tramadol (Rx)

Pain

Indicated for moderate-to-severe pain management in adults which alternative therapies are inadequate

Initiate dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse

Immediate release

• Chronic: 25 mg PO every morning initially; increased by 25-50 mg/day every 3 days up to 50-100 mg PO q4-6hr PRN; not to exceed 400 mg/day
• Acute: 50-100 mg PO q4-6hr PRN; not to exceed 400 mg/day

Extended release

• 100 mg PO once daily initially; increased by 100 mg/day every 5 days; not to exceed 300 mg/day

• Conversion from immediate release to extended release

  • Round total daily dose down to nearest 100 mg; titrate subsequent dose base on individual need

Oral solution

• 25 mg/day PO initially; may titrate in 25-mg increments as separate doses every 3 days to 100 mg/day (25 mg QID), THEN
• May increase total daily dose by 50-mg increments as tolerated every 3 days to 200 mg/day (50 mg QID)
• After titration, 50-100 mg q4-6 hr PRN for pain relief, not to exceed 400 mg/day
• For rapid onset of analgesic effect and benefits outweigh risks of discontinuation due to adverse events associated with high initial doses: 50-100 mg q4-6 hr PRN for pain relief, not to exceed 400 mg/day

Dosage Modifications

Renal impairment

• CrCl ≥30 mL/minute: No dosage adjustments necessary; use with caution

• Severe (CrCl <30 mL/min)

  • Oral solution: Increase dosing interval to q12hr, not to exceed 200 mg/day
  • Immediate release: 50-100 mg PO q12hr
  • Extended release: Not recommended

• Patients on dialysis

  • May receive regular dose on dialysis days; only 7% of dose is removed by hemodialysis

Hepatic impairment

• Mild-to-moderate: No dosage adjustments necessary; use with caution

• Severe

  • Oral solution and immediate release: 50 mg PO q12hr
  • Extended release: Not recommended

Dosing Considerations

Closely monitor for respiratory depression, especially within the first 24–72 hr of initiating therapy and following dosage increases and adjust dosage accordingly

Do not use concomitantly with other tramadol-containing products

Access to naloxone for opioid overdose

• Assess need for naloxone upon initiating and renewing treatment

• Consider prescribing naloxone

  • Based on patient’s risk factors for overdose (eg, concomitant use of CNS depressants, a history of opioid use disorder, prior opioid overdose); presence of risk factors should not prevent proper pain management
  • Household members (including children) or other close contacts at risk for accidental ingestion or overdose

• Consult patients and caregivers on the following:

  • Availability of naloxone for emergency treatment of opioid overdose
  • Ways to obtain naloxone as permitted by individual state dispensing and prescribing requirements or guidelines (eg, by prescription, directly from a pharmacist, as part of a community-based program)

Discontinuation

• Do not abruptly discontinue in patients who may be physically dependent on opioids
• Rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide
• For physically opioid-dependent: Initiate small increment taper (eg, ≥10-25% of total daily dose) to avoid withdrawal symptoms, and proceed with decreasing the dose every 2-4 weeks
• Patients who have been taking opioids for shorter periods of time may tolerate a more rapid taper

Limitations of use

• Owing to risks of addiction, abuse, and misuse with opioids, reserve use in patients for whom alternative treatment options [eg, non-opioid analgesics]

  • Are not or not expected to be tolerated
  • Have not or are not expected to provide adequate analgesia

HIV-Associated Neuropathy (Orphan)

Orphan indication sponsor

• TheraQuest Biosciences, LLC, 146 Medinah Drive, Blue Bell, PA 19422-3212

Postherpetic Neuralgia (Orphan)

Orphan indication sponsor

• TheraQuest Biosciences, LLC, 146 Medinah Drive, Blue Bell, PA 19422-3212

Safety and efficacy not established

Life-threatening respiratory depression and death have occurred in children who received tramadol

Tramadol is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to increased exposure to an active metabolite

Pain

>65 years: Initiate at lower end of dosing range; not to exceed 300 mg/day if >75 years

>75 years

• Immediate release or oral solution: Not to exceed 300 mg/day
• Extended release: Use with caution

Dosage Modifications

Renal impairment

• CrCl ≥30 mL/minute: No dosage adjustments necessary; use with caution

• Severe (CrCl <30 mL/min)

  • Oral solution: Increase dosing interval to q12hr, not to exceed 200 mg/day
  • Immediate release: 50-100 mg PO q12hr
  • Extended release: Not recommended

• Patients on dialysis

  • May receive regular dose on dialysis days; only 7% of dose is removed by hemodialysis

Hepatic impairment

• Mild-to-moderate: No dosage adjustments necessary; use with caution

• Severe

  • Oral solution and immediate release: 50 mg PO q12hr
  • Extended release: Not recommended

Contraindicated (5)

• alvimopan

  alvimopan, tramadol. receptor binding competition. Contraindicated. Alvimopan is contraindicated in opioid tolerant patients (ie, those who have taken therapeutic doses of opioids for >7 consecutive days immediately prior to taking alvimopan). Patients recently exposed to opioids are expected to be more sensitive to the effects of alvimopan and therefore may experience abdominal pain, nausea and vomiting, and diarrhea. No significant interaction is expected with concurrent use of opioid analgesics and alvimopan in patients who received opioid analgesics for 7 or fewer consecutive days prior to alvimopan.

• procarbazine

  procarbazine and tramadol both increase serotonin levels. Contraindicated.

• rasagiline

  rasagiline and tramadol both increase serotonin levels. Contraindicated.

• safinamide

  tramadol, safinamide. Either increases toxicity of the other by serotonin levels. Contraindicated. Concomitant use could result in life-threatening serotonin syndrome.

• selegiline

  selegiline and tramadol both increase serotonin levels. Contraindicated. At least 14 days should elapse between discontinuation of selegiline and initiation of analgesic.

Serious - Use Alternative (74)

• abametapir

  abametapir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.

• acrivastine

  acrivastine and tramadol both increase sedation. Avoid or Use Alternate Drug.

• alfentanil

  tramadol, alfentanil. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• amisulpride

  amisulpride and tramadol both increase sedation. Avoid or Use Alternate Drug.

• apalutamide

  apalutamide will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.

• asenapine transdermal

  asenapine transdermal and tramadol both increase sedation. Avoid or Use Alternate Drug.

• belladonna and opium

  tramadol, belladonna and opium. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• benzhydrocodone/acetaminophen

  benzhydrocodone/acetaminophen, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.
  
  benzhydrocodone/acetaminophen and tramadol both increase sedation. Avoid or Use Alternate Drug.

• bremelanotide

  bremelanotide will decrease the level or effect of tramadol by Other (see comment). Avoid or Use Alternate Drug. Bremelanotide may slow gastric emptying and potentially reduces the rate and extent of absorption of concomitantly administered oral medications. Avoid use when taking any oral drug that is dependent on threshold concentrations for efficacy. Interactions listed are representative examples and do not include all possible clinical examples.

• buprenorphine

  tramadol, buprenorphine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.
  
  buprenorphine, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• buprenorphine buccal

  buprenorphine buccal, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.
  
  tramadol, buprenorphine buccal. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• buprenorphine subdermal implant

  buprenorphine subdermal implant and tramadol both increase sedation. Avoid or Use Alternate Drug.

• butorphanol

  tramadol, butorphanol. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.
  
  butorphanol, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• calcium/magnesium/potassium/sodium oxybates

  tramadol, calcium/magnesium/potassium/sodium oxybates. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• clonidine

  clonidine, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration enhances CNS depressant effects.

• codeine

  tramadol, codeine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• cyclobenzaprine

  tramadol and cyclobenzaprine both increase serotonin levels. Avoid or Use Alternate Drug.

• dacomitinib

  dacomitinib will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug. Avoid use with CYP2D6 substrates where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities.

• desvenlafaxine

  tramadol and desvenlafaxine both increase serotonin levels. Avoid or Use Alternate Drug.

• dextromoramide

  tramadol, dextromoramide. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• diamorphine

  tramadol, diamorphine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• diazepam intranasal

  diazepam intranasal, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• difenoxin hcl

  tramadol, difenoxin hcl. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• diphenoxylate hcl

  tramadol, diphenoxylate hcl. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• dipipanone

  tramadol, dipipanone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• duloxetine

  duloxetine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug.

• eluxadoline

  tramadol, eluxadoline. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid coadministration with other drugs that cause constipation. Increases risk for constipation related serious adverse reactions. .

• fentanyl

  fentanyl, tramadol. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

• fentanyl intranasal

  fentanyl intranasal, tramadol. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

• fentanyl transdermal

  fentanyl transdermal, tramadol. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

• fentanyl transmucosal

  fentanyl transmucosal, tramadol. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

• fexinidazole

  fexinidazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.

• givosiran

  givosiran will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP2D6 substrates with givosiran. If unavoidable, decrease the CYP2D6 substrate dosage in accordance with approved product labeling.

• hydrocodone

  tramadol, hydrocodone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.
  
  hydrocodone, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• hydromorphone

  tramadol, hydromorphone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• idelalisib

  idelalisib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates

• iobenguane I 131

  tramadol will decrease the level or effect of iobenguane I 131 by Other (see comment). Avoid or Use Alternate Drug. Based on the mechanism of action of iobenguane, drugs that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells, and thus, reduce iobenguane efficacy. Discontinue interfering drugs for at least 5 half-lives before administration of either the dosimetry or an iobenguane dose. Do not administer these drugs until at least 7 days after each iobenguane dose.

• isocarboxazid

  isocarboxazid and tramadol both increase serotonin levels. Avoid or Use Alternate Drug.
  
  isocarboxazid increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• ivosidenib

  ivosidenib will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternative therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

• levorphanol

  tramadol, levorphanol. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• linezolid

  linezolid and tramadol both increase serotonin levels. Avoid or Use Alternate Drug. Linezolid may increase serotonin as a result of MAO-A inhibition. If linezolid must be administered, discontinue serotonergic drug immediately and monitor for CNS toxicity. Serotonergic therapy may be resumed 24 hours after last linezolid dose or after 2 weeks of monitoring, whichever comes first.
  
  linezolid increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• lonafarnib

  lonafarnib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration with sensitive CYP3A substrates. If coadministration unavoidable, monitor for adverse reactions and reduce CYP3A substrate dose in accordance with product labeling.

• lorcaserin

  tramadol and lorcaserin both increase serotonin levels. Avoid or Use Alternate Drug.

