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Celecoxib and tramadol: Drug information

Celecoxib and tramadol: Drug information
2025© UpToDate, Inc. and its affiliates and/or licensors. All Rights Reserved.
For additional information see "Celecoxib and tramadol: Patient drug information"

For abbreviations, symbols, and age group definitions show table
ALERT: US Boxed Warning
Addiction, abuse, and misuse:

Because the use of celecoxib/tramadol exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions.

Opioid analgesic Risk Evaluation and Mitigation Strategy (REMS):

Health care providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription.

Life-threatening respiratory depression:

Serious, life-threatening, or fatal respiratory depression may occur with use of celecoxib/tramadol, especially during initiation. To reduce the risk of respiratory depression, proper dosing of celecoxib/tramadol is essential.

Accidental ingestion:

Accidental ingestion of even one dose of celecoxib/tramadol, especially by children, can result in a fatal overdose of tramadol.

Cardiovascular thrombotic events:

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use.

Celecoxib/tramadol is contraindicated during the perioperative setting of coronary artery bypass graft (CABG) surgery.

GI bleeding, ulceration, and perforation:

NSAIDs cause an increased risk of serious GI adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

Ultra-rapid metabolism of tramadol and other risk factors for life-threatening respiratory depression in children:

Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least 1 case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism. Celecoxib/tramadol is contraindicated in children <12 years of age and in children <18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of celecoxib/tramadol in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.

Neonatal opioid withdrawal syndrome:

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome (NOWS), which may be life threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery.

Interactions with drugs affecting cytochrome P450 isoenzymes:

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with celecoxib/tramadol requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1.

Risks from concomitant use with benzodiazepines or other CNS depressants:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of celecoxib/tramadol and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.

Brand Names: US
  • Seglentis [DSC]
Pharmacologic Category
  • Analgesic Combination (Opioid);
  • Analgesic, Nonopioid;
  • Analgesic, Opioid;
  • Nonsteroidal Anti-inflammatory Drug (NSAID), COX-2 Selective
Dosing: Adult

Dosage guidance:

Safety: Consider prescribing naloxone or nalmefene for patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, patients with sleep-disordered breathing, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), and/or concomitant benzodiazepine use (Ref).

Dosing: Dosing provided is based on typical doses; some patients may require higher or lower doses. Individualize dosing based on patient-specific factors (eg, severity of pain, comorbidities, degree of opioid experience/tolerance) and titrate to patient-specific treatment goals (eg, improvement in function and quality of life, decrease in pain using a validated pain rating scale). Use the lowest effective dose for the shortest period of time.

Clinical considerations: Opioids may be part of a comprehensive, multimodal, patient-specific treatment plan for managing severe pain. Maximize nonopioid analgesia (when appropriate) prior to initiation of opioid analgesia (Ref).

Acute pain

Acute pain: Note: For acute non–cancer-related pain severe enough to require an opioid, utilize multimodal pain control, maximize nonopioid analgesics, and limit the quantity prescribed to the expected duration of pain severe enough to require opioids (Ref).

Oral: Celecoxib 56 mg/tramadol 44 mg: Two tablets every 12 hours as needed; maximum dose: 4 tablets per 24 hours.

Discontinuation of therapy: When reducing the dose, discontinuing, or tapering long-term opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established. Individualize tapering based on discussions with patient to minimize withdrawal, while considering patient-specific goals and concerns and the opioid’s pharmacokinetics. Proposed initial schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days) (Ref). Slower tapers may be appropriate after long-term use (eg, >1 year), whereas more rapid tapers may be appropriate in patients experiencing severe adverse effects. During tapering, patients may be at an increased risk of overdose if they return to their original (or higher) opioid dose or use illicit opioids, due to rapid loss of tolerance; consider prescribing naloxone or nalmefene. Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt autonomic withdrawal symptoms and other adjunctive agents to treat GI symptoms and muscle spasms, as needed. Continue to offer nonopioid analgesics as needed for pain management during the taper (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Severe impairment: Use is not recommended (has not been studied).

Dosing: Liver Impairment: Adult

Mild impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Moderate to severe impairment: Use is not recommended (has not been studied).

Dosing: Older Adult

Note: Minimize opioid use in older adults unless for the management of severe acute pain. Opioids are associated with an increased risk of falls and inducing or worsening delirium in older adults (Ref).

Refer to adult dosing.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults. Also see individual agents.

>10%:

Gastrointestinal: Nausea (30%), vomiting (16%)

Nervous system: Dizziness (17%), headache (12%)

1% to 10%:

Gastrointestinal: Decreased appetite (3%)

Nervous system: Drowsiness (8%)

Frequency not defined:

Cardiovascular: Thromboembolic complications (including acute myocardial infarction and cerebrovascular accident)

Gastrointestinal: Gastrointestinal hemorrhage, gastrointestinal perforation, gastrointestinal ulcer

Nervous system: Drug abuse, drug dependence

Respiratory: Respiratory depression

Postmarketing: Nervous system: Allodynia (opioid-induced hyperalgesia) (FDA Safety Communication 2023)

Contraindications

Hypersensitivity (eg, anaphylactic reactions, serious skin reactions) to tramadol, opioids, celecoxib, sulfonamides or any component of the formulation; pediatric patients <12 years of age; postoperative management in pediatric patients <18 years of age who have undergone tonsillectomy and/or adenoidectomy; significant respiratory depression; in the setting of coronary artery bypass graft (CABG) surgery; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; GI obstruction (known or suspected), including paralytic ileus; concomitant use with or within 14 days following monoamine oxidase inhibitor therapy; history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other nonsteroidal anti-inflammatory drugs.

