greater risk for serious complications from crofelemer, such as constipation with chronic use. Use caution and monitor GI symptoms during coadministration.
Cyclizine: (Moderate) Concomitant use of opioid agonists with cyclizine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with cyclizine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Cyclobenzaprine: (Major) Concomitant use of tramadol with cyclobenzaprine may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications with cyclobenzaprine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Cyproheptadine: (Moderate) Concomitant use of opioid agonists with cyproheptadine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cyproheptadine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Dacomitinib: (Moderate) Coadministration of dacomitinib with tramadol may decrease tramadol metabolism resulting in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. Tramadol is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Dantrolene: (Major) Concomitant use of tramadol with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Dapsone: (Moderate) Coadministration of dapsone with acetaminophen may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
Daridorexant: (Major) Concomitant use of opiate agonists with daridorexant may cause excessive sedation and somnolence. Limit the use of opiates with daridorexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing cough medicines that contain opiates in patients taking daridorexant.
Darifenacin: (Moderate) Coadministration of darifenacin with tramadol may decrease tramadol metabolism resulting in decreased tramadol efficacy and/or increased tramadol-induced risks for respiratory depression, serotonin syndrome, or seizures. Tramadol is a CYP2D6 substrate; darifenacin is a moderate CYP2D6 inhibitor. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol that may increase the risk of tramadol-related adverse events including respiratory depression, serotonin syndrome, and seizures. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates such as tramadol increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
Darunavir: (Major) Concurrent use of tramadol with darunavir may decrease the CYP3A4 and CYP2D6 metabolism of tramadol; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Darunavir; Cobicistat: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. (Major) Concurrent use of tramadol with darunavir may decrease the CYP3A4 and CYP2D6 metabolism of tramadol; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. (Major) Concurrent use of tramadol with darunavir may decrease the CYP3A4 and CYP2D6 metabolism of tramadol; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations. (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Delavirdine: (Moderate) Since tramadol is primarily metabolized by cytochrome P450 isoenzyme CYP2D6, agents that inhibit this enzyme, such as delavirdine, decrease the metabolism of tramadol. Concomitant use of these agents and tramadol may increase plasma levels of tramadol and decrease concentration of the active metabolite leading to decreased analgesic effects and possibly increased side effects due to higher tramadol concentrations.
Desflurane: (Moderate) Concurrent use with opiate agonists can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
Desmopressin: (Major) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with water intoxication, hyponatremia, or SIADH including opiate agonists. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia.
Desogestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In one case, 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. In addition, although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer recommends that primary substrates of CYP2D6, such as tramadol, be dosed at the original level when coadministered with desvenlafaxine 100 mg or lower, or when desvenlafaxine is discontinued. The dose of these CYP2D6 substrates should be reduced by up to one-half if coadministered with desvenlafaxine 400 mg/day.
Deutetrabenazine: (Major) Concomitant use of opiate agonists with deutetrabenazine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with deutetrabenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking deutetrabenazine, use a lower initial dose of the opiate and titrate to clinical response. If deutetrabenazine is prescribed for a patient taking an opiate agonist, use a lower initial dose of deutetrabenazine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Dexbrompheniramine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Dexchlorpheniramine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Dexmedetomidine: (Moderate) Concomitant use of opioid agonists with dexmedetomidine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with dexmedetomidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Dexpanthenol: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.
Dextromethorphan; Bupropion: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with bupropion is necessary. If bupropion is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and bupropion is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Dextromethorphan; Quinidine: (Moderate) As quinidine is a potent inhibitor of CYP2D6 and tramadol is partially metabolized by CYP2D6, concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Diazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Dicyclomine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and dicyclomine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Difelikefalin: (Major) Avoid concomitant use of opioids and other CNS depressants, such as difelikefalin. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Diflunisal: (Moderate) Acetaminophen plasma concentrations can increase by approximately 50% following administration of diflunisal. Acetaminophen has no effect on diflunisal concentrations. Acetaminophen in high doses has been associated with severe hepatotoxic reactions; therefore, caution should be exercised when using these agents concomitantly.
Digoxin: (Moderate) An increased incidence of digoxin toxicity has been reported in some patients during postmarketing reports with the concurrent use of tramadol and digoxin.
Dimenhydrinate: (Moderate) Concomitant use of opioid agonists with dimenhydrinate may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dimenhydrinate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Diphenhydramine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Diphenhydramine; Ibuprofen: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Diphenhydramine; Naproxen: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Diphenhydramine; Phenylephrine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Diphenoxylate; Atropine: (Major) Reserve concomitant use of tramadol and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events.
Dolasetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering dolasetron with other drugs that have serotonergic properties such as tramadol. If serotonin syndrome is suspected, discontinue dolasetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Doxylamine: (Major) Reserve concomitant use of opioids and doxylamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Doxylamine; Pyridoxine: (Major) Reserve concomitant use of opioids and doxylamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Dronabinol: (Moderate) Concomitant use of opioid agonists with dronabinol may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dronabinol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Dronedarone: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP2D6 and CYP3A. Tramadol is a substrate for CYP2D6 and CYP3A4. The concomitant administration of dronedarone with CYP2D6 and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
Droperidol: (Major) Concomitant use of opioid agonists with droperidol may cause excessive sedation and somnolence. Limit the use of opioid pain medications with droperidol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Drospirenone; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Duloxetine: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with duloxetine is necessary. If duloxetine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and duloxetine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Efavirenz: (Moderate) The (+) enantiomer of tramadol preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. Efavirenz is an inducer of CYP3A4 and CYP2B6. Coadministration may affect the metabolism of tramadol leading to altered tramadol exposure. Decreased serum tramadol concentrations and reduced efficacy may occur. In addition, both medications have been associated with the development of seizures; caution is advised. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The (+) enantiomer of tramadol preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. Efavirenz is an inducer of CYP3A4 and CYP2B6. Coadministration may affect the metabolism of tramadol leading to altered tramadol exposure. Decreased serum tramadol concentrations and reduced efficacy may occur. In addition, both medications have been associated with the development of seizures; caution is advised. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) The (+) enantiomer of tramadol preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. Efavirenz is an inducer of CYP3A4 and CYP2B6. Coadministration may affect the metabolism of tramadol leading to altered tramadol exposure. Decreased serum tramadol concentrations and reduced efficacy may occur. In addition, both medications have been associated with the development of seizures; caution is advised. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Elagolix: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with elagolix is necessary; consider increasing the dose of tramadol as needed. If elagolix is discontinued, consider a dose reduction of tramadol and frequently monitor for signs or respiratory depression and sedation. Tramadol is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with elagolix is necessary; consider increasing the dose of tramadol as needed. If elagolix is discontinued, consider a dose reduction of tramadol and frequently monitor for signs or respiratory depression and sedation. Tramadol is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Elbasvir; Grazoprevir: (Moderate) Administering acetaminophen; tramadol with elbasvir; grazoprevir may result in elevated tramadol plasma concentrations. Tramadol is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eletriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tramadol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Elexacaftor; tezacaftor; ivacaftor: (Minor) Use caution when administering ivacaftor and tramadol concurrently. Ivacaftor is an inhibitor of CYP3A and tramadol is partially metabolized by CYP3A. Co-administration can theoretically increase tramadol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Eliglustat: (Moderate) Coadministration of tramadol and eliglustat may result in a reduction in the metabolic conversion and clearance of tramadol, increasing the risk for serious adverse events including seizures and serotonin syndrome. In addition, coadministration of tramadol and eliglustat may result in decreased analgesia. If coadministration is necessary, monitor patients closely for tramadol-related adverse effects and diminished analgesic efficacy. The analgesic activity of tramadol is due to both the parent drug and the pharmacologically active metabolite M1. Because the metabolism of tramadol to M1 is dependent on CYP2D6 and eliglustat is an inhibitor of CYP2D6, therapeutic response may be affected.
Eltrombopag: (Moderate) Eltrombopag is a UDP-glucuronyltransferase inhibitor. Acetaminophen is a substrate of UDP-glucuronyltransferases. The significance or effect of this interaction is not known; however, elevated concentrations of acetaminophen are possible. Monitor patients for adverse reactions if these drugs are coadministered.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Enzalutamide: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with enzalutamide is necessary; consider increasing the dose of tramadol as needed. If enzalutamide is discontinued, consider a dose reduction of tramadol and frequently monitor for signs or respiratory depression and sedation. Tramadol is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Erythromycin: (Moderate) Administration of CYP3A4 inhibitors such as erythromycin with tramadol may affect the metabolism of tramadol leading to altered tramadol exposure. Increased serum tramadol concentrations may occur.
Escitalopram: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with escitalopram is necessary. If escitalopram is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and escitalopram is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Esketamine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Estazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Eszopiclone: (Moderate) Concomitant use of opioid agonists with eszopiclone may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with eszopiclone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
Ethacrynic Acid: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and tramadol; increase the dosage of the loop diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking opioids. Alcohol consumption may result in additive CNS depression and may increase the risk for opioid overdose. Consider the patient's use of alcohol when prescribing opioid medications. If the patient is unlikely to be compliant with avoiding alcohol, consider prescribing naloxone especially if additional risk factors for opioid overdose are present. (Major) The risk of developing hepatotoxicity from acetaminophen appears to be increased in patients who regularly consume alcohol. Patients who drink more than 3 alcohol-containing drinks a day and take acetaminophen are at increased risk of developing hepatotoxicity. Acute or chronic alcohol use increases acetaminophen-induced hepatotoxicity by inducing CYP2E1 leading to increased formation of the hepatotoxic metabolite of acetaminophen. Also, chronic alcohol use can deplete liver glutathione stores. Administration of acetaminophen should be limited or avoided altogether in patients with alcoholism or patients who consume alcohol regularly.
Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethinyl Estradiol; Norelgestromin: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethinyl Estradiol; Norgestrel: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethiodized Oil: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Ethotoin: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with hydantoins is necessary; consider increasing the dose of tramadol as needed. If hydantoins are discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and hydantoins are strong CYP3A inducers. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Etonogestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Everolimus: (Moderate) Monitor for an increase in tramadol-related adverse reactions, including serotonin syndrome, seizures, sedation, and respiratory depression, if coadministration with everolimus is necessary; the risk is greatest if everolimus is added to a stable dose of tramadol. Consider decreasing the dose of tramadol if necessary. Everolimus is a weak CYP3A4 inhibitor as well as a CYP2D6 inhibitor. Tramadol is metabolized by both CYP3A4 and CYP2D6.