• meperidine

  tramadol, meperidine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• methadone

  tramadol, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• methylene blue

  methylene blue and tramadol both increase serotonin levels. Avoid or Use Alternate Drug. Methylene blue may increase serotonin as a result of MAO-A inhibition. If methylene blue must be administered, discontinue serotonergic drug immediately and monitor for CNS toxicity. Serotonergic therapy may be resumed 24 hours after last methylene blue dose or after 2 weeks of monitoring, whichever comes first.

• metoclopramide intranasal

  tramadol, metoclopramide intranasal. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid use of metoclopramide intranasal or interacting drug, depending on importance of drug to patient.

• morphine

  tramadol, morphine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• nalbuphine

  tramadol, nalbuphine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.
  
  nalbuphine, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• olopatadine intranasal

  tramadol and olopatadine intranasal both increase sedation. Avoid or Use Alternate Drug. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.

• opium tincture

  tramadol, opium tincture. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• oxycodone

  tramadol, oxycodone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• oxymorphone

  tramadol, oxymorphone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• ozanimod

  ozanimod increases toxicity of tramadol by sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Avoid or Use Alternate Drug. Because the active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for serious adverse reactions, including hypertensive crisis. Therefore, coadministration of ozanimod with drugs that can increase norepinephrine or serotonin is not recommended. Monitor for hypertension with concomitant use.

• papaveretum

  tramadol, papaveretum. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• pentazocine

  tramadol, pentazocine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.
  
  pentazocine, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• phenelzine

  phenelzine and tramadol both increase serotonin levels. Avoid or Use Alternate Drug.
  
  phenelzine increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• posaconazole

  posaconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• procarbazine

  procarbazine increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. MAOIs may potentiate CNS depression and hypotension. Do not use within 14 days of MAOI use. .

• ribociclib

  ribociclib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• secobarbital

  secobarbital will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. May also enhance CNS depressant effect of tramadol

• selegiline transdermal

  selegiline transdermal increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death.

• selinexor

  selinexor, tramadol. unspecified interaction mechanism. Avoid or Use Alternate Drug. Patients treated with selinexor may experience neurological toxicities. Avoid taking selinexor with other medications that may cause dizziness or confusion.

• sodium oxybate

  tramadol, sodium oxybate. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• sufentanil

  tramadol, sufentanil. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• sufentanil SL

  sufentanil SL, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration may result in hypotension, profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• tapentadol

  tramadol, tapentadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• tedizolid

  tedizolid, tramadol. Either increases levels of the other by Mechanism: pharmacodynamic synergism. Avoid or Use Alternate Drug. both increase serotonin levels; increased risk of serotonin syndrome.

• tranylcypromine

  tranylcypromine and tramadol both increase serotonin levels. Avoid or Use Alternate Drug.
  
  tranylcypromine increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• tucatinib

  tucatinib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.

• valerian

  valerian and tramadol both increase sedation. Avoid or Use Alternate Drug.

• vilazodone

  tramadol, vilazodone. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug. Concomitant therapy should be discontinued immediately if signs or symptoms of serotonin syndrome emerge and supportive symptomatic treatment should be initiated.

• vortioxetine

  tramadol, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.

• voxelotor

  voxelotor will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.

Monitor Closely (297)

• 5-HTP

  5-HTP and tramadol both increase serotonin levels. Use Caution/Monitor.

• abiraterone

  abiraterone increases levels of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Avoid coadministration of abiraterone with substrates of CYP2D6. If alternative therapy cannot be used, exercise caution and consider increasing tramadol dose if clinically appropriate; if abiraterone is discontinued, consider reducing tramadol dose and frequently monitor for signs of respiratory depression and sedation.

• albuterol

  tramadol increases and albuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• alfentanil

  alfentanil and tramadol both increase sedation. Use Caution/Monitor.

• almotriptan

  almotriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• alprazolam

  alprazolam and tramadol both increase sedation. Use Caution/Monitor.

• amifampridine

  tramadol increases toxicity of amifampridine by Other (see comment). Modify Therapy/Monitor Closely. Comment: Amifampridine can cause seizures. Coadministration with drugs that lower seizure threshold may increase this risk.

• amiodarone

  amiodarone decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  amiodarone decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• amitriptyline

  tramadol and amitriptyline both increase sedation. Use Caution/Monitor.
  
  amitriptyline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• amobarbital

  amobarbital and tramadol both increase sedation. Use Caution/Monitor.

• amoxapine

  tramadol and amoxapine both increase sedation. Use Caution/Monitor.
  
  amoxapine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• apomorphine

  tramadol and apomorphine both increase sedation. Use Caution/Monitor.

• arformoterol

  tramadol increases and arformoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• aripiprazole

  tramadol and aripiprazole both increase sedation. Use Caution/Monitor.

• armodafinil

  tramadol increases and armodafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• artemether/lumefantrine

  artemether/lumefantrine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

• asenapine

  asenapine and tramadol both increase sedation. Use Caution/Monitor.

• atazanavir

  atazanavir increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity. .

• avapritinib

  avapritinib and tramadol both increase sedation. Use Caution/Monitor.

• azelastine

  azelastine and tramadol both increase sedation. Use Caution/Monitor.

• baclofen

  baclofen and tramadol both increase sedation. Use Caution/Monitor.

• belladonna and opium

  belladonna and opium and tramadol both increase sedation. Use Caution/Monitor.

• benperidol

  tramadol and benperidol both increase sedation. Use Caution/Monitor.

• benzphetamine

  tramadol increases and benzphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• bosentan

  bosentan will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• brexanolone

  brexanolone, tramadol. Either increases toxicity of the other by sedation. Use Caution/Monitor.

• brexpiprazole

  brexpiprazole and tramadol both increase sedation. Use Caution/Monitor.

• brimonidine

  brimonidine and tramadol both increase sedation. Use Caution/Monitor.

• brivaracetam

  brivaracetam and tramadol both increase sedation. Use Caution/Monitor.

• brompheniramine

  brompheniramine and tramadol both increase sedation. Use Caution/Monitor.

• buprenorphine

  buprenorphine and tramadol both increase sedation. Use Caution/Monitor.

• buprenorphine buccal

  buprenorphine buccal and tramadol both increase sedation. Use Caution/Monitor.

• buprenorphine, long-acting injection

  tramadol increases toxicity of buprenorphine, long-acting injection by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of buprenorphine and benzodiazepines or other CNS depressants increases risk of adverse reactions including overdose, respiratory depression, and death. Cessation of benzodiazepines or other CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering CNS depressants may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

• bupropion

  bupropion will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

• buspirone

  buspirone and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• butabarbital

  butabarbital and tramadol both increase sedation. Use Caution/Monitor.

• butalbital

  butalbital and tramadol both increase sedation. Use Caution/Monitor.

• butorphanol

  butorphanol and tramadol both increase sedation. Use Caution/Monitor.

• caffeine

  tramadol increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• carbamazepine

  carbamazepine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• carbinoxamine

  carbinoxamine and tramadol both increase sedation. Use Caution/Monitor.

• carisoprodol

  carisoprodol and tramadol both increase sedation. Use Caution/Monitor.

• celecoxib

  celecoxib decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  celecoxib decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• cenobamate

  cenobamate, tramadol. Either increases effects of the other by sedation. Use Caution/Monitor.

• ceritinib

  ceritinib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• chloral hydrate

  chloral hydrate and tramadol both increase sedation. Use Caution/Monitor.

• chlordiazepoxide

  chlordiazepoxide and tramadol both increase sedation. Use Caution/Monitor.

• chloroquine

  chloroquine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  chloroquine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• chlorpheniramine

  chlorpheniramine and tramadol both increase sedation. Use Caution/Monitor.

• chlorpromazine

  tramadol and chlorpromazine both increase sedation. Use Caution/Monitor.

• chlorzoxazone

  chlorzoxazone and tramadol both increase sedation. Use Caution/Monitor.

• cimetidine

  cimetidine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  cimetidine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• cinnarizine

  cinnarizine and tramadol both increase sedation. Use Caution/Monitor.

• citalopram

  citalopram and tramadol both increase serotonin levels. Use Caution/Monitor. Combination may increase risk of serotonin syndrome or neuroleptic malignant syndrome-like reactions.

• clarithromycin

  clarithromycin will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• clemastine

  clemastine and tramadol both increase sedation. Use Caution/Monitor.

• clobazam

  clobazam will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Lower doses of drugs metabolized by CYP2D6 may be required when used concomitantly.
  
  tramadol, clobazam. Other (see comment). Use Caution/Monitor. Comment: Concomitant administration can increase the potential for CNS effects (e.g., increased sedation or respiratory depression).

• clomipramine

  tramadol and clomipramine both increase sedation. Use Caution/Monitor.
  
  clomipramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• clonazepam

  clonazepam and tramadol both increase sedation. Use Caution/Monitor.

• clorazepate

  clorazepate and tramadol both increase sedation. Use Caution/Monitor.

• clozapine

  tramadol and clozapine both increase sedation. Use Caution/Monitor.

• cobicistat

  cobicistat will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. A decreased dose of tramadol may be required
  
  cobicistat will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. A decreased dose of tramadol may be required

• cocaine topical

  cocaine topical and tramadol both increase serotonin levels. Use Caution/Monitor.

• codeine

  codeine and tramadol both increase sedation. Use Caution/Monitor.

• crizotinib

  crizotinib increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A.

• crofelemer

  crofelemer increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Crofelemer has the potential to inhibit CYP3A4 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed.

• cyclizine

  cyclizine and tramadol both increase sedation. Use Caution/Monitor.

• cyclobenzaprine

  cyclobenzaprine and tramadol both increase sedation. Use Caution/Monitor.

• cyproheptadine

  cyproheptadine and tramadol both increase sedation. Use Caution/Monitor.

• dabrafenib

  dabrafenib will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• dantrolene

  dantrolene and tramadol both increase sedation. Use Caution/Monitor.

• daridorexant

  tramadol and daridorexant both increase sedation. Modify Therapy/Monitor Closely. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.

• darunavir

  darunavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. A decreased dose of tramadol may be required

• desflurane

  desflurane and tramadol both increase sedation. Use Caution/Monitor. Opioids may decrease MAC requirements, less inhalation anesthetic may be required.

• desipramine

  tramadol and desipramine both increase sedation. Use Caution/Monitor.
  
  desipramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• desvenlafaxine

  desvenlafaxine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Desvenlafaxine inhibits CYP2D6; with higher desvenlafaxine doses (ie, 400 mg) decrease the CYP2D6 substrate dose by up to 50%; no dosage adjustment needed with desvenlafaxine doses <100 mg

• deutetrabenazine

  tramadol and deutetrabenazine both increase sedation. Use Caution/Monitor.

• dexamethasone

  dexamethasone will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• dexchlorpheniramine

  dexchlorpheniramine and tramadol both increase sedation. Use Caution/Monitor.