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Note: Although the FDA-approved product labeling states this medication is contraindicated in patients with hypersensitivity to sulfonamide-containing drugs, the scientific basis of this cross-sensitivity has been challenged.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid reactions: Serious anaphylactoid reactions (including rare fatalities) often following initial dosing have been reported with tramadol. Pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome (SJS) have also been reported with use. Previous anaphylactoid reactions to opioids may increase risks for similar reactions to tramadol. If anaphylaxis or other hypersensitivity occurs, discontinue permanently; do not rechallenge. Even in patients without prior exposure to celecoxib, anaphylactic reactions and angioedema may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Contraindicated in patients who have experienced an anaphylactic reaction with nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin therapy.

• Cardiovascular events: Relative risk appears to be similar in those with and without known cardiovascular disease or risk factors for cardiovascular disease; however, absolute incidence of cardiovascular events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors. New-onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to angiotensin-converting enzyme [ACE] inhibitors, thiazide diuretics, or loop diuretics) and contribute to cardiovascular events; use with caution in patients with hypertension. May cause sodium and fluid retention; use with caution in patients with edema. Avoid use in patients with heart failure when possible (Heidenreich 2022). Avoid use in patients with recent myocardial infarction (MI) unless benefits outweigh risk of cardiovascular thrombotic events. Long-term cardiovascular risk in children has not been evaluated. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Drug reaction with eosinophilia and systemic symptoms: Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.

• GI events: Avoid use in patients with active GI bleeding. Use caution with a history of GI ulcers, concurrent therapy known to increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids, selective serotonin reuptake inhibitors), smoking, use of alcohol, or in elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with aspirin, a substantial increase in the risk of GI complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (ACCF/ACG/AHA [Bhatt 2008]).

• Hematologic effects: Anemia may occur with celecoxib use. Celecoxib does not usually affect PT, PTT, or platelet counts; does not inhibit platelet aggregation at approved doses.

• Hyperalgesia: Opioid-induced hyperalgesia (OIH) has occurred with short-term and prolonged use of opioid analgesics. Symptoms may include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily nonpainful stimuli; symptoms may be suggestive of OIH if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Consider decreasing the current opioid dose or opioid rotation in patients who experience OIH.

• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in patients ≥65 years of age, in patients with diabetes or renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE inhibitors).

• Hypoglycemia: Tramadol has been associated with hypoglycemia, including some cases resulting in hospitalization.

• Hyponatremia: Hyponatremia has been reported with tramadol use; many cases have been severe (sodium <120 mmol/L). Females >65 years of age may be at highest risk. Most cases have occurred within the first week of therapy. Some cases have occurred due to the syndrome of inappropriate antidiuretic hormone. Discontinue use and initiate appropriate treatment (fluid restriction) if signs and symptoms of hyponatremia occur.

• Hypotension: Tramadol may cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Avoid use in patients with circulatory shock.

• Respiratory depression: Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Patients and caregivers should be educated on how to recognize respiratory depression and the importance of getting emergency assistance immediately (eg, calling 911) in the event of known or suspected overdose.

• Seizures: Even when taken within the recommended dosage seizures may occur; risk is increased in patients receiving serotonin reuptake inhibitors (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], or anorectics), other opioids, tricyclic antidepressants or other cyclic compounds (including cyclobenzaprine, promethazine), neuroleptics, monoamine oxidase (MAO) inhibitors, drugs which may lower seizure threshold, or drugs which impair metabolism of tramadol (ie, CYP2D6 and 3A4 inhibitors). Patients with a history of seizures, or with a risk of seizures (head trauma, metabolic disorders, CNS infection, malignancy, or during alcohol/drug withdrawal) are also at increased risk.

• Serotonin syndrome: May occur with concomitant use of serotonergic agents (eg, SSRIs, SNRIs, triptans, tricyclic antidepressants), lithium, St John's wort, agents that impair metabolism of serotonin (eg, MAO inhibitors), or agents that impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors). Monitor patients for serotonin syndrome such as mental status changes (eg, agitation, hallucinations, coma); autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia); neuromuscular changes (eg, hyperreflexia, incoordination); and/or GI symptoms (eg, nausea, vomiting, diarrhea).

• Skin reactions: NSAIDs may cause serious skin adverse events (sometimes fatal), including acute generalized exanthematous pustulosis, DRESS, erythema multiforme, exfoliative dermatitis, fixed drug eruption (including generalized bullous fixed drug eruption), SJS, and TEN; may occur without warning and in patients without prior known sulfa allergy; discontinue use at first sign of rash (or any other hypersensitivity).