Exenatide: (Minor) Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
Fedratinib: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with fedratinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of fedratinib, a moderate CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Fenfluramine: (Moderate) Concomitant use of opioid agonists with fenfluramine may cause excessive sedation and somnolence. Limit the use of opioid agonists with fenfluramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Fentanyl: (Major) Concomitant use of tramadol with fentanyl may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Fesoterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fesoterodine, an anticholinergic drug for overactive bladder is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
Flavoxate: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and flavoxate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Flibanserin: (Moderate) Concomitant use of opioid agonists with flibanserin may cause excessive sedation and somnolence. Limit the use of opioid pain medication with flibanserin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Fluoxetine: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with fluoxetine is necessary. If fluoxetine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and fluoxetine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Fluphenazine: (Moderate) Concurrent use of tramadol and fluphenazine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that fluphenazine is a weak CYP2D6 inhibitor and has the potential to decrease the metabolism of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by fluphenazine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and fluphenazine.
Flurazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Fluvoxamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluvoxamine with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with an SSRI. The combination of SSRIs and tramadol has also been associated with an increased risk of seizures.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Fosamprenavir: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with fosamprenavir is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of fosamprenavir, a moderate CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Fosphenytoin: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with hydantoins is necessary; consider increasing the dose of tramadol as needed. If hydantoins are discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and hydantoins are strong CYP3A inducers. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Fostamatinib: (Moderate) Monitor for tramadol toxicities that may require tramadol dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a CYP3A4 substrate may increase the concentration of the CYP3A4 substrate. The active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; tramadol is a substrate for CYP3A4. Coadministration of fostamatinib with a sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%.
Frovatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tramadol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Furosemide: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and tramadol; increase the dosage of the loop diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Gabapentin: (Major) Concomitant use of opioid agonists with gabapentin may cause excessive sedation, somnolence, and respiratory depression. Limit the use of opioid pain medications with gabapentin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
General anesthetics: (Major) Concomitant use of tramadol with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Glycopyrrolate: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and glycopyrrolate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Glycopyrrolate; Formoterol: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and glycopyrrolate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Granisetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering granisetron with other drugs that have serotonergic properties such as tramadol. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of hydrocodone with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of hydrocodone with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Guanabenz: (Moderate) Guanabenz is associated with sedative effects. Guanabenz can potentiate the effects of CNS depressants such as opiate agonists, when administered concomitantly.
Guanfacine: (Moderate) Concomitant use of opioid agonists with guanfacine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with guanfacine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Haloperidol: (Major) Haloperidol can competitively inhibit the metabolism of tramadol by CYP2D6. Concurrent use of haloperidol and tramadol increases plasma levels of tramadol and decreases the concentration of the active tramadol metabolite. This may lead to decreased analgesic effects of tramadol and possibly increased tramadol-induced side effects, including seizures, due to increased tramadol concentrations and the decrease in seizure threshold caused by haloperidol. Additive CNS depression may also be seen with the concomitant use of tramadol and haloperidol.
Homatropine; Hydrocodone: (Major) Concomitant use of hydrocodone with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of hydrocodone with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and homatropine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Hydantoins: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with hydantoins is necessary; consider increasing the dose of tramadol as needed. If hydantoins are discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and hydantoins are strong CYP3A inducers. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Concomitant use of opioid agonists with methyldopa may cause excessive sedation and somnolence. Limit the use of opioid pain medication with methyldopa to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Hydrocodone: (Major) Concomitant use of hydrocodone with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of hydrocodone with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Hydrocodone; Ibuprofen: (Major) Concomitant use of hydrocodone with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of hydrocodone with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of hydrocodone with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Hydromorphone: (Major) Concomitant use of tramadol with hydromorphone may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Hydroxyzine: (Major) Concomitant use of opioid agonists with hydroxyzine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with hydroxyzine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Hyoscyamine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Contraindicated) Tramadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Ibuprofen; Oxycodone: (Major) Concomitant use of tramadol with oxycodone may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with tramadol, a CYP3A substrate, as tramadol toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Iloperidone: (Moderate) Coadministration should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and iloperidone.
Imatinib: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Moderate) Since tramadol is primarily metabolized by cytochrome P450 isoenzyme CYP2D6, agents that inhibit this enzyme, such as imatinib, decrease the metabolism of tramadol. Concomitant use of these agents and tramadol may increase plasma levels of tramadol and decrease concentration of the active metabolite leading to decreased analgesic effects and possibly increased side effects due to higher tramadol concentrations.
Indacaterol; Glycopyrrolate: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and glycopyrrolate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Indapamide: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when indapamide is administered with tramadol. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Insulin Glargine; Lixisenatide: (Minor) When 1,000 mg acetaminophen was given 1 or 4 hours after 10 mcg lixisenatide, the AUC was not significantly changed, but the acetaminophen Cmax was decreased by 29% and 31%, respectively and median Tmax was delayed by 2 and 1.75 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before lixisenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying) and the clinical impact has not been assessed. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least one hour prior to lixisenatide subcutaneous injection.
Iobenguane I 131: (Major) Discontinue tramadol for at least 5 half-lives before the administration of the dosimetry dose or a therapeutic dose of iobenguane I-131. Do not restart tramadol until at least 7 days after each iobenguane I-131 dose. Drugs that reduce catecholamine uptake or deplete catecholamine stores, such as tramadol, may interfere with iobenguane I-131 uptake into cells and interfere with dosimetry calculations resulting in altered iobenguane I-131 efficacy.