• dexfenfluramine

  tramadol increases and dexfenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.
  
  dexfenfluramine and tramadol both increase serotonin levels. Use Caution/Monitor.

• dexmedetomidine

  dexmedetomidine and tramadol both increase sedation. Use Caution/Monitor.

• dexmethylphenidate

  tramadol increases and dexmethylphenidate decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dextroamphetamine

  tramadol increases and dextroamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.
  
  dextroamphetamine and tramadol both increase serotonin levels. Use Caution/Monitor.

• dextroamphetamine transdermal

  tramadol, dextroamphetamine transdermal. Either increases effects of the other by serotonin levels. Modify Therapy/Monitor Closely. Initiate with lower doses and monitor for signs and symptoms of serotonin syndrome, particularly during initiation or dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine transdermal and concomitant serotonergic drug(s).

• dextromethorphan

  dextromethorphan and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• dextromoramide

  dextromoramide and tramadol both increase sedation. Use Caution/Monitor.

• diamorphine

  diamorphine and tramadol both increase sedation. Use Caution/Monitor.

• diazepam

  diazepam and tramadol both increase sedation. Use Caution/Monitor.

• diethylpropion

  tramadol increases and diethylpropion decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• difelikefalin

  difelikefalin and tramadol both increase sedation. Use Caution/Monitor.

• difenoxin hcl

  difenoxin hcl and tramadol both increase sedation. Use Caution/Monitor.

• dihydroergotamine

  dihydroergotamine and tramadol both increase serotonin levels. Use Caution/Monitor.

• dihydroergotamine intranasal

  dihydroergotamine intranasal and tramadol both increase serotonin levels. Use Caution/Monitor.

• dimenhydrinate

  dimenhydrinate and tramadol both increase sedation. Use Caution/Monitor.

• diphenhydramine

  diphenhydramine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  diphenhydramine and tramadol both increase sedation. Use Caution/Monitor.
  
  diphenhydramine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• diphenoxylate hcl

  diphenoxylate hcl and tramadol both increase sedation. Use Caution/Monitor.

• dipipanone

  dipipanone and tramadol both increase sedation. Use Caution/Monitor.

• dobutamine

  tramadol increases and dobutamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dopamine

  tramadol increases and dopamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dopexamine

  tramadol increases and dopexamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dosulepin

  tramadol and dosulepin both increase sedation. Use Caution/Monitor.

• doxepin

  tramadol and doxepin both increase sedation. Use Caution/Monitor.
  
  doxepin and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• doxylamine

  doxylamine and tramadol both increase sedation. Use Caution/Monitor.

• droperidol

  tramadol and droperidol both increase sedation. Use Caution/Monitor.

• duloxetine

  duloxetine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• efavirenz

  efavirenz will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• elagolix

  elagolix decreases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.

• eletriptan

  eletriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• eliglustat

  eliglustat increases levels of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the concomitant drug and titrate to clinical effect.

• elvitegravir/cobicistat/emtricitabine/tenofovir DF

  elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Cobicistat is a CYP3A4 inhibitor; contraindicated with CYP3A4 substrates for which elevated plasma concentrations are associated with serious and/or life-threatening events.
  
  elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Cobicistat is a CYP2D6 inhibitor; caution with CYP2D6 substrates for which elevated plasma concentrations are associated with serious and/or life-threatening events.

• encorafenib

  encorafenib, tramadol. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.

• enzalutamide

  enzalutamide will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• ephedrine

  tramadol increases and ephedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• epinephrine

  tramadol increases and epinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• epinephrine racemic

  tramadol increases and epinephrine racemic decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• ergotamine

  ergotamine and tramadol both increase serotonin levels. Use Caution/Monitor.

• erythromycin base

  erythromycin base will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• erythromycin ethylsuccinate

  erythromycin ethylsuccinate will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• erythromycin lactobionate

  erythromycin lactobionate will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• erythromycin stearate

  erythromycin stearate will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• escitalopram

  escitalopram and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• esketamine intranasal

  esketamine intranasal, tramadol. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely.

• eslicarbazepine acetate

  eslicarbazepine acetate will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• estazolam

  estazolam and tramadol both increase sedation. Use Caution/Monitor.

• ethanol

  tramadol and ethanol both increase sedation. Use Caution/Monitor.

• etomidate

  etomidate and tramadol both increase sedation. Use Caution/Monitor.

• etravirine

  etravirine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• fedratinib

  fedratinib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.

• fenfluramine

  tramadol increases and fenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.
  
  fenfluramine and tramadol both increase serotonin levels. Use Caution/Monitor.

• flibanserin

  tramadol and flibanserin both increase sedation. Modify Therapy/Monitor Closely. Risk for sedation increased if flibanserin is coadministration with other CNS depressants.

• fluoxetine

  fluoxetine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• fluphenazine

  tramadol and fluphenazine both increase sedation. Use Caution/Monitor.

• flurazepam

  flurazepam and tramadol both increase sedation. Use Caution/Monitor.

• fluvoxamine

  fluvoxamine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• formoterol

  tramadol increases and formoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• fosphenytoin

  fosphenytoin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• frovatriptan

  frovatriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• gabapentin

  gabapentin, tramadol. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

• gabapentin enacarbil

  gabapentin enacarbil, tramadol. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

• ganaxolone

  tramadol and ganaxolone both increase sedation. Use Caution/Monitor.

• haloperidol

  tramadol and haloperidol both increase sedation. Use Caution/Monitor.

• hydromorphone

  hydromorphone and tramadol both increase sedation. Use Caution/Monitor.

• hydroxyzine

  hydroxyzine and tramadol both increase sedation. Use Caution/Monitor.

• iloperidone

  tramadol and iloperidone both increase sedation. Use Caution/Monitor.
  
  iloperidone increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.

• imipramine

  tramadol and imipramine both increase sedation. Use Caution/Monitor.
  
  imipramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• indinavir

  indinavir increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity. .

• isoniazid

  isoniazid and tramadol both increase serotonin levels. Use Caution/Monitor.

• isoproterenol

  tramadol increases and isoproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• istradefylline

  istradefylline will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.

• itraconazole

  itraconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• ketamine

  ketamine and tramadol both increase sedation. Use Caution/Monitor.

• ketoconazole

  ketoconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• ketotifen, ophthalmic

  tramadol and ketotifen, ophthalmic both increase sedation. Use Caution/Monitor.

• L-tryptophan

  L-tryptophan and tramadol both increase serotonin levels. Use Caution/Monitor.

• larotrectinib

  larotrectinib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• lasmiditan

  lasmiditan, tramadol. Either increases effects of the other by sedation. Use Caution/Monitor. Coadministration of lasmiditan and other CNS depressant drugs, including alcohol have not been evaluated in clinical studies. Lasmiditan may cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions.

• lemborexant

  lemborexant, tramadol. Either increases effects of the other by sedation. Modify Therapy/Monitor Closely. Dosage adjustment may be necessary if lemborexant is coadministered with other CNS depressants because of potentially additive effects.

• lenacapavir

  lenacapavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration of tramadol and lenacapavir may require decrease in dose for tramadol.

• levalbuterol

  tramadol increases and levalbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• levoketoconazole

  levoketoconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• levomilnacipran

  levomilnacipran and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• levorphanol

  levorphanol and tramadol both increase sedation. Use Caution/Monitor.

• lisdexamfetamine

  tramadol increases and lisdexamfetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.
  
  tramadol, lisdexamfetamine. Either increases effects of the other by serotonin levels. Use Caution/Monitor. Initiate with lower doses and monitor for signs and symptoms of serotonin syndrome, particularly during initiation or dosage increase. If serotonin syndrome occurs, discontinue along with concomitant serotonergic drug(s).

• lithium

  lithium and tramadol both increase serotonin levels. Use Caution/Monitor.

• lofepramine

  tramadol and lofepramine both increase sedation. Use Caution/Monitor.
  
  lofepramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• lofexidine

  tramadol and lofexidine both increase sedation. Use Caution/Monitor.

• lopinavir

  lopinavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• loprazolam

  loprazolam and tramadol both increase sedation. Use Caution/Monitor.

• lorazepam

  lorazepam and tramadol both increase sedation. Use Caution/Monitor.

• lorcaserin

  lorcaserin will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

• lorlatinib

  lorlatinib will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• lormetazepam

  lormetazepam and tramadol both increase sedation. Use Caution/Monitor.

• loxapine

  tramadol and loxapine both increase sedation. Use Caution/Monitor.

• loxapine inhaled

  tramadol and loxapine inhaled both increase sedation. Use Caution/Monitor.

• lsd

  lsd and tramadol both increase serotonin levels. Use Caution/Monitor.

• lumefantrine

  lumefantrine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

• lurasidone

  lurasidone, tramadol. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.

• maprotiline

  tramadol and maprotiline both increase sedation. Use Caution/Monitor.
  
  maprotiline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• marijuana

  tramadol and marijuana both increase sedation. Use Caution/Monitor.

• melatonin

  tramadol and melatonin both increase sedation. Use Caution/Monitor.

• meperidine

  meperidine and tramadol both increase sedation. Use Caution/Monitor.
  
  meperidine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• meprobamate

  tramadol and meprobamate both increase sedation. Use Caution/Monitor.

• metaproterenol

  tramadol increases and metaproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• metaxalone

  metaxalone and tramadol both increase sedation. Use Caution/Monitor.

• methadone

  methadone and tramadol both increase sedation. Use Caution/Monitor.

• methamphetamine

  tramadol increases and methamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• methocarbamol

  methocarbamol and tramadol both increase sedation. Use Caution/Monitor.

• methylenedioxymethamphetamine

  tramadol increases and methylenedioxymethamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• midazolam

  midazolam and tramadol both increase sedation. Use Caution/Monitor.

• midazolam intranasal

  midazolam intranasal, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Concomitant use of barbiturates, alcohol, or other CNS depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

• midodrine

  tramadol increases and midodrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• mifepristone

  mifepristone will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• milnacipran

  milnacipran and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• mirabegron

  mirabegron will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

• mirtazapine

  tramadol and mirtazapine both increase sedation. Use Caution/Monitor.
  
  mirtazapine and tramadol both increase serotonin levels. Use Caution/Monitor.

• mitotane

  mitotane decreases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.

• modafinil

  tramadol increases and modafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• morphine

  morphine and tramadol both increase sedation. Use Caution/Monitor.
  
  morphine and tramadol both increase serotonin levels. Use Caution/Monitor.

• motherwort

  tramadol and motherwort both increase sedation. Use Caution/Monitor.

• moxonidine

  tramadol and moxonidine both increase sedation. Use Caution/Monitor.