• Sulfonamide ("sulfa") allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell–mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (SJS/TEN), some clinicians choose to avoid exposure to these classes.

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease.

• Biliary tract impairment: Use caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may cause spasm of the sphincter of Oddi.

• CNS depression/coma: Avoid use in patients with impaired consciousness or coma as these patients are susceptible to intracranial effects of CO2 retention.

• Delirium tremens: Use with caution in patients with delirium tremens.

• Diabetes: Use with caution in patients with diabetes; tramadol may cause hypoglycemia.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

• Hepatic impairment: Use is not recommended for patients with moderate or severe hepatic impairment. Transaminase elevations have been reported with use; closely monitor patients with any abnormal LFT. Rare (sometimes fatal), severe hepatic reactions (eg, fulminant hepatitis, hepatic necrosis, hepatic failure) have occurred with NSAID use; discontinue if signs or symptoms of liver disease develop, if systemic manifestations occur, or with persistent or worsening abnormal hepatic function tests.

• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2022]).

• Obesity: Use with caution in patients with severe obesity.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: NSAID use may compromise existing renal function. Dose-dependent decreases in prostaglandin synthesis may result from NSAID use, causing a reduction in renal blood flow which may cause renal decompensation (usually reversible). Patients with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics, ACE inhibitors, angiotensin II receptor blockers, and the elderly are at greater risk for renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Avoid use in patients with advanced renal disease; discontinue use with persistent or worsening abnormal renal function tests. Long-term NSAID use may result in renal papillary necrosis.

• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Sleep-related disorders: Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and central nervous system depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2022]).

• Suicide risk: Avoid use in patients who are suicidal; use with caution in patients taking tranquilizers and/or antidepressants, or those with an emotional disturbance including depression. Consider the use of alternative nonopioid analgesics in these patients.

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: Consider prescribing naloxone or nalmefene for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids.

Special populations:

• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• CYP2D6 "poor metabolizers": Poor metabolizers have decreased metabolism of tramadol to its active metabolite, which may diminish analgesia; avoid the use of tramadol and consider alternatives that are not metabolized by CYP2D6 (CPIC [Crews 2021]).

• CYP2D6 "ultrarapid metabolizers": Ultrarapid metabolizers have increased metabolism of tramadol to its active metabolite, which may increase the risk of toxicity; avoid the use of tramadol and consider alternatives that are not metabolized by CYP2D6 (CPIC [Crews 2021]). The occurrence of this phenotype is seen in ~1% to 2% of East Asian patients (Chinese, Japanese, Korean), 1% to 10% of Caucasian patients, 3% to 4% of Black patients, and may be >10% in certain racial/ethnic groups (ie, Oceanian, Northern African, Middle Eastern, Ashkenazi Jewish, and Puerto Rican patients). Deaths have also occurred in breastfeeding infants after being exposed to high concentrations of morphine because the mothers were ultrarapid metabolizers of codeine.

• Older adult: Use opioids with caution in older adults; may be more sensitive to adverse effects. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increased adverse effects. Monitor closely for adverse effects associated with opioid therapy (eg, respiratory and central nervous system depression, falls, cognitive impairment, constipation) (CDC [Dowell 2022]). Consider the use of alternative nonopioid analgesics in these patients when possible.

• Neonates: Neonatal withdrawal syndrome: Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

• Pediatric: Respiratory depression: Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.

Other warnings/precautions:

• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent on opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances; provide care as needed. Concurrent use of mixed agonist/antagonist (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists.

• Abuse/misuse/diversion: Use with caution in patients with a history of substance abuse disorder; potential for drug dependency exists. Other factors associated with increased risk for misuse include concomitant depression or other mental health conditions, higher opioid dosages, or taking other central nervous system depressants. Consider offering naloxone or nalmefene prescriptions in patients with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), concomitant benzodiazepine use, and patients at risk for returning to a high dose after losing tolerance (CDC [Dowell 2022]).

• Naloxone/nalmefene access: Discuss the availability of naloxone or nalmefene with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an OUD (current or history of), or have experienced opioid-induced respiratory depression/opioid overdose. Additionally, health care providers should consider prescribing naloxone or nalmefene to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone or nalmefene (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone or nalmefene, and getting emergency help.

• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated, the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

• REMS program: Additional information is available at www.opioidanalgesicrems.com or at 1-800-503-0784.

• Surgery: Opioids decrease bowel motility; monitor for decrease bowel motility in postoperative patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Seglentis: Celecoxib 56 mg and tramadol hydrochloride 44 mg [DSC]

Generic Equivalent Available: US

No

Pricing: US

Tablets (Seglentis Oral)

56-44 mg (per each): $5.43

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Administration: Adult

Oral: Administer without regard to meals.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Seglentis: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213426s003lbl.pdf#page=57

Use: Labeled Indications

Pain, acute: Management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of use: Because of the risks of substance use disorder, abuse, and misuse with opioids, which may occur at any dosage or duration, reserve celecoxib/tramadol for use in patients for whom alternative treatment options (eg, nonopioid analgesics) have not been tolerated or are not expected to be tolerated, or have not provided adequate analgesia or are not expected to provide adequate analgesia. Not intended to be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

Medication Safety Issues
High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (opioids, all formulations and routes of administration) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).