Iodixanol: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Iohexol: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Iomeprol: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Iopamidol: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Iopromide: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Ioversol: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with acetaminophen may result in increased serum concentrations of acetaminophen. Acetaminophen is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together. (Moderate) Concomitant use of isavuconazonium with tramadol may result in increased serum concentrations of tramadol. Tramadol is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Major) Use tramadol cautiously, if at all, in patients also receiving a MAOI or a drug with MAO-inhibiting activity such as isoniazid, INH. International recommendations contraindicate the concurrent use of tramadol and MAOIs or the use of tramadol within 14 days of discontinuing MAOI therapy. An increased risk of seizures and serotonin syndrome exists in patients receiving tramadol and MAOIs concurrently. Postmarketing reports of serotonin syndrome with use of tramadol and MAOIs and alpha-2-adrenergic blockers exist. If concomitant treatment of tramadol with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, especially during treatment initiation and dose increases.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Major) Use tramadol cautiously, if at all, in patients also receiving a MAOI or a drug with MAO-inhibiting activity such as isoniazid, INH. International recommendations contraindicate the concurrent use of tramadol and MAOIs or the use of tramadol within 14 days of discontinuing MAOI therapy. An increased risk of seizures and serotonin syndrome exists in patients receiving tramadol and MAOIs concurrently. Postmarketing reports of serotonin syndrome with use of tramadol and MAOIs and alpha-2-adrenergic blockers exist. If concomitant treatment of tramadol with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, especially during treatment initiation and dose increases. (Moderate) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents. (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with rifampin is necessary; consider increasing the dose of tramadol as needed. If rifampin is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Isoniazid, INH; Rifampin: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Major) Use tramadol cautiously, if at all, in patients also receiving a MAOI or a drug with MAO-inhibiting activity such as isoniazid, INH. International recommendations contraindicate the concurrent use of tramadol and MAOIs or the use of tramadol within 14 days of discontinuing MAOI therapy. An increased risk of seizures and serotonin syndrome exists in patients receiving tramadol and MAOIs concurrently. Postmarketing reports of serotonin syndrome with use of tramadol and MAOIs and alpha-2-adrenergic blockers exist. If concomitant treatment of tramadol with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, especially during treatment initiation and dose increases. (Moderate) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents. (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with rifampin is necessary; consider increasing the dose of tramadol as needed. If rifampin is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Isosulfan Blue: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Istradefylline: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with istradefylline 40 mg daily is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of istradefylline 40 mg daily, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Ivacaftor: (Minor) Use caution when administering ivacaftor and tramadol concurrently. Ivacaftor is an inhibitor of CYP3A and tramadol is partially metabolized by CYP3A. Co-administration can theoretically increase tramadol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Ketoconazole: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with ketoconazole is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of ketoconazole, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
Lamotrigine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Lanthanum Carbonate: (Minor) The manufacturer recommends that oral compounds known to interact with antacids, such as acetaminophen, should not be taken within 2 hours of dosing with lanthanum carbonate.
Lapatinib: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with lapatinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of lapatinib, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Larotrectinib: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with larotrectinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of larotrectinib, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Lasmiditan: (Moderate) Concomitant use of tramadol with lasmiditan may cause excessive sedation, somnolence, and serotonin syndrome. Limit the use of tramadol with lasmiditan to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
Lefamulin: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with oral lefamulin is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of oral lefamulin, a moderate CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. An interaction is not expected with intravenous lefamulin.
Lemborexant: (Moderate) Concomitant use of tramadol with lemborexant may cause excessive sedation and somnolence. Limit the use of tramadol with lemborexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Lenacapavir: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with lenacapavir is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of lenacapavir, a moderate CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Letermovir: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with letermovir is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of letermovir, a CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Levamlodipine: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with amlodipine is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of amlodipine, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Levocetirizine: (Major) Reserve concomitant use of opioids and cetirizine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Levoketoconazole: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with ketoconazole is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of ketoconazole, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Levomilnacipran: (Moderate) If concomitant use of tramadol and levomilnacipran is warranted, monitor patients for seizures and the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concomitant use of tramadol and levomilnacipran may increase seizure risk. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Levorphanol: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists; avoid concurrent use whenever possible. If used together, extreme caution is needed, and a reduced tramadol dose is recommended.
Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Epinephrine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Prilocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Linezolid: (Contraindicated) Tramadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Linezolid is a reversible, non-selective inhibitor of MAO. Concomitant use of tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol.
Lisdexamfetamine: (Moderate) If concomitant use of tramadol and lisdexamfetamine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Lithium: (Moderate) If concomitant use of tramadol and lithium is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Lixisenatide: (Minor) When 1,000 mg acetaminophen was given 1 or 4 hours after 10 mcg lixisenatide, the AUC was not significantly changed, but the acetaminophen Cmax was decreased by 29% and 31%, respectively and median Tmax was delayed by 2 and 1.75 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before lixisenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying) and the clinical impact has not been assessed. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least one hour prior to lixisenatide subcutaneous injection.
Lofexidine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tramadol. Lofexidine can potentiate the effects of CNS depressants.
Lomitapide: (Moderate) Caution should be exercised when lomitapide is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day PO for >= 3 days/week). The effect of concomitant administration of lomitapide with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
Lonafarnib: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with lonafarnib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of lonafarnib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Loop diuretics: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and tramadol; increase the dosage of the loop diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Lopinavir; Ritonavir: (Major) Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations. (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Lorazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Lorcaserin: (Moderate) Monitor patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome if coadministration with lorcaserin is necessary. If lorcaserin is discontinued, consider a tramadol dosage reduction until stable drug effects are achieved. Monitor patients closely for adverse events including respiratory depression and sedation. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concurrent use of lorcaserin, a CYP2D6 inhibitor, may increase tramadol exposure and decrease exposure to the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events.