• nabilone

  tramadol and nabilone both increase sedation. Use Caution/Monitor.

• nafcillin

  nafcillin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• nalbuphine

  nalbuphine and tramadol both increase sedation. Use Caution/Monitor.

• naratriptan

  naratriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• nefazodone

  nefazodone and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  nefazodone will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nelfinavir

  nelfinavir increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity. .

• nevirapine

  nevirapine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• norepinephrine

  tramadol increases and norepinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• nortriptyline

  tramadol and nortriptyline both increase sedation. Use Caution/Monitor.
  
  nortriptyline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• olanzapine

  tramadol and olanzapine both increase sedation. Use Caution/Monitor.

• oliceridine

  oliceridine, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.
  
  tramadol, oliceridine. Either increases effects of the other by serotonin levels. Modify Therapy/Monitor Closely.

• opium tincture

  opium tincture and tramadol both increase sedation. Use Caution/Monitor.

• orphenadrine

  orphenadrine and tramadol both increase sedation. Use Caution/Monitor.

• oxazepam

  oxazepam and tramadol both increase sedation. Use Caution/Monitor.

• oxcarbazepine

  oxcarbazepine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• oxycodone

  oxycodone and tramadol both increase sedation. Use Caution/Monitor.

• oxymorphone

  oxymorphone and tramadol both increase sedation. Use Caution/Monitor.

• paliperidone

  tramadol and paliperidone both increase sedation. Use Caution/Monitor.

• papaveretum

  papaveretum and tramadol both increase sedation. Use Caution/Monitor.

• papaverine

  tramadol and papaverine both increase sedation. Use Caution/Monitor.

• paroxetine

  paroxetine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  paroxetine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• peginterferon alfa 2b

  peginterferon alfa 2b, tramadol. Other (see comment). Use Caution/Monitor. Comment: When patients are administered peginterferon alpha-2b with CYP2D6 substrates, the therapeutic effect of these drugs may be altered. Peginterferon alpha-2b may increase or decrease levels of CYP2D6 substrate.

• pegvisomant

  tramadol decreases effects of pegvisomant by unknown mechanism. Use Caution/Monitor.

• pentazocine

  pentazocine and tramadol both increase sedation. Use Caution/Monitor.
  
  pentazocine and tramadol both increase serotonin levels. Use Caution/Monitor.

• pentobarbital

  pentobarbital and tramadol both increase sedation. Use Caution/Monitor.
  
  pentobarbital will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• perampanel

  perampanel and tramadol both increase sedation. Use Caution/Monitor.

• perphenazine

  tramadol and perphenazine both increase sedation. Use Caution/Monitor.

• phendimetrazine

  tramadol increases and phendimetrazine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• phenobarbital

  phenobarbital and tramadol both increase sedation. Use Caution/Monitor.
  
  phenobarbital will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• phentermine

  tramadol increases and phentermine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• phenylephrine

  tramadol increases and phenylephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• phenytoin

  phenytoin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• pholcodine

  tramadol and pholcodine both increase sedation. Use Caution/Monitor.

• pimozide

  tramadol and pimozide both increase sedation. Use Caution/Monitor.

• pirbuterol

  tramadol increases and pirbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• pregabalin

  pregabalin, tramadol. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

• primidone

  primidone and tramadol both increase sedation. Use Caution/Monitor.
  
  primidone will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• prochlorperazine

  tramadol and prochlorperazine both increase sedation. Use Caution/Monitor.

• promethazine

  promethazine and tramadol both increase sedation. Use Caution/Monitor.

• propafenone

  propafenone decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  propafenone decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• propofol

  propofol and tramadol both increase sedation. Use Caution/Monitor.

• propylhexedrine

  tramadol increases and propylhexedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• protriptyline

  tramadol and protriptyline both increase sedation. Use Caution/Monitor.
  
  protriptyline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• quazepam

  quazepam and tramadol both increase sedation. Use Caution/Monitor.

• quetiapine

  tramadol and quetiapine both increase sedation. Use Caution/Monitor.

• quinacrine

  quinacrine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  quinacrine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• quinidine

  quinidine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  quinidine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• ramelteon

  tramadol and ramelteon both increase sedation. Use Caution/Monitor.

• remifentanil

  tramadol, remifentanil. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Increases risk of serotonin syndrome.

• remimazolam

  remimazolam, tramadol. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely. Coadministration may result in profound sedation, respiratory depression, coma, and/or death. Continuously monitor vital signs during sedation and recovery period if coadministered. Carefully titrate remimazolam dose if administered with opioid analgesics and/or sedative/hypnotics.

• rifabutin

  rifabutin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• rifampin

  rifampin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• rifapentine

  rifapentine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• risperidone

  tramadol and risperidone both increase sedation. Use Caution/Monitor.

• ritonavir

  ritonavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• rizatriptan

  rizatriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• rolapitant

  rolapitant will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Rolapitant may increase plasma concentrations of CYP2D6 substrates for at least 28 days following rolapitant administration.

• rucaparib

  rucaparib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.

• salmeterol

  tramadol increases and salmeterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• SAMe

  SAMe and tramadol both increase serotonin levels. Use Caution/Monitor.

• saquinavir

  saquinavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• scullcap

  tramadol and scullcap both increase sedation. Use Caution/Monitor.

• secobarbital

  secobarbital and tramadol both increase sedation. Use Caution/Monitor.

• selegiline transdermal

  selegiline transdermal and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• sertraline

  sertraline decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  sertraline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  sertraline decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• sevoflurane

  sevoflurane and tramadol both increase sedation. Use Caution/Monitor.

• shepherd's purse

  tramadol and shepherd's purse both increase sedation. Use Caution/Monitor.

• St John's Wort

  St John's Wort and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• stiripentol

  stiripentol, tramadol. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.
  
  stiripentol, tramadol. Either increases effects of the other by sedation. Use Caution/Monitor. Concomitant use stiripentol with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence.

• sufentanil

  sufentanil and tramadol both increase sedation. Use Caution/Monitor.

• sumatriptan

  sumatriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• sumatriptan intranasal

  sumatriptan intranasal and tramadol both increase serotonin levels. Use Caution/Monitor.

• suvorexant

  suvorexant and tramadol both increase sedation. Modify Therapy/Monitor Closely. Dosage adjustments of suvorexant and concomitant CNS depressants may be necessary

• tapentadol

  tapentadol and tramadol both increase sedation. Use Caution/Monitor.
  
  tramadol and tapentadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• tazemetostat

  tazemetostat will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• tecovirimat

  tecovirimat will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.

• temazepam

  temazepam and tramadol both increase sedation. Use Caution/Monitor.

• terbinafine

  terbinafine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Assess need to reduce dose of CYP2D6-metabolized drug.

• terbutaline

  tramadol increases and terbutaline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• thioridazine

  thioridazine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  tramadol and thioridazine both increase sedation. Use Caution/Monitor.
  
  thioridazine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• thiothixene

  tramadol and thiothixene both increase sedation. Use Caution/Monitor.

• tipranavir

  tipranavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• topiramate

  tramadol and topiramate both increase sedation. Modify Therapy/Monitor Closely.

• trazodone

  tramadol and trazodone both increase sedation. Use Caution/Monitor.
  
  trazodone and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• triazolam

  triazolam and tramadol both increase sedation. Use Caution/Monitor.

• triclofos

  triclofos and tramadol both increase sedation. Use Caution/Monitor.

• trifluoperazine

  tramadol and trifluoperazine both increase sedation. Use Caution/Monitor.

• trimipramine

  tramadol and trimipramine both increase sedation. Use Caution/Monitor.
  
  trimipramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• triprolidine

  triprolidine and tramadol both increase sedation. Use Caution/Monitor.

• venlafaxine

  venlafaxine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• voriconazole

  voriconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• xylometazoline

  tramadol increases and xylometazoline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• yohimbine

  tramadol increases and yohimbine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• ziconotide

  tramadol and ziconotide both increase sedation. Use Caution/Monitor.

• ziprasidone

  tramadol and ziprasidone both increase sedation. Use Caution/Monitor.

• zolmitriptan

  zolmitriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• zotepine

  tramadol and zotepine both increase sedation. Use Caution/Monitor.

Minor (19)

• acetazolamide

  acetazolamide will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• anastrozole

  anastrozole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• asenapine

  asenapine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• brimonidine

  brimonidine increases effects of tramadol by pharmacodynamic synergism. Minor/Significance Unknown. Increased CNS depression.

• cyclophosphamide

  cyclophosphamide will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• darifenacin

  darifenacin will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• dextroamphetamine

  dextroamphetamine increases effects of tramadol by unspecified interaction mechanism. Minor/Significance Unknown.

• dronedarone

  dronedarone will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• eucalyptus

  tramadol and eucalyptus both increase sedation. Minor/Significance Unknown.

• lidocaine

  lidocaine increases toxicity of tramadol by pharmacodynamic synergism. Minor/Significance Unknown. Risk of increased CNS depression.

• maraviroc

  maraviroc will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• marijuana

  marijuana will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• nilotinib

  nilotinib will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• parecoxib

  parecoxib will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• paroxetine

  paroxetine decreases effects of tramadol by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of tramadol to active metabolite.

• ranolazine

  ranolazine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• sage

  tramadol and sage both increase sedation. Minor/Significance Unknown.

• tipranavir

  tipranavir will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• ziconotide

  ziconotide, tramadol. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Additive decreased GI motility. Additive analgesia. Ziconotide does NOT potentiate opioid induced respiratory depression.

• 5-HTP

  Monitor Closely (1)5-HTP and tramadol both increase serotonin levels. Use Caution/Monitor.

• abametapir

  Serious - Use Alternative (1)abametapir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.

• abiraterone

  Monitor Closely (1)abiraterone increases levels of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Avoid coadministration of abiraterone with substrates of CYP2D6. If alternative therapy cannot be used, exercise caution and consider increasing tramadol dose if clinically appropriate; if abiraterone is discontinued, consider reducing tramadol dose and frequently monitor for signs of respiratory depression and sedation.

• acetazolamide

  Minor (1)acetazolamide will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• acrivastine

  Serious - Use Alternative (1)acrivastine and tramadol both increase sedation. Avoid or Use Alternate Drug.

• albuterol

  Monitor Closely (1)tramadol increases and albuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• alfentanil

  Monitor Closely (1)alfentanil and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, alfentanil. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• almotriptan

  Monitor Closely (1)almotriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• alprazolam

  Monitor Closely (1)alprazolam and tramadol both increase sedation. Use Caution/Monitor.