Older Adult: High-risk medication:

Beers Criteria: Tramadol is identified in the Beers Criteria as a potentially inappropriate medication to be used with caution in patients 65 years and older due to the potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults (Beers Criteria [AGS 2023]).

Pediatric patients: High-risk medication:

KIDs List: Tramadol, when used in pediatric patients <18 years of age, is identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list and should be used with caution due to risk of respiratory depression unless pharmacogenetic testing completed (weak recommendation; low quality of evidence) (PPA [Meyers 2020]).

Metabolism/Transport Effects

Refer to individual components.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of 5-Aminosalicylic Acid Derivatives. Risk C: Monitor

Acemetacin: May increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid

Agents with Clinically Relevant Anticholinergic Effects: May increase adverse/toxic effects of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor

Ajmaline: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor

Ajmaline: Sulfonamides may increase adverse/toxic effects of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor

Aliskiren: Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of Aliskiren. Nonsteroidal Anti-Inflammatory Agents may decrease antihypertensive effects of Aliskiren. Risk C: Monitor

Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Almotriptan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Alvimopan: Opioid Agonists may increase adverse/toxic effects of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider Therapy Modification

Amifampridine: Agents With Seizure Threshold Lowering Potential may increase neuroexcitatory and/or seizure-potentiating effects of Amifampridine. Risk C: Monitor

Aminoglycosides: Nonsteroidal Anti-Inflammatory Agents may decrease excretion of Aminoglycosides. Data only in premature infants. Risk C: Monitor

Aminolevulinic Acid (Systemic): Photosensitizing Agents may increase photosensitizing effects of Aminolevulinic Acid (Systemic). Risk X: Avoid

Aminolevulinic Acid (Topical): Photosensitizing Agents may increase photosensitizing effects of Aminolevulinic Acid (Topical). Risk C: Monitor

Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor

Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Amphetamines: May increase analgesic effects of Opioid Agonists. Risk C: Monitor

Amphetamines: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor

Androgens: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor

Angiotensin II Receptor Blockers: Nonsteroidal Anti-Inflammatory Agents may decrease therapeutic effects of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Angiotensin II Receptor Blockers may increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Risk C: Monitor

Angiotensin-Converting Enzyme Inhibitors: Nonsteroidal Anti-Inflammatory Agents may decrease antihypertensive effects of Angiotensin-Converting Enzyme Inhibitors. Angiotensin-Converting Enzyme Inhibitors may increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Risk C: Monitor

Anticoagulants: Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase anticoagulant effects of Anticoagulants. Risk C: Monitor

Antidiabetic Agents: May increase hypoglycemic effects of Hypoglycemia-Associated Agents. Risk C: Monitor

Antiemetics (5HT3 Antagonists): May increase serotonergic effects of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Antipsychotic Agents: Serotonergic Agents (High Risk) may increase adverse/toxic effects of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor

ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor

ARIPiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor

Artemether and Lumefantrine: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor

Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification

Aspirin: May increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Specifically, the risk of gastrointestinal adverse effects may be increased. Management: Concurrent use of aspirin at doses beyond cardioprotective levels is not recommended. While concurrent use of low-dose aspirin with a COX-2 inhibitor is permissible, patients should be monitored closely for signs/symptoms of GI ulceration/bleeding. Risk D: Consider Therapy Modification

Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Benperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor

Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Beta-Blockers: Nonsteroidal Anti-Inflammatory Agents may decrease antihypertensive effects of Beta-Blockers. Risk C: Monitor

Bile Acid Sequestrants: May decrease absorption of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor

Bisphosphonate Derivatives: Nonsteroidal Anti-Inflammatory Agents may increase adverse/toxic effects of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Risk C: Monitor

Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification

Brexpiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor

Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification

Buprenorphine: May decrease therapeutic effects of Opioid Agonists. Management: Seek alternatives to buprenorphine in patients receiving pure opioid agonists. If combined in certain pain management situations (eg, surgery), monitor for symptoms of therapeutic failure/high dose requirements or opioid withdrawal symptoms. Risk D: Consider Therapy Modification

BuPROPion: May increase neuroexcitatory and/or seizure-potentiating effects of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor

BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

BusPIRone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor

CarBAMazepine: TraMADol may decrease therapeutic effects of CarBAMazepine. TraMADol may increase CNS depressant effects of CarBAMazepine. CarBAMazepine may decrease serum concentration of TraMADol. Risk X: Avoid

Cardiac Glycosides: Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of Cardiac Glycosides. Risk C: Monitor

Cariprazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification

Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification

Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification

Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor

Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor

CNS Depressants: May increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification

Corticosteroids (Systemic): May increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Risk C: Monitor