Lorlatinib: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of tramadol as needed. If lorlatinib is discontinued, consider a dose reduction of tramadol and frequently monitor for signs or respiratory depression and sedation. Tramadol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Loxapine: (Moderate) Concomitant use of opioid agonists with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Also, concomitant use of tramadol increases the seizure risk in patients taking loxapine.
Lumacaftor; Ivacaftor: (Minor) Use caution when administering ivacaftor and tramadol concurrently. Ivacaftor is an inhibitor of CYP3A and tramadol is partially metabolized by CYP3A. Co-administration can theoretically increase tramadol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the analgesic effect of tramadol by decreasing its systemic exposure. If used together, monitor patients closely for loss of tramadol efficacy; a tramadol dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Tramadol preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2B6.
Lumateperone: (Moderate) Concomitant use of opioid agonists like tramadol with lumateperone may cause excessive sedation and somnolence. Limit the use of opioid pain medication with lumateperone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Also, concomitant use of tramadol increases the seizure risk in patients taking lumateperone.
Lurasidone: (Moderate) Concomitant use of opioid agonists like tramadol with lurasidone may cause excessive sedation and somnolence. Limit the use of opioid pain medication with lurasidone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Also, concomitant use of tramadol increases the seizure risk in patients taking lurasidone.
Maprotiline: (Major) Concomitant use of opioid agonists with maprotiline may cause excessive sedation and somnolence. Use of tramadol may also increase the risk of seizures in patients receiving other drugs associated with seizures such as maprotiline. Limit the use of opioid pain medications with maprotiline to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and seizures.
Maribavir: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with maribavir is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of maribavir, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Mavacamten: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with mavacamten is necessary; consider increasing the dose of tramadol as needed. If mavacamten is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and mavacamten is a moderate CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Melatonin: (Moderate) Concomitant use of opioid agonists with melatonin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with melatonin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Meperidine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists; avoid concurrent use whenever possible. If used together, extreme caution is needed, and a reduced tramadol dose is recommended.
Meperidine; Promethazine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists; avoid concurrent use whenever possible. If used together, extreme caution is needed, and a reduced tramadol dose is recommended. (Major) Reserve concomitant prescribing of tramadol and promethazine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, seizures, coma, and death.
Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Meprobamate: (Moderate) Tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants such as meprobamate. 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.
Metaxalone: (Major) Concomitant use of opioid agonists with metaxalone may cause respiratory depression, profound sedation, and death. Limit the use of opioid pain medication with metaxalone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use of metaxalone and opioid agonists increases the risk for serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary.
Methadone: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists; avoid concurrent use whenever possible. If used together, extreme caution is needed, and a reduced tramadol dose is recommended.
Methamphetamine: (Moderate) If concomitant use of tramadol and methamphetamine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Contraindicated) Tramadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Methocarbamol: (Major) Concomitant use of tramadol with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Methohexital: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Methscopolamine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and methscopolamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Methyclothiazide: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Methyldopa: (Moderate) Concomitant use of opioid agonists with methyldopa may cause excessive sedation and somnolence. Limit the use of opioid pain medication with methyldopa to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Methylene Blue: (Contraindicated) Tramadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol.
Methylphenidate Derivatives: (Moderate) Concurrent use of tramadol and methylphenidate derivatives might increase the risk for serotonin syndrome. If concomitant use is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are also postmarketing reports of serotonin syndrome during concurrent use of methylphenidate or methylphenidate derivatives with other serotonergic medications.
Metoclopramide: (Moderate) The effects of metoclopramide on gastrointestinal motility are antagonized by narcotic analgesics. Concomitant use of opioid agonists with metoclopramide may also cause excessive sedation and somnolence. Limit the use of opioid pain medications with metoclopramide to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Metolazone: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Metyrapone: (Major) Coadministration of metyrapone and acetaminophen may result in acetaminophen toxicity. Acetaminophen glucuronidation is inhibited by metyrapone. It may be advisable for patients to avoid acetaminophen while taking metyrapone.
Metyrosine: (Moderate) The concomitant administration of metyrosine with opiate agonists can result in additive sedative effects.
Midazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Milnacipran: (Moderate) If concomitant use of tramadol and milnacipran is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists. Caution should be exercised when using these agents concurrently.
Mipomersen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as tramadol may be increased when co-administered with mirabegron. Tramadol is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
Mirtazapine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Mitapivat: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with mitapivat is necessary; consider increasing the dose of tramadol as needed. If mitapivat is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and mitapivat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Mitotane: (Major) Use caution if mitotane and tramadol are used concomitantly, and monitor for decreased efficacy of tramadol and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer. The metabolism of tramadol is stereoselective; the (+) enantiomer preferentially undergoes N-demethylation, mediated by CYP3A4 and CYP2B6, and the (-) enantiomer undergoes O-demethylation via CYP2D6. O-demethylation leads to the production of the active metabolite M1, which is critical to tramadol activity. Because of the role of CYP3A4 in tramadol metabolism, coadministration with mitotane may affect patient response to tramadol. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
Mobocertinib: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with mobocertinib is necessary; consider increasing the dose of tramadol as needed. If mobocertinib is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and mobocertinib is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Molindone: (Major) Concomitant use of opioid agonists like tramadol with molindone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with molindone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also, concomitant use of tramadol increases the seizure risk in patients taking molindone.