• alvimopan

  Contraindicated (1)alvimopan, tramadol. receptor binding competition. Contraindicated. Alvimopan is contraindicated in opioid tolerant patients (ie, those who have taken therapeutic doses of opioids for >7 consecutive days immediately prior to taking alvimopan). Patients recently exposed to opioids are expected to be more sensitive to the effects of alvimopan and therefore may experience abdominal pain, nausea and vomiting, and diarrhea. No significant interaction is expected with concurrent use of opioid analgesics and alvimopan in patients who received opioid analgesics for 7 or fewer consecutive days prior to alvimopan.

• amifampridine

  Monitor Closely (1)tramadol increases toxicity of amifampridine by Other (see comment). Modify Therapy/Monitor Closely. Comment: Amifampridine can cause seizures. Coadministration with drugs that lower seizure threshold may increase this risk.

• amiodarone

  Monitor Closely (2)amiodarone decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  amiodarone decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• amisulpride

  Serious - Use Alternative (1)amisulpride and tramadol both increase sedation. Avoid or Use Alternate Drug.

• amitriptyline

  Monitor Closely (2)amitriptyline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  tramadol and amitriptyline both increase sedation. Use Caution/Monitor.

• amobarbital

  Monitor Closely (1)amobarbital and tramadol both increase sedation. Use Caution/Monitor.

• amoxapine

  Monitor Closely (2)amoxapine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  tramadol and amoxapine both increase sedation. Use Caution/Monitor.

• anastrozole

  Minor (1)anastrozole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• apalutamide

  Serious - Use Alternative (1)apalutamide will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.

• apomorphine

  Monitor Closely (1)tramadol and apomorphine both increase sedation. Use Caution/Monitor.

• arformoterol

  Monitor Closely (1)tramadol increases and arformoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• aripiprazole

  Monitor Closely (1)tramadol and aripiprazole both increase sedation. Use Caution/Monitor.

• armodafinil

  Monitor Closely (1)tramadol increases and armodafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• artemether/lumefantrine

  Monitor Closely (1)artemether/lumefantrine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

• asenapine

  Monitor Closely (1)asenapine and tramadol both increase sedation. Use Caution/Monitor.Minor (1)asenapine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• asenapine transdermal

  Serious - Use Alternative (1)asenapine transdermal and tramadol both increase sedation. Avoid or Use Alternate Drug.

• atazanavir

  Monitor Closely (1)atazanavir increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity. .

• avapritinib

  Monitor Closely (1)avapritinib and tramadol both increase sedation. Use Caution/Monitor.

• azelastine

  Monitor Closely (1)azelastine and tramadol both increase sedation. Use Caution/Monitor.

• baclofen

  Monitor Closely (1)baclofen and tramadol both increase sedation. Use Caution/Monitor.

• belladonna and opium

  Monitor Closely (1)belladonna and opium and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, belladonna and opium. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• benperidol

  Monitor Closely (1)tramadol and benperidol both increase sedation. Use Caution/Monitor.

• benzhydrocodone/acetaminophen

  Serious - Use Alternative (2)benzhydrocodone/acetaminophen, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.
  
  benzhydrocodone/acetaminophen and tramadol both increase sedation. Avoid or Use Alternate Drug.

• benzphetamine

  Monitor Closely (1)tramadol increases and benzphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• bosentan

  Monitor Closely (1)bosentan will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• bremelanotide

  Serious - Use Alternative (1)bremelanotide will decrease the level or effect of tramadol by Other (see comment). Avoid or Use Alternate Drug. Bremelanotide may slow gastric emptying and potentially reduces the rate and extent of absorption of concomitantly administered oral medications. Avoid use when taking any oral drug that is dependent on threshold concentrations for efficacy. Interactions listed are representative examples and do not include all possible clinical examples.

• brexanolone

  Monitor Closely (1)brexanolone, tramadol. Either increases toxicity of the other by sedation. Use Caution/Monitor.

• brexpiprazole

  Monitor Closely (1)brexpiprazole and tramadol both increase sedation. Use Caution/Monitor.

• brimonidine

  Monitor Closely (1)brimonidine and tramadol both increase sedation. Use Caution/Monitor.Minor (1)brimonidine increases effects of tramadol by pharmacodynamic synergism. Minor/Significance Unknown. Increased CNS depression.

• brivaracetam

  Monitor Closely (1)brivaracetam and tramadol both increase sedation. Use Caution/Monitor.

• brompheniramine

  Monitor Closely (1)brompheniramine and tramadol both increase sedation. Use Caution/Monitor.

• buprenorphine

  Monitor Closely (1)buprenorphine and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (2)tramadol, buprenorphine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.
  
  buprenorphine, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• buprenorphine buccal

  Monitor Closely (1)buprenorphine buccal and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (2)buprenorphine buccal, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.
  
  tramadol, buprenorphine buccal. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• buprenorphine subdermal implant

  Serious - Use Alternative (1)buprenorphine subdermal implant and tramadol both increase sedation. Avoid or Use Alternate Drug.

• buprenorphine, long-acting injection

  Monitor Closely (1)tramadol increases toxicity of buprenorphine, long-acting injection by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of buprenorphine and benzodiazepines or other CNS depressants increases risk of adverse reactions including overdose, respiratory depression, and death. Cessation of benzodiazepines or other CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering CNS depressants may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

• bupropion

  Monitor Closely (1)bupropion will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

• buspirone

  Monitor Closely (1)buspirone and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• butabarbital

  Monitor Closely (1)butabarbital and tramadol both increase sedation. Use Caution/Monitor.

• butalbital

  Monitor Closely (1)butalbital and tramadol both increase sedation. Use Caution/Monitor.

• butorphanol

  Monitor Closely (1)butorphanol and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (2)tramadol, butorphanol. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.
  
  butorphanol, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• caffeine

  Monitor Closely (1)tramadol increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• calcium/magnesium/potassium/sodium oxybates

  Serious - Use Alternative (1)tramadol, calcium/magnesium/potassium/sodium oxybates. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• carbamazepine

  Monitor Closely (1)carbamazepine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• carbinoxamine

  Monitor Closely (1)carbinoxamine and tramadol both increase sedation. Use Caution/Monitor.

• carisoprodol

  Monitor Closely (1)carisoprodol and tramadol both increase sedation. Use Caution/Monitor.

• celecoxib

  Monitor Closely (2)celecoxib decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  celecoxib decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• cenobamate

  Monitor Closely (1)cenobamate, tramadol. Either increases effects of the other by sedation. Use Caution/Monitor.

• ceritinib

  Monitor Closely (1)ceritinib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• chloral hydrate

  Monitor Closely (1)chloral hydrate and tramadol both increase sedation. Use Caution/Monitor.

• chlordiazepoxide

  Monitor Closely (1)chlordiazepoxide and tramadol both increase sedation. Use Caution/Monitor.

• chloroquine

  Monitor Closely (2)chloroquine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  chloroquine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• chlorpheniramine

  Monitor Closely (1)chlorpheniramine and tramadol both increase sedation. Use Caution/Monitor.

• chlorpromazine

  Monitor Closely (1)tramadol and chlorpromazine both increase sedation. Use Caution/Monitor.

• chlorzoxazone

  Monitor Closely (1)chlorzoxazone and tramadol both increase sedation. Use Caution/Monitor.

• cimetidine

  Monitor Closely (2)cimetidine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  cimetidine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• cinnarizine

  Monitor Closely (1)cinnarizine and tramadol both increase sedation. Use Caution/Monitor.

• citalopram

  Monitor Closely (1)citalopram and tramadol both increase serotonin levels. Use Caution/Monitor. Combination may increase risk of serotonin syndrome or neuroleptic malignant syndrome-like reactions.

• clarithromycin

  Monitor Closely (1)clarithromycin will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• clemastine

  Monitor Closely (1)clemastine and tramadol both increase sedation. Use Caution/Monitor.

• clobazam

  Monitor Closely (2)clobazam will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Lower doses of drugs metabolized by CYP2D6 may be required when used concomitantly.
  
  tramadol, clobazam. Other (see comment). Use Caution/Monitor. Comment: Concomitant administration can increase the potential for CNS effects (e.g., increased sedation or respiratory depression).

• clomipramine

  Monitor Closely (2)clomipramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  tramadol and clomipramine both increase sedation. Use Caution/Monitor.

• clonazepam

  Monitor Closely (1)clonazepam and tramadol both increase sedation. Use Caution/Monitor.

• clonidine

  Serious - Use Alternative (1)clonidine, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration enhances CNS depressant effects.

• clorazepate

  Monitor Closely (1)clorazepate and tramadol both increase sedation. Use Caution/Monitor.

• clozapine

  Monitor Closely (1)tramadol and clozapine both increase sedation. Use Caution/Monitor.

• cobicistat

  Monitor Closely (2)cobicistat will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. A decreased dose of tramadol may be required
  
  cobicistat will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. A decreased dose of tramadol may be required

• cocaine topical

  Monitor Closely (1)cocaine topical and tramadol both increase serotonin levels. Use Caution/Monitor.

• codeine

  Monitor Closely (1)codeine and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, codeine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• crizotinib

  Monitor Closely (1)crizotinib increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A.

• crofelemer

  Monitor Closely (1)crofelemer increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Crofelemer has the potential to inhibit CYP3A4 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed.

• cyclizine

  Monitor Closely (1)cyclizine and tramadol both increase sedation. Use Caution/Monitor.

• cyclobenzaprine

  Monitor Closely (1)cyclobenzaprine and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol and cyclobenzaprine both increase serotonin levels. Avoid or Use Alternate Drug.

• cyclophosphamide

  Minor (1)cyclophosphamide will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• cyproheptadine

  Monitor Closely (1)cyproheptadine and tramadol both increase sedation. Use Caution/Monitor.

• dabrafenib

  Monitor Closely (1)dabrafenib will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• dacomitinib

  Serious - Use Alternative (1)dacomitinib will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug. Avoid use with CYP2D6 substrates where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities.

• dantrolene

  Monitor Closely (1)dantrolene and tramadol both increase sedation. Use Caution/Monitor.

• daridorexant

  Monitor Closely (1)tramadol and daridorexant both increase sedation. Modify Therapy/Monitor Closely. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.

• darifenacin

  Minor (1)darifenacin will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• darunavir

  Monitor Closely (1)darunavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. A decreased dose of tramadol may be required

• desflurane

  Monitor Closely (1)desflurane and tramadol both increase sedation. Use Caution/Monitor. Opioids may decrease MAC requirements, less inhalation anesthetic may be required.

• desipramine

  Monitor Closely (2)desipramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  tramadol and desipramine both increase sedation. Use Caution/Monitor.