CycloSPORINE (Systemic): Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of CycloSPORINE (Systemic). Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase serum concentration of Nonsteroidal Anti-Inflammatory Agents. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (eg, hypertension) during concomitant therapy with NSAIDs. Risk D: Consider Therapy Modification

CYP2C9 Inducers (Moderate): May decrease serum concentration of Celecoxib. Risk C: Monitor

CYP2C9 Inhibitors (Moderate): May increase serum concentration of Celecoxib. Risk C: Monitor

CYP2D6 Inhibitors (Moderate): May increase serum concentration of TraMADol. CYP2D6 Inhibitors (Moderate) may decrease active metabolite exposure of TraMADol. Risk C: Monitor

CYP2D6 Inhibitors (Strong): May increase serum concentration of TraMADol. CYP2D6 Inhibitors (Strong) may decrease active metabolite exposure of TraMADol. Risk C: Monitor

CYP3A4 Inducers (Moderate): May decrease serum concentration of TraMADol. Risk C: Monitor

CYP3A4 Inducers (Strong): May decrease serum concentration of TraMADol. Risk C: Monitor

CYP3A4 Inhibitors (Moderate): May increase serum concentration of TraMADol. CYP3A4 Inhibitors (Moderate) may increase active metabolite exposure of TraMADol. Risk C: Monitor

CYP3A4 Inhibitors (Strong): May increase serum concentration of TraMADol. CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of TraMADol. Risk C: Monitor

Dapoxetine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid

Dapsone (Topical): May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Risk C: Monitor

Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification

Deferasirox: Nonsteroidal Anti-Inflammatory Agents may increase adverse/toxic effects of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor

Desmopressin: Nonsteroidal Anti-Inflammatory Agents may increase hyponatremic effects of Desmopressin. Risk C: Monitor

Desmopressin: Opioid Agonists may increase hyponatremic effects of Desmopressin. Risk C: Monitor

DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification

Dexmethylphenidate-Methylphenidate: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Dextromethorphan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Digoxin: TraMADol may increase serum concentration of Digoxin. Risk C: Monitor

Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor

Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Diuretics: Opioid Agonists may increase adverse/toxic effects of Diuretics. Opioid Agonists may decrease therapeutic effects of Diuretics. Risk C: Monitor

DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification

Drospirenone-Containing Products: May increase hyperkalemic effects of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor

DULoxetine: May increase adverse/toxic effects of TraMADol. The risk for serotonin syndrome/serotonin toxicity and seizures may be increased with this combination. DULoxetine may decrease therapeutic effects of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes), reduced tramadol effectiveness and seizures if these agents are combined. Risk C: Monitor

Eletriptan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Eluxadoline: Opioid Agonists may increase constipating effects of Eluxadoline. Risk X: Avoid

Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor

Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Eplerenone: Nonsteroidal Anti-Inflammatory Agents may decrease antihypertensive effects of Eplerenone. Nonsteroidal Anti-Inflammatory Agents may increase hyperkalemic effects of Eplerenone. Risk C: Monitor

Ergot Derivatives: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Estrogen Derivatives: Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase thrombogenic effects of Estrogen Derivatives. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase serum concentration of Estrogen Derivatives. Risk C: Monitor

Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid

Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification

Fusidic Acid (Systemic): May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider Therapy Modification

Gastrointestinal Agents (Prokinetic): Opioid Agonists may decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor

Gepirone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor

Grapefruit Juice: May increase serum concentration of TraMADol. Grapefruit Juice may increase active metabolite exposure of TraMADol. Risk C: Monitor

Herbal Products with Glucose Lowering Effects: May increase hypoglycemic effects of Hypoglycemia-Associated Agents. Risk C: Monitor

HydrALAZINE: Nonsteroidal Anti-Inflammatory Agents may decrease antihypertensive effects of HydrALAZINE. Risk C: Monitor

HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification

Hypoglycemia-Associated Agents: May increase hypoglycemic effects of Hypoglycemia-Associated Agents. Risk C: Monitor

Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): May decrease therapeutic effects of Opioid Agonists. Opioid Agonists may decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor

Iobenguane Radiopharmaceutical Products: TraMADol may decrease therapeutic effects of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer tramadol until at least 7 days after each iobenguane dose. Risk X: Avoid

Iohexol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification

Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Ketorolac (Nasal): May increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid

Ketorolac (Systemic): Nonsteroidal Anti-Inflammatory Agents may increase adverse/toxic effects of Ketorolac (Systemic). Risk X: Avoid

Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification

Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Linezolid: May increase serotonergic effects of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Risk X: Avoid

Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Lithium: Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of Lithium. Management: Consider reducing the lithium dose when initiating a NSAID. Monitor for increased lithium therapeutic/toxic effects if a NSAID is initiated/dose increased, or decreased effects if a NSAID is discontinued/dose decreased. Risk D: Consider Therapy Modification

Local Anesthetics: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor

Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Loop Diuretics: Nonsteroidal Anti-Inflammatory Agents may decrease diuretic effects of Loop Diuretics. Loop Diuretics may increase nephrotoxic effects of Nonsteroidal Anti-Inflammatory Agents. Management: Monitor for evidence of kidney injury or decreased therapeutic effects of loop diuretics with concurrent use of an NSAID. Consider avoiding concurrent use in CHF or cirrhosis. Concomitant use of bumetanide with indomethacin is not recommended. Risk D: Consider Therapy Modification

Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification

Lumacaftor and Ivacaftor: May decrease serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor

Macimorelin: Coadministration of Nonsteroidal Anti-Inflammatory Agents and Macimorelin may alter diagnostic results. Risk X: Avoid

Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Maitake: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor

Mavorixafor: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk X: Avoid

Mecamylamine: Sulfonamides may increase adverse/toxic effects of Mecamylamine. Risk X: Avoid

Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

MetFORMIN: Nonsteroidal Anti-Inflammatory Agents may increase adverse/toxic effects of MetFORMIN. Risk C: Monitor

Methotrexate: Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of Methotrexate. Management: Avoid coadministration of higher dose methotrexate (such as that used for the treatment of oncologic conditions) and NSAIDs. Use caution if coadministering lower dose methotrexate and NSAIDs. Risk D: Consider Therapy Modification

Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification

Methoxsalen (Systemic): Photosensitizing Agents may increase photosensitizing effects of Methoxsalen (Systemic). Risk C: Monitor

Methoxyflurane: Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of Methoxyflurane. Risk X: Avoid

Methylene Blue: May increase serotonergic effects of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Risk X: Avoid

Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Metoclopramide: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor

Mifamurtide: Nonsteroidal Anti-Inflammatory Agents may decrease therapeutic effects of Mifamurtide. Risk X: Avoid

Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Monoamine Oxidase Inhibitors (Antidepressant): May increase adverse/toxic effects of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased.. Risk X: Avoid

Monoamine Oxidase Inhibitors (Type B): Serotonergic Opioids (High Risk) may increase serotonergic effects of Monoamine Oxidase Inhibitors (Type B). This could result in serotonin syndrome. Risk X: Avoid

Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Naftazone: May increase antiplatelet effects of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor

Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Nalfurafine: Opioid Agonists may increase adverse/toxic effects of Nalfurafine. Opioid Agonists may decrease therapeutic effects of Nalfurafine. Risk C: Monitor

Nalmefene: May decrease therapeutic effects of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider Therapy Modification

Naltrexone: May decrease therapeutic effects of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid

Nefazodone: May increase adverse/toxic effects of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Nefazodone may increase serum concentration of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes), seizures, and tramadol adverse effects when these agents are combined. Risk C: Monitor

Nitric Oxide: May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor

Nonsteroidal Anti-Inflammatory Agents (Topical): Nonsteroidal Anti-Inflammatory Agents (Topical) may increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of gastrointestinal (GI) toxicity is increased. Management: Coadministration of systemic nonsteroidal anti-inflammatory drugs (NSAIDs) and topical NSAIDs is not recommended. If systemic NSAIDs and topical NSAIDs, ensure the benefits outweigh the risks and monitor for increased NSAID toxicities. Risk D: Consider Therapy Modification

Nonsteroidal Anti-Inflammatory Agents: May increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk for gastrointestinal toxicity is increased. Risk X: Avoid

Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid

Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Omacetaxine: Nonsteroidal Anti-Inflammatory Agents may increase adverse/toxic effects of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Risk C: Monitor

Ondansetron: May decrease therapeutic effects of TraMADol. Ondansetron may increase serotonergic effects of TraMADol. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and diminished tramadol efficacy when these agents are combined. Risk C: Monitor

Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification

Opioids (Mixed Agonist / Antagonist): May decrease analgesic effects of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid

Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Opipramol: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid

Oxitriptan: Serotonergic Agents (High Risk) may increase serotonergic effects of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification

OxyCODONE: CNS Depressants may increase CNS depressant effects of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification

Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid

Peginterferon Alfa-2b: May decrease serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor

Pegvisomant: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor

Pegvisomant: Opioid Agonists may decrease therapeutic effects of Pegvisomant. Risk C: Monitor

Periciazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Perphenazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

PHENobarbital: May increase CNS depressant effects of TraMADol. PHENobarbital may decrease serum concentration of TraMADol. Management: Avoid use of tramadol and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D: Consider Therapy Modification

Phenylbutazone: May increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid

Pipamperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pipamperone. Specifically, the risk of seizures may be increased. Risk X: Avoid

Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor

Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor

Polyethylene Glycol-Electrolyte Solution: Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of Polyethylene Glycol-Electrolyte Solution. Risk C: Monitor

Porfimer: Photosensitizing Agents may increase photosensitizing effects of Porfimer. Risk X: Avoid

Potassium Salts: Nonsteroidal Anti-Inflammatory Agents may increase hyperkalemic effects of Potassium Salts. Risk C: Monitor