Monoamine oxidase inhibitors: (Contraindicated) Tramadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use increases the risk for seizures, serotonin syndrome, and opioid toxicity, including respiratory depression.
Morphine: (Major) Concomitant use of morphine with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of morphine with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Morphine; Naltrexone: (Major) Concomitant use of morphine with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of morphine with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Nabilone: (Major) Avoid coadministration of opioid agonists with nabilone due to the risk of additive CNS depression.
Nalbuphine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as tramadol. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. There is also a potential increased risk of seizures if tramadol is given with other opiates.
Naratriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tramadol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Nefazodone: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with nefazodone is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concurrent use of nefazodone, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with opiate agonists.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) If concomitant use of tramadol and palonosetron is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Nevirapine: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with nevirapine is necessary; consider increasing the dose of tramadol as needed. If nevirapine is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and nevirapine is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Nilotinib: (Major) The concomitant use of nilotinib and tramadol may reduce the clearance of tramadol and increase the risk for serious adverse events including seizures and serotonin syndrome. If coadministration of these drugs is required, consider reducing the dose of tramadol and monitor patients for signs of toxicity. Nilotinib is a moderate CYP3A4 inhibitor and tramadol is a CYP3A4 substrate.
Nirmatrelvir; Ritonavir: (Major) Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations. (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Monitor for decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) when administering tramadol concurrently with ritonavir-boosted nirmatrelvir. Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir-boosted nirmatrelvir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) and increased concentrations of tramadol.
Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as opiate agonists. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with opiate agonists.
Non-Ionic Contrast Media: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Norethindrone; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Norgestimate; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Odevixibat: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of tramadol as needed. If odevixibat is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Olanzapine: (Moderate) If concomitant use of tramadol and olanzapine is warranted, monitor patients for seizures, excessive sedation and/or somnolence, and the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concomitant use of tramadol and olanzapine may increase seizure risk and cause additive CNS depression. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Olanzapine; Fluoxetine: (Moderate) If concomitant use of tramadol and olanzapine is warranted, monitor patients for seizures, excessive sedation and/or somnolence, and the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concomitant use of tramadol and olanzapine may increase seizure risk and cause additive CNS depression. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with fluoxetine is necessary. If fluoxetine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and fluoxetine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Olanzapine; Samidorphan: (Contraindicated) Salmidorphan is contraindicated in patients who are using opiate agonists or undergoing acute opioid withdrawal. Salmidorphan increases the risk of precipitating acute opioid withdrawal in patients dependent on opioids. Before initiating salmidorphan, there should be at least a 7-day opioid-free interval from the last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. In emergency situations, if a salmidorphan-treated patient requires opiates for anesthesia or analgesia, discontinue salmidorphan. The opiate agonist should be administered by properly trained individual(s), and the patient properly monitored in a setting equipped and staffed for cardiopulmonary resuscitation. In non-emergency situations, if a salmidorphan-treated patient requires opiate agonist treatment (e.g., for analgesia) discontinue salmidorphan at least 5 days before opioid treatment. Salmidorphan, as an opioid antagonist, may cause opioid treatment to be less effective or ineffective shortly after salmidorphan discontinuation. (Moderate) If concomitant use of tramadol and olanzapine is warranted, monitor patients for seizures, excessive sedation and/or somnolence, and the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concomitant use of tramadol and olanzapine may increase seizure risk and cause additive CNS depression. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Oliceridine: (Major) Concomitant use of oliceridine with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of oliceridine with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with amlodipine is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of amlodipine, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Olutasidenib: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with olutasidenib is necessary; consider increasing the dose of tramadol as needed. If olutasidenib is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and olutasidenib is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Omaveloxolone: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with omaveloxolone is necessary; consider increasing the dose of tramadol as needed. If omaveloxolone is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and omaveloxolone is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ombitasvir; Paritaprevir; Ritonavir: (Major) Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations. (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Omeprazole; Sodium Bicarbonate: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
Ondansetron: (Moderate) Monitor for opioid withdrawal and for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant ondansetron and tramadol use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome. Also, data from 2 small trials indicate that concomitant use of ondansetron may result in reduced analgesic activity of tramadol; patients receiving ondansetron used tramadol more frequently leading to an increased cumulative dose in patient-controlled administration of tramadol.
Oritavancin: (Moderate) Tramadol is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of tramadol may be reduced if these drugs are administered concurrently.
Orphenadrine: (Major) Concomitant use of tramadol with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Osilodrostat: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with osilodrostat is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of osilodrostat, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Oxazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Oxybutynin: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and oxybutynin use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Oxycodone: (Major) Concomitant use of tramadol with oxycodone may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Oxymorphone: (Major) Concomitant use of tramadol with oxymorphone may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Ozanimod: (Contraindicated) Do not use tramadol in patients taking MAOIs or within 14 days of stopping them. An active metabolite of ozanimod inhibits MAO-B. MAO inhibitor interactions with tramadol may manifest as serotonin syndrome, hypertensive crisis, or opioid toxicity (e.g., respiratory depression, coma). An active metabolite of ozanimod inhibits MAO-B. Although a small number of patients treated with ozanimod were concomitantly exposed to opioids, this exposure was not adequate to rule out the possibility of an adverse reaction from coadministration.