• desvenlafaxine

  Monitor Closely (1)desvenlafaxine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Desvenlafaxine inhibits CYP2D6; with higher desvenlafaxine doses (ie, 400 mg) decrease the CYP2D6 substrate dose by up to 50%; no dosage adjustment needed with desvenlafaxine doses <100 mgSerious - Use Alternative (1)tramadol and desvenlafaxine both increase serotonin levels. Avoid or Use Alternate Drug.

• deutetrabenazine

  Monitor Closely (1)tramadol and deutetrabenazine both increase sedation. Use Caution/Monitor.

• dexamethasone

  Monitor Closely (1)dexamethasone will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• dexchlorpheniramine

  Monitor Closely (1)dexchlorpheniramine and tramadol both increase sedation. Use Caution/Monitor.

• dexfenfluramine

  Monitor Closely (2)tramadol increases and dexfenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.
  
  dexfenfluramine and tramadol both increase serotonin levels. Use Caution/Monitor.

• dexmedetomidine

  Monitor Closely (1)dexmedetomidine and tramadol both increase sedation. Use Caution/Monitor.

• dexmethylphenidate

  Monitor Closely (1)tramadol increases and dexmethylphenidate decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dextroamphetamine

  Monitor Closely (2)tramadol increases and dextroamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.
  
  dextroamphetamine and tramadol both increase serotonin levels. Use Caution/Monitor.Minor (1)dextroamphetamine increases effects of tramadol by unspecified interaction mechanism. Minor/Significance Unknown.

• dextroamphetamine transdermal

  Monitor Closely (1)tramadol, dextroamphetamine transdermal. Either increases effects of the other by serotonin levels. Modify Therapy/Monitor Closely. Initiate with lower doses and monitor for signs and symptoms of serotonin syndrome, particularly during initiation or dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine transdermal and concomitant serotonergic drug(s).

• dextromethorphan

  Monitor Closely (1)dextromethorphan and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• dextromoramide

  Monitor Closely (1)dextromoramide and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, dextromoramide. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• diamorphine

  Monitor Closely (1)diamorphine and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, diamorphine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• diazepam

  Monitor Closely (1)diazepam and tramadol both increase sedation. Use Caution/Monitor.

• diazepam intranasal

  Serious - Use Alternative (1)diazepam intranasal, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• diethylpropion

  Monitor Closely (1)tramadol increases and diethylpropion decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• difelikefalin

  Monitor Closely (1)difelikefalin and tramadol both increase sedation. Use Caution/Monitor.

• difenoxin hcl

  Monitor Closely (1)difenoxin hcl and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, difenoxin hcl. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• dihydroergotamine

  Monitor Closely (1)dihydroergotamine and tramadol both increase serotonin levels. Use Caution/Monitor.

• dihydroergotamine intranasal

  Monitor Closely (1)dihydroergotamine intranasal and tramadol both increase serotonin levels. Use Caution/Monitor.

• dimenhydrinate

  Monitor Closely (1)dimenhydrinate and tramadol both increase sedation. Use Caution/Monitor.

• diphenhydramine

  Monitor Closely (3)diphenhydramine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  diphenhydramine and tramadol both increase sedation. Use Caution/Monitor.
  
  diphenhydramine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• diphenoxylate hcl

  Monitor Closely (1)diphenoxylate hcl and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, diphenoxylate hcl. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• dipipanone

  Monitor Closely (1)dipipanone and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, dipipanone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• dobutamine

  Monitor Closely (1)tramadol increases and dobutamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dopamine

  Monitor Closely (1)tramadol increases and dopamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dopexamine

  Monitor Closely (1)tramadol increases and dopexamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• dosulepin

  Monitor Closely (1)tramadol and dosulepin both increase sedation. Use Caution/Monitor.

• doxepin

  Monitor Closely (2)doxepin and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  tramadol and doxepin both increase sedation. Use Caution/Monitor.

• doxylamine

  Monitor Closely (1)doxylamine and tramadol both increase sedation. Use Caution/Monitor.

• dronedarone

  Minor (1)dronedarone will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• droperidol

  Monitor Closely (1)tramadol and droperidol both increase sedation. Use Caution/Monitor.

• duloxetine

  Monitor Closely (1)duloxetine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.Serious - Use Alternative (1)duloxetine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug.

• efavirenz

  Monitor Closely (1)efavirenz will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• elagolix

  Monitor Closely (1)elagolix decreases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.

• eletriptan

  Monitor Closely (1)eletriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• eliglustat

  Monitor Closely (1)eliglustat increases levels of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the concomitant drug and titrate to clinical effect.

• eluxadoline

  Serious - Use Alternative (1)tramadol, eluxadoline. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid coadministration with other drugs that cause constipation. Increases risk for constipation related serious adverse reactions. .

• elvitegravir/cobicistat/emtricitabine/tenofovir DF

  Monitor Closely (2)elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Cobicistat is a CYP3A4 inhibitor; contraindicated with CYP3A4 substrates for which elevated plasma concentrations are associated with serious and/or life-threatening events.
  
  elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Cobicistat is a CYP2D6 inhibitor; caution with CYP2D6 substrates for which elevated plasma concentrations are associated with serious and/or life-threatening events.

• encorafenib

  Monitor Closely (1)encorafenib, tramadol. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.

• enzalutamide

  Monitor Closely (1)enzalutamide will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• ephedrine

  Monitor Closely (1)tramadol increases and ephedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• epinephrine

  Monitor Closely (1)tramadol increases and epinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• epinephrine racemic

  Monitor Closely (1)tramadol increases and epinephrine racemic decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• ergotamine

  Monitor Closely (1)ergotamine and tramadol both increase serotonin levels. Use Caution/Monitor.

• erythromycin base

  Monitor Closely (1)erythromycin base will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• erythromycin ethylsuccinate

  Monitor Closely (1)erythromycin ethylsuccinate will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• erythromycin lactobionate

  Monitor Closely (1)erythromycin lactobionate will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• erythromycin stearate

  Monitor Closely (1)erythromycin stearate will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• escitalopram

  Monitor Closely (1)escitalopram and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• esketamine intranasal

  Monitor Closely (1)esketamine intranasal, tramadol. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely.

• eslicarbazepine acetate

  Monitor Closely (1)eslicarbazepine acetate will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• estazolam

  Monitor Closely (1)estazolam and tramadol both increase sedation. Use Caution/Monitor.

• ethanol

  Monitor Closely (1)tramadol and ethanol both increase sedation. Use Caution/Monitor.

• etomidate

  Monitor Closely (1)etomidate and tramadol both increase sedation. Use Caution/Monitor.

• etravirine

  Monitor Closely (1)etravirine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• eucalyptus

  Minor (1)tramadol and eucalyptus both increase sedation. Minor/Significance Unknown.

• fedratinib

  Monitor Closely (1)fedratinib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.

• fenfluramine

  Monitor Closely (2)tramadol increases and fenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.
  
  fenfluramine and tramadol both increase serotonin levels. Use Caution/Monitor.

• fentanyl

  Serious - Use Alternative (1)fentanyl, tramadol. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

• fentanyl intranasal

  Serious - Use Alternative (1)fentanyl intranasal, tramadol. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

• fentanyl transdermal

  Serious - Use Alternative (1)fentanyl transdermal, tramadol. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

• fentanyl transmucosal

  Serious - Use Alternative (1)fentanyl transmucosal, tramadol. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

• fexinidazole

  Serious - Use Alternative (1)fexinidazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.

• flibanserin

  Monitor Closely (1)tramadol and flibanserin both increase sedation. Modify Therapy/Monitor Closely. Risk for sedation increased if flibanserin is coadministration with other CNS depressants.

• fluoxetine

  Monitor Closely (1)fluoxetine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• fluphenazine

  Monitor Closely (1)tramadol and fluphenazine both increase sedation. Use Caution/Monitor.

• flurazepam

  Monitor Closely (1)flurazepam and tramadol both increase sedation. Use Caution/Monitor.

• fluvoxamine

  Monitor Closely (1)fluvoxamine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• formoterol

  Monitor Closely (1)tramadol increases and formoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• fosphenytoin

  Monitor Closely (1)fosphenytoin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• frovatriptan

  Monitor Closely (1)frovatriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• gabapentin

  Monitor Closely (1)gabapentin, tramadol. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

• gabapentin enacarbil

  Monitor Closely (1)gabapentin enacarbil, tramadol. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

• ganaxolone

  Monitor Closely (1)tramadol and ganaxolone both increase sedation. Use Caution/Monitor.

• givosiran

  Serious - Use Alternative (1)givosiran will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP2D6 substrates with givosiran. If unavoidable, decrease the CYP2D6 substrate dosage in accordance with approved product labeling.

• haloperidol

  Monitor Closely (1)tramadol and haloperidol both increase sedation. Use Caution/Monitor.

• hydrocodone

  Serious - Use Alternative (2)hydrocodone, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.
  
  tramadol, hydrocodone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• hydromorphone

  Monitor Closely (1)hydromorphone and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, hydromorphone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• hydroxyzine

  Monitor Closely (1)hydroxyzine and tramadol both increase sedation. Use Caution/Monitor.

• idelalisib

  Serious - Use Alternative (1)idelalisib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates

• iloperidone

  Monitor Closely (2)tramadol and iloperidone both increase sedation. Use Caution/Monitor.
  
  iloperidone increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.

• imipramine

  Monitor Closely (2)imipramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  tramadol and imipramine both increase sedation. Use Caution/Monitor.

• indinavir

  Monitor Closely (1)indinavir increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity. .

• iobenguane I 131

  Serious - Use Alternative (1)tramadol will decrease the level or effect of iobenguane I 131 by Other (see comment). Avoid or Use Alternate Drug. Based on the mechanism of action of iobenguane, drugs that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells, and thus, reduce iobenguane efficacy. Discontinue interfering drugs for at least 5 half-lives before administration of either the dosimetry or an iobenguane dose. Do not administer these drugs until at least 7 days after each iobenguane dose.

• isocarboxazid

  Serious - Use Alternative (2)isocarboxazid and tramadol both increase serotonin levels. Avoid or Use Alternate Drug.
  
  isocarboxazid increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• isoniazid

  Monitor Closely (1)isoniazid and tramadol both increase serotonin levels. Use Caution/Monitor.

• isoproterenol

  Monitor Closely (1)tramadol increases and isoproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• istradefylline

  Monitor Closely (1)istradefylline will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.

• itraconazole

  Monitor Closely (1)itraconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• ivosidenib

  Serious - Use Alternative (1)ivosidenib will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternative therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

• ketamine

  Monitor Closely (1)ketamine and tramadol both increase sedation. Use Caution/Monitor.

• ketoconazole

  Monitor Closely (1)ketoconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• ketotifen, ophthalmic

  Monitor Closely (1)tramadol and ketotifen, ophthalmic both increase sedation. Use Caution/Monitor.

• L-tryptophan

  Monitor Closely (1)L-tryptophan and tramadol both increase serotonin levels. Use Caution/Monitor.

• larotrectinib

  Monitor Closely (1)larotrectinib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• lasmiditan

  Monitor Closely (1)lasmiditan, tramadol. Either increases effects of the other by sedation. Use Caution/Monitor. Coadministration of lasmiditan and other CNS depressant drugs, including alcohol have not been evaluated in clinical studies. Lasmiditan may cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions.

• lemborexant

  Monitor Closely (1)lemborexant, tramadol. Either increases effects of the other by sedation. Modify Therapy/Monitor Closely. Dosage adjustment may be necessary if lemborexant is coadministered with other CNS depressants because of potentially additive effects.

• lenacapavir

  Monitor Closely (1)lenacapavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration of tramadol and lenacapavir may require decrease in dose for tramadol.

• levalbuterol

  Monitor Closely (1)tramadol increases and levalbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• levoketoconazole

  Monitor Closely (1)levoketoconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• levomilnacipran

  Monitor Closely (1)levomilnacipran and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• levorphanol

  Monitor Closely (1)levorphanol and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, levorphanol. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• lidocaine

  Minor (1)lidocaine increases toxicity of tramadol by pharmacodynamic synergism. Minor/Significance Unknown. Risk of increased CNS depression.

• linezolid

  Serious - Use Alternative (2)linezolid and tramadol both increase serotonin levels. Avoid or Use Alternate Drug. Linezolid may increase serotonin as a result of MAO-A inhibition. If linezolid must be administered, discontinue serotonergic drug immediately and monitor for CNS toxicity. Serotonergic therapy may be resumed 24 hours after last linezolid dose or after 2 weeks of monitoring, whichever comes first.
  
  linezolid increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• lisdexamfetamine

  Monitor Closely (2)tramadol, lisdexamfetamine. Either increases effects of the other by serotonin levels. Use Caution/Monitor. Initiate with lower doses and monitor for signs and symptoms of serotonin syndrome, particularly during initiation or dosage increase. If serotonin syndrome occurs, discontinue along with concomitant serotonergic drug(s).
  
  tramadol increases and lisdexamfetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• lithium

  Monitor Closely (1)lithium and tramadol both increase serotonin levels. Use Caution/Monitor.

• lofepramine

  Monitor Closely (2)lofepramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  tramadol and lofepramine both increase sedation. Use Caution/Monitor.

• lofexidine

  Monitor Closely (1)tramadol and lofexidine both increase sedation. Use Caution/Monitor.

• lonafarnib

  Serious - Use Alternative (1)lonafarnib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration with sensitive CYP3A substrates. If coadministration unavoidable, monitor for adverse reactions and reduce CYP3A substrate dose in accordance with product labeling.

• lopinavir

  Monitor Closely (1)lopinavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• loprazolam

  Monitor Closely (1)loprazolam and tramadol both increase sedation. Use Caution/Monitor.

• lorazepam

  Monitor Closely (1)lorazepam and tramadol both increase sedation. Use Caution/Monitor.

• lorcaserin

  Monitor Closely (1)lorcaserin will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.Serious - Use Alternative (1)tramadol and lorcaserin both increase serotonin levels. Avoid or Use Alternate Drug.

• lorlatinib

  Monitor Closely (1)lorlatinib will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• lormetazepam

  Monitor Closely (1)lormetazepam and tramadol both increase sedation. Use Caution/Monitor.

• loxapine

  Monitor Closely (1)tramadol and loxapine both increase sedation. Use Caution/Monitor.

• loxapine inhaled

  Monitor Closely (1)tramadol and loxapine inhaled both increase sedation. Use Caution/Monitor.

• lsd

  Monitor Closely (1)lsd and tramadol both increase serotonin levels. Use Caution/Monitor.

• lumefantrine

  Monitor Closely (1)lumefantrine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

• lurasidone

  Monitor Closely (1)lurasidone, tramadol. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.

• maprotiline

  Monitor Closely (2)maprotiline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  tramadol and maprotiline both increase sedation. Use Caution/Monitor.

• maraviroc

  Minor (1)maraviroc will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• marijuana

  Monitor Closely (1)tramadol and marijuana both increase sedation. Use Caution/Monitor.Minor (1)marijuana will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• melatonin

  Monitor Closely (1)tramadol and melatonin both increase sedation. Use Caution/Monitor.

• meperidine

  Monitor Closely (2)meperidine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  meperidine and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, meperidine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• meprobamate

  Monitor Closely (1)tramadol and meprobamate both increase sedation. Use Caution/Monitor.

• metaproterenol

  Monitor Closely (1)tramadol increases and metaproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• metaxalone

  Monitor Closely (1)metaxalone and tramadol both increase sedation. Use Caution/Monitor.

• methadone

  Monitor Closely (1)methadone and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• methamphetamine

  Monitor Closely (1)tramadol increases and methamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• methocarbamol

  Monitor Closely (1)methocarbamol and tramadol both increase sedation. Use Caution/Monitor.

• methylene blue

  Serious - Use Alternative (1)methylene blue and tramadol both increase serotonin levels. Avoid or Use Alternate Drug. Methylene blue may increase serotonin as a result of MAO-A inhibition. If methylene blue must be administered, discontinue serotonergic drug immediately and monitor for CNS toxicity. Serotonergic therapy may be resumed 24 hours after last methylene blue dose or after 2 weeks of monitoring, whichever comes first.

• methylenedioxymethamphetamine

  Monitor Closely (1)tramadol increases and methylenedioxymethamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• metoclopramide intranasal

  Serious - Use Alternative (1)tramadol, metoclopramide intranasal. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid use of metoclopramide intranasal or interacting drug, depending on importance of drug to patient.

• midazolam

  Monitor Closely (1)midazolam and tramadol both increase sedation. Use Caution/Monitor.

• midazolam intranasal

  Monitor Closely (1)midazolam intranasal, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Concomitant use of barbiturates, alcohol, or other CNS depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

• midodrine

  Monitor Closely (1)tramadol increases and midodrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• mifepristone

  Monitor Closely (1)mifepristone will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• milnacipran

  Monitor Closely (1)milnacipran and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• mirabegron

  Monitor Closely (1)mirabegron will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

• mirtazapine

  Monitor Closely (2)tramadol and mirtazapine both increase sedation. Use Caution/Monitor.
  
  mirtazapine and tramadol both increase serotonin levels. Use Caution/Monitor.

• mitotane

  Monitor Closely (1)mitotane decreases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.

• modafinil

  Monitor Closely (1)tramadol increases and modafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• morphine

  Monitor Closely (2)morphine and tramadol both increase sedation. Use Caution/Monitor.
  
  morphine and tramadol both increase serotonin levels. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, morphine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• motherwort

  Monitor Closely (1)tramadol and motherwort both increase sedation. Use Caution/Monitor.

• moxonidine

  Monitor Closely (1)tramadol and moxonidine both increase sedation. Use Caution/Monitor.

• nabilone

  Monitor Closely (1)tramadol and nabilone both increase sedation. Use Caution/Monitor.

• nafcillin

  Monitor Closely (1)nafcillin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• nalbuphine

  Monitor Closely (1)nalbuphine and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (2)tramadol, nalbuphine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.
  
  nalbuphine, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• naratriptan

  Monitor Closely (1)naratriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• nefazodone

  Monitor Closely (2)nefazodone will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  nefazodone and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• nelfinavir

  Monitor Closely (1)nelfinavir increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity. .

• nevirapine

  Monitor Closely (1)nevirapine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• nilotinib

  Minor (1)nilotinib will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• norepinephrine

  Monitor Closely (1)tramadol increases and norepinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• nortriptyline

  Monitor Closely (2)nortriptyline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  tramadol and nortriptyline both increase sedation. Use Caution/Monitor.

• olanzapine

  Monitor Closely (1)tramadol and olanzapine both increase sedation. Use Caution/Monitor.

• oliceridine

  Monitor Closely (2)oliceridine, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.
  
  tramadol, oliceridine. Either increases effects of the other by serotonin levels. Modify Therapy/Monitor Closely.

• olopatadine intranasal

  Serious - Use Alternative (1)tramadol and olopatadine intranasal both increase sedation. Avoid or Use Alternate Drug. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.

• opium tincture

  Monitor Closely (1)opium tincture and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, opium tincture. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• orphenadrine

  Monitor Closely (1)orphenadrine and tramadol both increase sedation. Use Caution/Monitor.

• oxazepam

  Monitor Closely (1)oxazepam and tramadol both increase sedation. Use Caution/Monitor.

• oxcarbazepine

  Monitor Closely (1)oxcarbazepine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• oxycodone

  Monitor Closely (1)oxycodone and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, oxycodone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• oxymorphone

  Monitor Closely (1)oxymorphone and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, oxymorphone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• ozanimod

  Serious - Use Alternative (1)ozanimod increases toxicity of tramadol by sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Avoid or Use Alternate Drug. Because the active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for serious adverse reactions, including hypertensive crisis. Therefore, coadministration of ozanimod with drugs that can increase norepinephrine or serotonin is not recommended. Monitor for hypertension with concomitant use.

• paliperidone

  Monitor Closely (1)tramadol and paliperidone both increase sedation. Use Caution/Monitor.

• papaveretum

  Monitor Closely (1)papaveretum and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, papaveretum. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• papaverine

  Monitor Closely (1)tramadol and papaverine both increase sedation. Use Caution/Monitor.

• parecoxib

  Minor (1)parecoxib will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• paroxetine

  Monitor Closely (2)paroxetine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  paroxetine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.Minor (1)paroxetine decreases effects of tramadol by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of tramadol to active metabolite.

• peginterferon alfa 2b

  Monitor Closely (1)peginterferon alfa 2b, tramadol. Other (see comment). Use Caution/Monitor. Comment: When patients are administered peginterferon alpha-2b with CYP2D6 substrates, the therapeutic effect of these drugs may be altered. Peginterferon alpha-2b may increase or decrease levels of CYP2D6 substrate.

• pegvisomant

  Monitor Closely (1)tramadol decreases effects of pegvisomant by unknown mechanism. Use Caution/Monitor.

• pentazocine

  Monitor Closely (2)pentazocine and tramadol both increase sedation. Use Caution/Monitor.
  
  pentazocine and tramadol both increase serotonin levels. Use Caution/Monitor.Serious - Use Alternative (2)tramadol, pentazocine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.
  
  pentazocine, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

• pentobarbital

  Monitor Closely (2)pentobarbital will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers
  
  pentobarbital and tramadol both increase sedation. Use Caution/Monitor.

• perampanel

  Monitor Closely (1)perampanel and tramadol both increase sedation. Use Caution/Monitor.

• perphenazine

  Monitor Closely (1)tramadol and perphenazine both increase sedation. Use Caution/Monitor.

• phendimetrazine

  Monitor Closely (1)tramadol increases and phendimetrazine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• phenelzine

  Serious - Use Alternative (2)phenelzine and tramadol both increase serotonin levels. Avoid or Use Alternate Drug.
  
  phenelzine increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• phenobarbital

  Monitor Closely (2)phenobarbital will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers
  
  phenobarbital and tramadol both increase sedation. Use Caution/Monitor.

• phentermine

  Monitor Closely (1)tramadol increases and phentermine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• phenylephrine

  Monitor Closely (1)tramadol increases and phenylephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• phenytoin

  Monitor Closely (1)phenytoin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• pholcodine

  Monitor Closely (1)tramadol and pholcodine both increase sedation. Use Caution/Monitor.

• pimozide

  Monitor Closely (1)tramadol and pimozide both increase sedation. Use Caution/Monitor.

• pirbuterol

  Monitor Closely (1)tramadol increases and pirbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• posaconazole

  Serious - Use Alternative (1)posaconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• pregabalin

  Monitor Closely (1)pregabalin, tramadol. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

• primidone

  Monitor Closely (2)primidone will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers
  
  primidone and tramadol both increase sedation. Use Caution/Monitor.

• procarbazine

  Contraindicated (1)procarbazine and tramadol both increase serotonin levels. Contraindicated.Serious - Use Alternative (1)procarbazine increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. MAOIs may potentiate CNS depression and hypotension. Do not use within 14 days of MAOI use. .

• prochlorperazine

  Monitor Closely (1)tramadol and prochlorperazine both increase sedation. Use Caution/Monitor.

• promethazine

  Monitor Closely (1)promethazine and tramadol both increase sedation. Use Caution/Monitor.

• propafenone

  Monitor Closely (2)propafenone decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  propafenone decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• propofol

  Monitor Closely (1)propofol and tramadol both increase sedation. Use Caution/Monitor.

• propylhexedrine

  Monitor Closely (1)tramadol increases and propylhexedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• protriptyline

  Monitor Closely (2)protriptyline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  tramadol and protriptyline both increase sedation. Use Caution/Monitor.

• quazepam

  Monitor Closely (1)quazepam and tramadol both increase sedation. Use Caution/Monitor.

• quetiapine

  Monitor Closely (1)tramadol and quetiapine both increase sedation. Use Caution/Monitor.

• quinacrine

  Monitor Closely (2)quinacrine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  quinacrine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• quinidine

  Monitor Closely (2)quinidine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  quinidine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• ramelteon

  Monitor Closely (1)tramadol and ramelteon both increase sedation. Use Caution/Monitor.

• ranolazine

  Minor (1)ranolazine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• rasagiline

  Contraindicated (1)rasagiline and tramadol both increase serotonin levels. Contraindicated.

• remifentanil

  Monitor Closely (1)tramadol, remifentanil. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Increases risk of serotonin syndrome.

• remimazolam

  Monitor Closely (1)remimazolam, tramadol. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely. Coadministration may result in profound sedation, respiratory depression, coma, and/or death. Continuously monitor vital signs during sedation and recovery period if coadministered. Carefully titrate remimazolam dose if administered with opioid analgesics and/or sedative/hypnotics.

• ribociclib

  Serious - Use Alternative (1)ribociclib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• rifabutin

  Monitor Closely (1)rifabutin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• rifampin

  Monitor Closely (1)rifampin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• rifapentine

  Monitor Closely (1)rifapentine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

• risperidone

  Monitor Closely (1)tramadol and risperidone both increase sedation. Use Caution/Monitor.

• ritonavir

  Monitor Closely (1)ritonavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

• rizatriptan

  Monitor Closely (1)rizatriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• rolapitant

  Monitor Closely (1)rolapitant will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Rolapitant may increase plasma concentrations of CYP2D6 substrates for at least 28 days following rolapitant administration.

• rucaparib

  Monitor Closely (1)rucaparib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.

• safinamide

  Contraindicated (1)tramadol, safinamide. Either increases toxicity of the other by serotonin levels. Contraindicated. Concomitant use could result in life-threatening serotonin syndrome.

• sage

  Minor (1)tramadol and sage both increase sedation. Minor/Significance Unknown.

• salmeterol

  Monitor Closely (1)tramadol increases and salmeterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• SAMe

  Monitor Closely (1)SAMe and tramadol both increase serotonin levels. Use Caution/Monitor.

• saquinavir

  Monitor Closely (1)saquinavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• scullcap

  Monitor Closely (1)tramadol and scullcap both increase sedation. Use Caution/Monitor.

• secobarbital

  Monitor Closely (1)secobarbital and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)secobarbital will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. May also enhance CNS depressant effect of tramadol

• selegiline

  Contraindicated (1)selegiline and tramadol both increase serotonin levels. Contraindicated. At least 14 days should elapse between discontinuation of selegiline and initiation of analgesic.

• selegiline transdermal

  Monitor Closely (1)selegiline transdermal and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.Serious - Use Alternative (1)selegiline transdermal increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death.

• selinexor

  Serious - Use Alternative (1)selinexor, tramadol. unspecified interaction mechanism. Avoid or Use Alternate Drug. Patients treated with selinexor may experience neurological toxicities. Avoid taking selinexor with other medications that may cause dizziness or confusion.

• sertraline

  Monitor Closely (3)sertraline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  sertraline decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  sertraline decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• sevoflurane

  Monitor Closely (1)sevoflurane and tramadol both increase sedation. Use Caution/Monitor.

• shepherd's purse

  Monitor Closely (1)tramadol and shepherd's purse both increase sedation. Use Caution/Monitor.

• sodium oxybate

  Serious - Use Alternative (1)tramadol, sodium oxybate. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• St John's Wort

  Monitor Closely (1)St John's Wort and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• stiripentol

  Monitor Closely (2)stiripentol, tramadol. Either increases effects of the other by sedation. Use Caution/Monitor. Concomitant use stiripentol with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence.
  
  stiripentol, tramadol. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.

• sufentanil

  Monitor Closely (1)sufentanil and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, sufentanil. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• sufentanil SL

  Serious - Use Alternative (1)sufentanil SL, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration may result in hypotension, profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

• sumatriptan

  Monitor Closely (1)sumatriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• sumatriptan intranasal

  Monitor Closely (1)sumatriptan intranasal and tramadol both increase serotonin levels. Use Caution/Monitor.

• suvorexant

  Monitor Closely (1)suvorexant and tramadol both increase sedation. Modify Therapy/Monitor Closely. Dosage adjustments of suvorexant and concomitant CNS depressants may be necessary

• tapentadol

  Monitor Closely (2)tramadol and tapentadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  tapentadol and tramadol both increase sedation. Use Caution/Monitor.Serious - Use Alternative (1)tramadol, tapentadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

• tazemetostat

  Monitor Closely (1)tazemetostat will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• tecovirimat

  Monitor Closely (1)tecovirimat will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.

• tedizolid

  Serious - Use Alternative (1)tedizolid, tramadol. Either increases levels of the other by Mechanism: pharmacodynamic synergism. Avoid or Use Alternate Drug. both increase serotonin levels; increased risk of serotonin syndrome.

• temazepam

  Monitor Closely (1)temazepam and tramadol both increase sedation. Use Caution/Monitor.

• terbinafine

  Monitor Closely (1)terbinafine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Assess need to reduce dose of CYP2D6-metabolized drug.

• terbutaline

  Monitor Closely (1)tramadol increases and terbutaline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• thioridazine

  Monitor Closely (3)thioridazine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.
  
  tramadol and thioridazine both increase sedation. Use Caution/Monitor.
  
  thioridazine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

• thiothixene

  Monitor Closely (1)tramadol and thiothixene both increase sedation. Use Caution/Monitor.

• tipranavir

  Monitor Closely (1)tipranavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.Minor (1)tipranavir will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

• topiramate

  Monitor Closely (1)tramadol and topiramate both increase sedation. Modify Therapy/Monitor Closely.

• tranylcypromine

  Serious - Use Alternative (2)tranylcypromine and tramadol both increase serotonin levels. Avoid or Use Alternate Drug.
  
  tranylcypromine increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

• trazodone

  Monitor Closely (2)trazodone and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  tramadol and trazodone both increase sedation. Use Caution/Monitor.

• triazolam

  Monitor Closely (1)triazolam and tramadol both increase sedation. Use Caution/Monitor.

• triclofos

  Monitor Closely (1)triclofos and tramadol both increase sedation. Use Caution/Monitor.

• trifluoperazine

  Monitor Closely (1)tramadol and trifluoperazine both increase sedation. Use Caution/Monitor.

• trimipramine

  Monitor Closely (2)trimipramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.
  
  tramadol and trimipramine both increase sedation. Use Caution/Monitor.

• triprolidine

  Monitor Closely (1)triprolidine and tramadol both increase sedation. Use Caution/Monitor.

• tucatinib

  Serious - Use Alternative (1)tucatinib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.

• valerian

  Serious - Use Alternative (1)valerian and tramadol both increase sedation. Avoid or Use Alternate Drug.

• venlafaxine

  Monitor Closely (1)venlafaxine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

• vilazodone

  Serious - Use Alternative (1)tramadol, vilazodone. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug. Concomitant therapy should be discontinued immediately if signs or symptoms of serotonin syndrome emerge and supportive symptomatic treatment should be initiated.

• voriconazole

  Monitor Closely (1)voriconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• vortioxetine

  Serious - Use Alternative (1)tramadol, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.

• voxelotor

  Serious - Use Alternative (1)voxelotor will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.

• xylometazoline

  Monitor Closely (1)tramadol increases and xylometazoline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• yohimbine

  Monitor Closely (1)tramadol increases and yohimbine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• ziconotide

  Monitor Closely (1)tramadol and ziconotide both increase sedation. Use Caution/Monitor.Minor (1)ziconotide, tramadol. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Additive decreased GI motility. Additive analgesia. Ziconotide does NOT potentiate opioid induced respiratory depression.

• ziprasidone

  Monitor Closely (1)tramadol and ziprasidone both increase sedation. Use Caution/Monitor.

• zolmitriptan

  Monitor Closely (1)zolmitriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

• zotepine

  Monitor Closely (1)tramadol and zotepine both increase sedation. Use Caution/Monitor.