Potassium-Sparing Diuretics: Nonsteroidal Anti-Inflammatory Agents may increase hyperkalemic effects of Potassium-Sparing Diuretics. Nonsteroidal Anti-Inflammatory Agents may decrease antihypertensive effects of Potassium-Sparing Diuretics. Risk C: Monitor

PRALAtrexate: Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of PRALAtrexate. More specifically, NSAIDS may decrease the renal excretion of pralatrexate. Management: Avoid coadministration of pralatrexate with nonsteroidal anti-inflammatory drugs (NSAIDs). If coadministration cannot be avoided, closely monitor for increased pralatrexate serum levels or toxicity. Risk D: Consider Therapy Modification

Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor

Prilocaine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor for signs of methemoglobinemia when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid use of these agents with prilocaine/lidocaine cream in infants less than 12 months of age. Risk C: Monitor

Primaquine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Primaquine. Specifically, the risk for methemoglobinemia may be increased. Management: Avoid concomitant use of primaquine and other drugs that are associated with methemoglobinemia when possible. If combined, monitor methemoglobin levels closely. Risk D: Consider Therapy Modification

Primidone: May increase CNS depressant effects of TraMADol. Primidone may decrease serum concentration of TraMADol. Management: Avoid use of tramadol and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a moderate CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D: Consider Therapy Modification

Probenecid: May increase serum concentration of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor

Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Promazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Prostaglandins (Ophthalmic): Nonsteroidal Anti-Inflammatory Agents may decrease therapeutic effects of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents may also enhance the therapeutic effects of Prostaglandins (Ophthalmic). Risk C: Monitor

Prothionamide: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor

Quinolones: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Quinolones may decrease therapeutic effects of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor

Quinolones: Nonsteroidal Anti-Inflammatory Agents may increase neuroexcitatory and/or seizure-potentiating effects of Quinolones. Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of Quinolones. Risk C: Monitor

Ramosetron: Opioid Agonists may increase constipating effects of Ramosetron. Risk C: Monitor

Rifapentine: May decrease serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor

Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification

ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor

Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor

Salicylates: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor

Samidorphan: May decrease therapeutic effects of Opioid Agonists. Risk X: Avoid

Selective Serotonin Reuptake Inhibitor: TraMADol may increase adverse/toxic effects of Selective Serotonin Reuptake Inhibitor. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and seizures when these agents are combined. Risk C: Monitor

Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): May increase adverse/toxic effects of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may decrease therapeutic effects of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes), seizures, and decreased tramadol efficacy when these agents are combined. Risk C: Monitor

Serotonergic Agents (High Risk, Miscellaneous): Serotonergic Opioids (High Risk) may increase serotonergic effects of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor

Serotonergic Non-Opioid CNS Depressants: May increase serotonergic effects of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Serotonergic Non-Opioid CNS Depressants may increase CNS depressant effects of Serotonergic Opioids (High Risk). Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider Therapy Modification

Serotonergic Opioids (High Risk): May increase serotonergic effects of TraMADol. This could result in serotonin syndrome. Serotonergic Opioids (High Risk) may increase CNS depressant effects of TraMADol. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider Therapy Modification

Serotonin 5-HT1D Receptor Agonists (Triptans): May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Serotonin/Norepinephrine Reuptake Inhibitor: May increase adverse/toxic effects of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and seizures when these agents are combined. Risk C: Monitor

Sertindole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sertindole. Specifically, the risk of seizures may be increased. Risk C: Monitor

Sincalide: Drugs that Affect Gallbladder Function may decrease therapeutic effects of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider Therapy Modification

Sodium Nitrite: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor

Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor

Sodium Phosphates: May increase nephrotoxic effects of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of acute phosphate nephropathy may be enhanced. Risk C: Monitor

Somatostatin Analogs: Opioid Agonists may decrease analgesic effects of Somatostatin Analogs. Opioid Agonists may increase analgesic effects of Somatostatin Analogs. Risk C: Monitor

St John's Wort: May increase serotonergic effects of TraMADol. This could result in serotonin syndrome. St John's Wort may decrease serum concentration of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and reduced tramadol effects (including withdrawal symptoms) when combined. Monitor for increased tramadol effects if St John's wort is discontinued. Risk C: Monitor

Succinylcholine: May increase bradycardic effects of Opioid Agonists. Risk C: Monitor

Sulpiride: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sulpiride. Specifically, the risk of seizures may be increased. Risk C: Monitor

Sulprostone: Nonsteroidal Anti-Inflammatory Agents may decrease therapeutic effects of Sulprostone. Risk X: Avoid

Suvorexant: CNS Depressants may increase CNS depressant effects of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification

Syrian Rue: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Tacrolimus (Systemic): Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of Tacrolimus (Systemic). Risk C: Monitor

Tenofovir Products: Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose due to a potential risk of acute renal failure. Diclofenac appears to confer the most risk. Risk D: Consider Therapy Modification

Tenoxicam: May increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid

Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid

Thiazide and Thiazide-Like Diuretics: Nonsteroidal Anti-Inflammatory Agents may decrease therapeutic effects of Thiazide and Thiazide-Like Diuretics. Thiazide and Thiazide-Like Diuretics may increase nephrotoxic effects of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor

Thioridazine: CYP2D6 Inhibitors (Weak) may increase serum concentration of Thioridazine. Management: Consider avoiding concomitant use of thioridazine and weak CYP2D6 inhibitors. If combined, monitor closely for QTc interval prolongation and arrhythmias. Some weak CYP2D6 inhibitors list use with thioridazine as a contraindication. Risk D: Consider Therapy Modification

Tilidine: May increase therapeutic effects of Opioid Agonists. Risk X: Avoid

Tolperisone: Nonsteroidal Anti-Inflammatory Agents may increase adverse/toxic effects of Tolperisone. Specifically, the risk of hypersensitivity reactions may be increased. Tolperisone may increase therapeutic effects of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor

Tricyclic Antidepressants: Serotonergic Opioids (High Risk) may increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Tricyclic Antidepressants may increase CNS depressant effects of Serotonergic Opioids (High Risk). Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider Therapy Modification

Triflusal: Nonsteroidal Anti-Inflammatory Agents may decrease protein binding of Triflusal. Specifically, NSAIDs may decrease protein binding of the active Triflusal metabolite. Triflusal may decrease protein binding of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor

Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Vancomycin: Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of Vancomycin. Risk C: Monitor

Vanzacaftor, Tezacaftor, and Deutivacaftor: May increase serum concentration of CYP2C9 Substrates (High risk with Inhibitors). Risk C: Monitor

Verteporfin: Photosensitizing Agents may increase photosensitizing effects of Verteporfin. Risk C: Monitor

Vitamin K Antagonists: TraMADol may increase anticoagulant effects of Vitamin K Antagonists. Risk C: Monitor

Zolpidem: CNS Depressants may increase CNS depressant effects of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider Therapy Modification

Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification

Reproductive Considerations

Nonsteroidal anti-inflammatory drugs (NSAIDs) may delay or prevent rupture of ovarian follicles which may be associated with infertility. Long-term opioid use may lead to sexual dysfunction or infertility in males and females.

Refer to individual monographs for additional information.

Pregnancy Considerations

Tramadol crosses the placenta.

Prolonged use of opioids during pregnancy may result in neonatal opioid withdrawal syndrome, which may be life threatening if not recognized and treated. If prolonged opioid use is required during pregnancy, ensure that appropriate treatment will be available.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may cause premature closure of the ductus arteriosus. Product labeling for this combination specifically states use should be avoided starting at 30 weeks' gestation. If NSAID use is necessary between 20 and 30 weeks' gestation, limit use to the lowest effective dose and shortest duration possible.

Refer to individual monographs for additional information.

Breastfeeding Considerations

Celecoxib, tramadol, and the active M1 metabolite of tramadol are present in breast milk.

The manufacturer does not recommend use lactating patients for obstetrical preoperative medication or for post-partum analgesia. Refer to individual monographs for additional information.

Monitoring Parameters

Pain relief; respiratory status, especially in the first 24 to 72 hours of treatment, and mental status/alertness (especially in patients on concomitant CNS depressants, including benzodiazepines); CBC; hemoglobin/hematocrit (patients with anemia); basic metabolic panel; occult blood loss and periodic LFTs; monitor renal function (urine output, serum BUN and creatinine); BP (baseline and during treatment), heart rate; blood glucose if hypoglycemia is suspected; signs/symptoms of hyponatremia (eg, confusion, disorientation) especially during initiation of therapy; signs/symptoms of tolerance, substance use disorder, abuse, misuse, or suicidal ideation; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013); signs and symptoms of serotonin syndrome such as mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile BP, hyperthermia), neuromuscular changes (eg, hyperreflexia, incoordination), and/or GI symptoms (eg, nausea, vomiting, diarrhea); observe for weight gain, edema; observe for bleeding; evaluate GI effects (abdominal pain, bleeding, dyspepsia); signs and symptoms of neonatal withdrawal syndrome in infants born to mothers using opioids during pregnancy (eg. irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight); skin reactions; during discontinuation of therapy monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances.

Alternate recommendations: Subacute or chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. In patients with subacute pain initially treated for acute pain, reassess pain and function after 30 days to address potentially reversible causes of pain and prevent unintentional long-term opioid therapy. In patients on long-term therapy, re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Toxicology testing is recommended prior to initiation and at least yearly (includes controlled prescription medications, illicit drugs of abuse, and benzodiazepines). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (CDC [Dowell 2022]).

Mechanism of Action

Celecoxib: Inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclooxygenase-2 (COX-2), which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inflammatory properties. Celecoxib does not inhibit cyclooxygenase-1 (COX-1) at therapeutic concentrations.

Tramadol: Tramadol and its active metabolite (M1) binds to μ-opiate receptors in the CNS causing inhibition of ascending pain pathways, altering the perception of and response to pain; also inhibits the reuptake of norepinephrine and serotonin, which are neurotransmitters involved in the descending inhibitory pain pathway responsible for pain relief (Grond 2004).

Pharmacokinetics (Adult Data Unless Noted)

Refer to individual agents.

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