Pacritinib: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with pacritinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of pacritinib, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Palbociclib: (Moderate) If coadministration of palbociclib is necessary, monitor for increased tramadol-related adverse effects (e.g., seizures, serotonin syndrome and opioid toxicity including potentially fatal respiratory depression). Consider a tramadol dose reduction until stable drug effects are achieved. If palbociclib is discontinued, monitor for opioid withdrawal symptoms and consider increasing the tramadol dose. Coadministration of palbociclib, a weak time-dependent CYP3A4 inhibitor, may increase tramadol plasma concentrations and may result in increased metabolism of tramadol through 2D6 resulting in higher levels of the active metabolite, M1.
Paliperidone: (Moderate) Concurrent use of tramadol and paliperidone should be administered with caution. Antipsychotics, such as paliperidone, may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and paliperidone.
Palonosetron: (Moderate) If concomitant use of tramadol and palonosetron is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Panobinostat: (Major) Avoid the concomitant use of panobinostat and tramadol as increased tramadol levels and an increased risk of adverse effects may occur if these agents are used together. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tramadol toxicity including seizures and serotonin syndrome. Panobinostat is a CYP2D6 inhibitor and tramadol is primarily metabolized by CYP2D6. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Paroxetine: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with paroxetine is necessary. If paroxetine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and paroxetine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and tramadol, a CYP3A4 substrate, may cause an increase in systemic concentrations of tramadol. Use caution when administering these drugs concomitantly.
Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to tramadol if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while tramadol is a CYP2D6 substrate.
Pegvisomant: (Moderate) In clinical trials, patients taking opiate agonists often required higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opiate agonists. The mechanism of this interaction is unknown.
Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Pentazocine: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as tramadol. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. There is also a potential increased risk of seizures if tramadol and pentazocine are given concurrently. Concurrent use of pentazocine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
Pentazocine; Naloxone: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as tramadol. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. There is also a potential increased risk of seizures if tramadol and pentazocine are given concurrently. Concurrent use of pentazocine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
Pentobarbital: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Perampanel: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Perindopril; Amlodipine: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with amlodipine is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of amlodipine, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Perphenazine: (Major) Seizures have been reported in patients receiving monotherapy with tramadol or antipsychotics at recommended doses. Concomitant use of tramadol and antipsychotics may increase the risk of seizures and result in other additive CNS effects. The manufacturer of tramadol cautions that serotonin syndrome may occur during use of drugs that impair the metabolism of tramadol such as CYP2D6 inhibitors, including antipsychotics like perphenazine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6 inhibitor may in theory also decrease tramadol efficacy.
Perphenazine; Amitriptyline: (Major) Seizures have been reported in patients receiving monotherapy with tramadol or antipsychotics at recommended doses. Concomitant use of tramadol and antipsychotics may increase the risk of seizures and result in other additive CNS effects. The manufacturer of tramadol cautions that serotonin syndrome may occur during use of drugs that impair the metabolism of tramadol such as CYP2D6 inhibitors, including antipsychotics like perphenazine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6 inhibitor may in theory also decrease tramadol efficacy.
Pexidartinib: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with pexidartinib is necessary; consider increasing the dose of tramadol as needed. If pexidartinib is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Phenobarbital: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Major) Reserve concomitant use of tramadol and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Major) Reserve concomitant use of tramadol and scopolamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Phentermine; Topiramate: (Moderate) Reserve concomitant prescribing of opioids and other CNS depressants, such as topiramate, for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Phenytoin: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with hydantoins is necessary; consider increasing the dose of tramadol as needed. If hydantoins are discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and hydantoins are strong CYP3A inducers. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Pimozide: (Major) Concurrent use of tramadol and pimozide should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and pimozide.
Pirtobrutinib: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with pirtobrutinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of pirtobrutinib, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Pneumococcal Vaccine, Polyvalent: (Moderate) Concomitant administration of antipyretics, such as acetaminophen, may decrease an individual's immunological response to the pneumococcal vaccine. A post-marketing study conducted in Poland using a non-US vaccination schedule (2, 3, 4, and 12 months of age) evaluated the impact of prophylactic oral acetaminophen on antibody responses to Prevnar 13. Data show that acetaminophen, given at the time of vaccination and then dosed at 6 to 8 hour intervals for 3 doses on a scheduled basis, reduced the antibody response to some serotypes after the third dose of Prevnar 13 when compared to the antibody responses of infants who only received antipyretics 'as needed' for treatment. However, reduced antibody responses were not observed after the fourth dose of Prevnar 13 with prophylactic acetaminophen.
Posaconazole: (Major) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with posaconazole is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of posaconazole, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. (Moderate) Posaconazole and acetaminophen should be coadministered with caution due to an increased potential for acetaminophen-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of acetaminophen. These drugs used in combination may result in elevated acetaminophen plasma concentrations, causing an increased risk for acetaminophen-related adverse events.
Pramipexole: (Major) Concomitant use of opioid agonists with pramipexole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pramipexole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents like pramipexole have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Pramlintide: (Major) Pramlintide slows gastric emptying and the rate of nutrient delivery to the small intestine. Medications with the potential to slow GI motility, such as opiate agonists, should be used with caution, if at all, with pramlintide until more data are available from the manufacturer. Monitor blood glucose. (Minor) Because pramlintide has the potential to delay the absorption of concomitantly administered medications, medications should be administered at least 1 hour before or 2 hours after pramlintide injection when the rapid onset of a concomitantly administered oral medication is a critical determinant of effectiveness (i.e., analgesics).
Prasugrel: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Pregabalin: (Major) Concomitant use of opioid agonists with pregabalin may cause excessive sedation, somnolence, and respiratory depression. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Primidone: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Procarbazine: (Major) Avoid use of tramadol concurrently or within 14 days of discontinuing a drug with monamine oxidase inhibitor (MAOI)-like activity, such as procarbazine. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during treatment initiation and dose increases. International recommendations contraindicate the use of tramadol within 14 days of an MAOI. There is an increased risk of seizures and serotonin syndrome in patients receiving these drugs currently. In animal studies, an increased number of deaths was noted with the combination due to interference with detoxification mechanisms.
Prochlorperazine: (Moderate) Concurrent use of tramadol and prochlorperazine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and prochlorperazine.
Promethazine: (Major) Reserve concomitant prescribing of tramadol and promethazine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, seizures, coma, and death.
Promethazine; Dextromethorphan: (Major) Reserve concomitant prescribing of tramadol and promethazine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, seizures, coma, and death.
Promethazine; Phenylephrine: (Major) Reserve concomitant prescribing of tramadol and promethazine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, seizures, coma, and death.
Propafenone: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with propafenone is necessary. If propafenone is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and propafenone is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Propantheline: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant tramadol and propantheline use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Pseudoephedrine; Triprolidine: (Moderate) Concomitant use of opioid agonists with triprolidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with triprolidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Quazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Quetiapine: (Moderate) If concomitant use of tramadol and quetiapine is warranted, monitor patients for seizures, excessive sedation and/or somnolence, and the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concomitant use of tramadol and quetiapine may increase seizure risk and cause additive CNS depression. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and tramadol; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Quinidine: (Moderate) As quinidine is a potent inhibitor of CYP2D6 and tramadol is partially metabolized by CYP2D6, concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Quinine: (Moderate) Quinine inhibits CYP2D6 and may theoretically increase concentrations of other drugs metabolized by this enzyme including tramadol.
Ramelteon: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Ranolazine: (Moderate) As ranolazine is a weak to moderate CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Rasagiline: (Contraindicated) Rasagiline is contraindicated for use with tramadol due to the risk of serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least 14 days should elapse between the discontinuation of rasagiline and the initiation of tramadol.
Remifentanil: (Major) Concomitant use of tramadol and remifentanil increases the risk of adverse effects including seizures, serotonin syndrome, and additive opioid toxicity. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected or significant adverse events occur.
Remimazolam: (Major) Concomitant use of opioid agonists with remimazolam may cause respiratory depression, hypotension, profound sedation, and death. Titrate the dose of remimazolam to the desired clinical response and continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation.
Ribociclib: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with ribociclib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of ribociclib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Ribociclib; Letrozole: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with ribociclib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of ribociclib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Rifabutin: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Rifampin: (Moderate) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents. (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with rifampin is necessary; consider increasing the dose of tramadol as needed. If rifampin is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Rifapentine: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with rifapentine is necessary; consider increasing the dose of tramadol as needed. If rifapentine is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Risperidone: (Major) Concurrent use of tramadol and risperidone should be avoided if possible due to a possible increased risk of seizures. Seizures have been reported in patients receiving monotherapy with tramadol or antipsychotics at recommended doses. In addition, due to the primary CNS effects of risperidone, caution should be used when risperidone is given in combination with other centrally-acting medications such as tramadol.
Ritonavir: (Major) Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations. (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Rizatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tramadol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Rolapitant: (Major) Use caution if tramadol and rolapitant are used concurrently, and monitor for tramadol-related adverse effects as well as possible changes to the efficacy of tramadol. Rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6; therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 is expected to result in reduced metabolic clearance of tramadol, which in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures; serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Ropinirole: (Major) Concomitant use of opioid agonists with ropinirole may cause excessive sedation and somnolence. Limit the use of opioid pain medication with ropinirole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Rotigotine: (Major) Concomitant use of opioid agonists with rotigotine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with rotigotine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents like rotigotine have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Rucaparib: (Moderate) Monitor for an increase in tramadol-related adverse reactions, including serotonin syndrome, seizures, sedation, and respiratory depression, if coadministration with rucaparib is necessary; the risk is greatest if rucaparib is added to a stable dose of tramadol. Consider decreasing the dose of tramadol if necessary. Rucaparib is a weak CYP3A4 inhibitor and tramadol is metabolized by both CYP3A4 and CYP2D6. Coadministration with a CYP3A4 inhibitor may result in a greater amount of tramadol metabolism via CYP2D6, and greater levels of the active metabolite, M1.
Safinamide: (Contraindicated) Concomitant use of safinamide with opioids is contraindicated due to the risk of serotonin syndrome. Allow at least 14 days between discontinuation of safinamide and initiation of treatment with opioids.
Scopolamine: (Major) Reserve concomitant use of tramadol and scopolamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Secobarbital: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Selegiline: (Contraindicated) Tramadol use is contraindicated in patients who are receiving or who have received selegiline within the previous 14 days. Concomitant use increases the risk for seizures, serotonin syndrome, and opioid toxicity, including respiratory depression.
Selpercatinib: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with selpercatinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of selpercatinib, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Serotonin-Receptor Agonists: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tramadol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Sertraline: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with sertraline is necessary. If sertraline is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and sertraline is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence