TraMADol (Systemic)
Drug class: Antineoplastic Agents
Usage of TraMADol (Systemic)
Pain
Conventional tablets: Management of pain that is severe enough to require an opiate analgesic and for which alternative treatment options (e.g., nonopiate analgesics) have not been, or are not expected to be, adequate or tolerated. Efficacy established in patients with moderately severe acute or chronic pain, including postoperative, gynecologic, obstetric, and cancer pain.
Extended-release tablets or capsules: Management of pain that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic and for which alternative treatment options (e.g., nonopiate analgesics, immediate-release opiates) are inadequate or not tolerated; not indicated for as-needed (“prn”) use. Efficacy established in 2 studies in patients with moderate to moderately severe chronic pain associated with osteoarthritis; several other studies failed to provide adequate evidence of efficacy.
Tramadol/acetaminophen tablets: Short-term (≤5 days) management of acute pain that is severe enough to require an opiate analgesic and for which alternative treatment options (e.g., nonopiate analgesics) have not been, or are not expected to be, adequate or tolerated.
Tramadol/celecoxib tablets: Management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatment options (e.g., nonopiate analgesics) have not been, or are not expected to be, adequate or tolerated.
American College of Rheumatology (ACR) states tramadol can be considered in patients with osteoarthritis in whom NSAIAs are contraindicated (e.g., those with renal impairment) or in whom acetaminophen or NSAIAs have not produced an adequate response.
In symptomatic treatment of acute pain, reserve opiate analgesics for pain resulting from severe injuries, severe medical conditions, or surgical procedures, or when nonopiate alternatives for relieving pain and restoring function are expected to be ineffective or are contraindicated. Use smallest effective dosage for shortest possible duration since long-term opiate use often begins with treatment of acute pain. Optimize concomitant use of other appropriate therapies. (See Managing Opiate Therapy for Acute Pain under Dosage and Administration.)
Generally use opiates for management of chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing ) that is not associated with active cancer treatment, palliative care, or end-of-life care only if other appropriate nonpharmacologic and nonopiate pharmacologic strategies have been ineffective and expected benefits for both pain relief and functional improvement are anticipated to outweigh risks.
If used for chronic pain, opiate analgesics should be part of an integrated approach that also includes appropriate nonpharmacologic modalities (e.g., cognitive-behavioral therapy, relaxation techniques, biofeedback, functional restoration, exercise therapy, certain interventional procedures) and other appropriate pharmacologic therapies (e.g., nonopiate analgesics, analgesic adjuncts such as selected anticonvulsants and antidepressants for certain neuropathic pain conditions).
Available evidence insufficient to determine whether long-term opiate therapy for chronic pain results in sustained pain relief or improvements in function and quality of life or is superior to other pharmacologic or nonpharmacologic treatments. Use is associated with serious risks (e.g., opiate use disorder [OUD], overdose). (See Managing Opiate Therapy for Chronic Noncancer Pain under Dosage and Administration.)
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How to use TraMADol (Systemic)
General
Managing Opiate Therapy for Acute Pain
Managing Opiate Therapy for Chronic Noncancer Pain
Administration
Oral Administration
Administer orally alone or in fixed combination with acetaminophen.
Do not use extended-release tramadol preparations concomitantly with other tramadol-containing preparations.
Conventional TabletsAdminister without regard to meals.
Extended-release TabletsAdminister once daily without regard to food, but in a consistent manner relative to food intake.
Swallow tablets whole with liquid; do not crush, chew, split, or dissolve.
Extended-release CapsulesAdminister once daily without regard to food, but in a consistent manner relative to food intake.
Swallow capsules whole with liquid; do not break, chew, split, or dissolve.
Fixed Combination with AcetaminophenManufacturer makes no specific recommendation regarding administration with food.
Dosage
Available as tramadol hydrochloride; dosage expressed in terms of the salt.
Use lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient.
Individualize initial dosage based on severity of pain, response, prior analgesic use, and risk factors for addiction, abuse, and misuse.
When switching patients receiving chronic opiate therapy from one opiate analgesic to another, generally reduce the calculated equianalgesic dosage of the new opiate agonist by about 25–50% to avoid inadvertent overdosage. This calculation does not apply when switching to methadone; consult specific recommendations for methadone dosage.
When used concomitantly with other CNS depressants, use lowest effective dosages and shortest possible duration of concomitant therapy. (See Specific Drugs under Interactions.)
Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression. Monitor closely for respiratory depression, especially during the first 24–72 hours of therapy and following any increase in dosage.
Frequent communication among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family is important during periods of changing analgesic requirements, including the initial dosage titration period.
Titrate dosage to a level that provides adequate analgesia and minimizes adverse effects. If level of pain increases after dosage stabilization, attempt to identify source of increased pain before increasing dosage.
Continually assess adequacy of pain control and reevaluate for adverse effects, as well as for development of addiction, abuse, or misuse. During long-term therapy, continually reevaluate continued need for opiate analgesics.
Patients with chronic pain who experience episodes of breakthrough pain may require dosage adjustment or supplemental analgesia (i.e., “rescue” therapy with an immediate-release analgesic).
When discontinuing tramadol in a patient who may be physically dependent on opiates, generally reduce dosage by 25–50% every 2–4 days. If manifestations of withdrawal occur, increase dosage to the prior level and taper more slowly (increase interval between dosage reductions and/or reduce amount of each incremental change in dose).
Adults
Pain Conventional Tablets OralInitially, 25 mg daily in the morning; titrate dosage slowly to reduce risk of adverse effects. Increase dosage in 25-mg increments as separate doses every 3 days to a dosage of 100 mg daily (25 mg 4 times daily); then may increase total daily dosage by 50 mg every 3 days as tolerated, up to 200 mg daily (50 mg 4 times daily.) After titration, 50–100 mg can be given every 4–6 hours, up to 400 mg daily.
If more rapid onset of analgesia is required, may initiate therapy at 50–100 mg every 4–6 hours (up to 400 mg daily), but risk of adverse events may be increased.
Extended-release Tablets and Capsules OralPatients not currently receiving tramadol (including those being switched from other opiate analgesics): Initially, 100 mg once daily; increase dosage in 100-mg increments every 5 days, as needed and tolerated, up to 300 mg daily. Ratios for conversion from other opiate analgesics to extended-release tramadol preparations not established in clinical trials.
Patients currently receiving immediate-release tramadol: Calculate total daily dosage of the immediate-release drug and round down to the next lower 100-mg increment; make subsequent dosage adjustments based on patient requirements. Monitor closely for sedation and respiratory depression (data on relative bioavailability of immediate-release and extended-release preparations are lacking).
Because of limitations in dose selection, some patients may not be successfully switched from immediate-release to extended-release tramadol preparations.
Discontinue all other around-the-clock opiate analgesics when therapy with extended-release tramadol is initiated.
Fixed Combination with Acetaminophen Oral75 mg of tramadol hydrochloride every 4–6 hours as needed (up to 300 mg daily).
Fixed Combination with Celecoxib Oral2 tablets (56 mg of celecoxib and 44 mg of tramadol hydrochloride each) every 12 hours as needed.
Prescribing Limits
Adults
Pain OralFor acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for the expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days).
CDC recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily for chronic pain and avoid dosages equivalent to ≥90 mg of morphine sulfate daily or carefully justify their decision to prescribe such dosages. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily.
Some states have set prescribing limits (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with a specialist is mandated or recommended).
Conventional Tablets OralMaximum 400 mg daily.
Extended-release Tablets or Capsules OralMaximum 300 mg daily.
Fixed Combination with Acetaminophen OralMaximum 300 mg daily.
Special Populations
Hepatic Impairment
In patients with cirrhosis, 50 mg (as conventional tablets) every 12 hours. (See Special Populations under Pharmacokinetics.)
Extended-release oral formulations not recommended for use in patients with severe (Child-Pugh class C) hepatic impairment. Available tablet or capsule strengths and once-daily dosing do not provide sufficient dosing flexibility for safe use in these patients.
Tramadol in fixed combination with acetaminophen not recommended in patients with hepatic impairment.
Renal Impairment
Reduced dosage recommended in patients with severe renal impairment (Clcr <30 mL/minute). (See Special Populations under Pharmacokinetics.)
Severe Renal ImpairmentConventional tablets: 50–100 mg of tramadol every 12 hours (maximum 200 mg daily). In hemodialysis patients, administer the patient’s regular dose on dialysis days (not substantially removed by dialysis).
Fixed combination with acetaminophen: Maximum of 75 mg of tramadol hydrochloride (in combination with acetaminophen) every 12 hours.
Extended-release oral formulations not recommended. Available tablet or capsule strengths and once-daily dosing do not provide sufficient dosing flexibility for safe use.
Geriatric Patients
Cautious dosage selection; initiate therapy at the lower end of the dosage range.
In patients >75 years of age, maximum 300 mg daily.
Titrate dosage slowly with close monitoring for CNS and respiratory depression. (See Geriatric Use under Cautions.)
Warnings
Contraindications
Warnings/Precautions
Warnings
Addiction, Abuse, and MisuseRisk of addiction, abuse, and misuse. Addiction can occur with appropriately prescribed or illicitly obtained opiates, and at recommended dosages or with misuse or abuse. Abuse of tramadol can result in overdosage and death; concurrent abuse of alcohol or other CNS depressants increases risk of toxicity. Abuse potential is less than that of morphine or oxycodone but similar to that of propoxyphene (see Actions).
Assess each patient’s risk for addiction, abuse, and misuse prior to prescribing; monitor all patients for development of these behaviors or conditions. Personal or family history of substance abuse (drug or alcohol addiction or abuse) or mental illness (e.g., major depression) increases risk. The potential for addiction, abuse, and misuse should not prevent opiate prescribing for appropriate pain management, but does necessitate intensive counseling about risks and proper use and intensive monitoring for signs of addiction, abuse, and misuse.
Extended-release formulations are associated with a greater risk of overdosage and death because of the larger amount of drug contained in each dosage unit.
Abuse or misuse of extended-release formulations by splitting, crushing, breaking, cutting, or chewing the tablets or capsules, snorting the contents, or injecting the dissolved contents will result in uncontrolled delivery of tramadol and can result in fatal overdosage. IV injection of excipients in these formulations can result in local tissue necrosis, infection, pulmonary granulomas, embolism, and death and increase the risk of endocarditis and valvular heart injury.
Prescribe in smallest appropriate quantity and instruct patients on secure storage and proper disposal to prevent theft.
Respiratory DepressionSerious, life-threatening, or fatal respiratory depression can occur with use of opiates, even when used as recommended; can occur at any time during therapy, but risk is greatest during initiation of therapy and following dosage increases. Monitor for respiratory depression, especially during first 24–72 hours of therapy and following any dosage increase.
Carbon dioxide retention from opiate-induced respiratory depression can exacerbate the drug's sedative effects and, in certain patients, can lead to elevated intracranial pressure. (See Increased Intracranial Pressure or Head Trauma under Cautions.)
Geriatric, cachectic, or debilitated patients are at increased risk for life-threatening respiratory depression. Closely monitor such patients, particularly following initiation of therapy, during dosage titration, and during concomitant therapy with other respiratory depressants. Consider use of nonopiate analgesics.
Even recommended doses of tramadol may decrease respiratory drive to the point of apnea in patients with COPD or cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression. Closely monitor such patients, particularly following initiation of therapy, during dosage titration, and during concomitant therapy with other respiratory depressants. Consider use of nonopiate analgesics.
Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression. Overestimation of the dosage when transferring patients from another opiate analgesic can result in fatal overdosage with the first dose; large initial doses in nontolerant patients also can result in fatal overdosage.
Accidental ingestion of even 1 dose, especially by a child, can result in respiratory depression and fatal overdosage.
For clinically important respiratory depression resulting from tramadol overdosage, administer an opiate antagonist. (See Seizures under Cautions.)
Routinely discuss availability of the opiate antagonist naloxone with all patients receiving new or reauthorized prescriptions for opiate analgesics, including tramadol.
Consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose) or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage. Even if patients are not receiving an opiate analgesic, consider prescribing naloxone if the patient is at increased risk of opiate overdosage (e.g., those with current or past diagnosis of OUD, those who have experienced a prior opiate overdose).
Interactions with Drugs Affecting Hepatic Microsomal EnzymesEffects of concomitant use or discontinuance of CYP3A4 inducers, CYP3A4 inhibitors, or CYP2D6 inhibitors on concentrations of tramadol and active metabolite M1 are complex and must be carefully considered. (See Interactions.)
Concomitant Use with Benzodiazepines or Other CNS DepressantsConcomitant use of opiates, including tramadol, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death. Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.
Reserve concomitant use of tramadol and other CNS depressants for patients in whom alternative treatment options are inadequate. (See Specific Drugs under Interactions.)
Sensitivity Reactions
Serious and fatal anaphylactoid reactions reported, often following the first dose. Patients with a history of anaphylactoid reactions to codeine or other opiate agonists may be at increased risk and should not receive tramadol. If anaphylaxis or other hypersensitivity reaction occurs, discontinue tramadol immediately and permanently.
Pruritus, urticaria, bronchospasm, angioedema, toxic epidermal necrolysis, and Stevens-Johnson syndrome also reported.
Other Warnings and Precautions
Only clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain should prescribe extended-release tramadol preparations.
Opiate Agonist PrecautionsMay cause effects similar to those produced by other opiate agonists; observe usual precautions of opiate agonist therapy.
Serotonin SyndromePotentially life-threatening serotonin syndrome may occur with tramadol use, particularly with concurrent use of other serotonergic drugs, drugs that impair serotonin metabolism (e.g., MAO inhibitors), or drugs that impair tramadol metabolism (e.g., CYP2D6 and CYP3A4 inhibitors). (See Interactions.)
Manifestations may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).
SeizuresSeizures reported in patients receiving tramadol at recommended dosages; however, risk is increased with dosages above the recommended range.
Tramadol increases risk of seizures in patients taking SSRIs, SNRIs, anorectic agents, tricyclic antidepressants or other tricyclic compounds (e.g., cyclobenzaprine, promethazine), or other opiate agonists; may increase the risk in those taking MAO inhibitors, antipsychotic agents, or other drugs that decrease the seizure threshold.
Seizure risk also increased in patients with epilepsy, a history of seizures, or a recognized risk for seizures (e.g., head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections).
Naloxone administration in patients with tramadol overdose may increase the risk of seizures.
SuicideTramadol-related deaths reported in patients with a history of emotional disturbance, suicidality, or misuse of tranquilizers, alcohol, or other CNS-active drugs.
Do not use in patients who are suicidal or addiction prone. Use with caution in patients with history of misuse, patients receiving CNS-active drugs (e.g., tranquilizers, antidepressants), those with excessive alcohol consumption, and those with emotional disturbance or depression. Consider nonopiate analgesics in suicidal or depressed patients.
PharmacogenomicsIndividuals who carry the genotype associated with ultrarapid metabolism of CYP2D6 substrates (e.g., approximately 1–7% of Caucasians, 10–30% of Ethiopians and Saudi Arabians) convert tramadol to the active metabolite, O-desmethyltramadol (M1), more rapidly and completely than other individuals. (See Pharmacokinetics.)
Because individuals who are ultrarapid metabolizers of CYP2D6 substrates are likely to have higher than expected serum concentrations of M1, FDA states that tramadol should not be used in such patients.
Adrenal InsufficiencyAdrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists. Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.
If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function. If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued. In some patients, switching to a different opiate improved symptoms.
HypotensionMay cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients, especially in individuals whose ability to maintain their BP is compromised by depleted blood volume or concomitant use of certain CNS depressants (e.g., phenothiazines, general anesthetics). Monitor BP following initiation of therapy and dosage increases in such patients. (See Specific Drugs under Interactions.)
Vasodilation produced by the drug may further reduce cardiac output and BP in patients with circulatory shock. Avoid use in such patients.
Increased Intracranial Pressure or Head TraumaPotential for increased carbon dioxide retention and secondary elevation of intracranial pressure; in patients particularly susceptible to these effects (e.g., those with evidence of elevated intracranial pressure or brain tumors), monitor closely for sedation and respiratory depression, particularly during initiation of therapy.
Opiates may obscure the clinical course in patients with head injuries.
Avoid use in patients with impaired consciousness or coma.
GI ConditionsMay cause spasm of the sphincter of Oddi and increase serum amylase concentrations; monitor patients with biliary disease, including acute pancreatitis, for worsening symptoms.
Contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.
Dependence and TolerancePhysical dependence and tolerance can develop during prolonged therapy. Abrupt discontinuance or substantial dosage reduction may result in symptoms of withdrawal (e.g., restlessness, lacrimation, rhinorrhea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased BP, respiratory rate, or heart rate). Symptoms may be avoided by tapering the dosage when the drug is discontinued.
Avoid concomitant use of opiate partial agonists. (See Specific Drugs under Interactions.)
Infants born to women who are physically dependent on opiates also will be physically dependent. (See Pregnancy under Cautions.)
CNS DepressionPerformance of activities requiring mental alertness and physical coordination may be impaired.
Concurrent use with other CNS depressants may potentiate CNS depression and may result in profound sedation, respiratory depression, coma, or death. (See Concomitant Use with Benzodiazepines or Other CNS Depressants under Cautions.)
HypogonadismHypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy; causality not established. Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility. Perform appropriate laboratory testing in patients with manifestations of hypogonadism.
Use of Fixed CombinationsWhen used in fixed combination with acetaminophen, consider the cautions, precautions, and contraindications associated with acetaminophen.
Because of the potential for hepatotoxicity at higher than recommended dosages, do not use the fixed-combination (tramadol and acetaminophen) preparation concomitantly with other acetaminophen-containing products.
Specific Populations
PregnancyAnalysis of data from the National Birth Defects Prevention Study (large population-based, case-control study) suggests therapeutic use of opiates in pregnant women during organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis. Manufacturers state that data for tramadol are insufficient to establish risk of major birth defects and spontaneous abortion.
In animal studies, tramadol was embryotoxic and fetotoxic; teratogenicity not observed. Based on animal data, apprise patient of potential fetal risk.
Use of opiates in pregnant women during labor can result in neonatal respiratory depression. Use of tramadol immediately before or during labor is not recommended. Monitor neonates exposed to opiates during labor for respiratory depression and excessive sedation; an opiate antagonist must be available for reversal of opiate-induced respiratory depression.
Prolonged maternal use of opiates during pregnancy can result in neonatal opiate withdrawal syndrome; in contrast to adults, withdrawal syndrome in neonates may be life-threatening and requires management according to protocols developed by neonatology experts. Syndrome presents with irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity vary depending on the specific opiate used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.
LactationDistributed into milk; use not recommended. Risk of opiate toxicity in nursing infants, especially if the mother is an ultrarapid metabolizer of tramadol. (See Pharmacogenomics under Cautions.)
Closely monitor infants exposed to tramadol through breast milk for manifestations of opiate toxicity (e.g., sedation, difficulty breast-feeding or breathing, hypotonia); if such manifestations occur, caregiver should seek immediate medical treatment for the infant.
Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped.
Pediatric UseSafety and efficacy of tramadol not established in pediatric patients.
Use contraindicated in children <12 years of age; also contraindicated in children <18 years of age following tonsillectomy and/or adenoidectomy. FDA states that tramadol is not recommended in children 12–18 years of age who are obese or have conditions such as obstructive sleep apnea or compromised respiratory function.
Respiratory depression, including deaths, reported in children <18 years of age; children who are obese, have obstructive sleep apnea or severe lung disease, or have evidence of ultrarapid metabolism of CYP2D6 substrates are at increased risk. If tramadol is used in children 12–18 years of age, caregivers should monitor closely for manifestations of opiate toxicity and seek immediate medical treatment for the child if such manifestations occur.
Geriatric UseSelect dosage with caution because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients. Use with caution, particularly in patients >75 years of age.
Increased incidence of adverse effects in geriatric patients compared with younger adults.
Respiratory depression is the chief risk; monitor closely for CNS and respiratory depression.
Clearance reduced in patients >75 years of age; maximum dosage is 300 mg daily. (See Special Populations under Pharmacokinetics and also see Geriatric Patients under Dosage and Administration.)
May be useful to monitor renal function; tramadol clearance may be decreased and risk of adverse effects increased in patients with impaired renal function.
Hepatic ImpairmentMetabolism reduced in patients with advanced cirrhosis. (See Special Populations under Pharmacokinetics.)
Dosage adjustment may be necessary. (See Hepatic Impairment under Dosage and Administration.)
Renal ImpairmentClearance of tramadol and/or active M1 metabolite may be decreased depending on degree of renal impairment. (See Special Populations under Pharmacokinetics.)
Dosage adjustment necessary in patients with severe renal impairment. (See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
Asthenia, CNS stimulation, constipation, diarrhea, dizziness, dry mouth, dyspepsia, flushing, headache, nausea, pruritus, somnolence, anorexia, sweating, vomiting.
What other drugs will affect TraMADol (Systemic)
Metabolized by CYP isoenzymes 2B6, 2D6, and 3A4; formation of M1 dependent on CYP2D6.
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP2D6: Potential pharmacokinetic interaction (increased plasma tramadol concentrations, decreased plasma M1 concentrations). Increased tramadol concentrations may increase or prolong therapeutic effects and increase risk of adverse effects (e.g., seizures, serotonin syndrome); decreased M1 concentrations may reduce therapeutic effects and precipitate withdrawal. If concomitant therapy required, monitor closely for serious adverse effects (e.g., seizures, serotonin syndrome) and opiate toxicity or withdrawal. If CYP2D6 inhibitor is discontinued, monitor closely for adverse effects (e.g, respiratory depression, sedation) and consider reducing tramadol dosage until drug effects are stable.
Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma tramadol concentrations; larger amounts of parent drug available for metabolism may result in higher M1 concentrations). If concomitant therapy required, monitor closely for serious adverse effects (e.g., seizures, serotonin syndrome) and opiate toxicity, and consider decreasing tramadol dosage until drug effects are stable. If CYP3A4 inhibitor is discontinued, monitor for opiate withdrawal and consider increasing tramadol dosage until drug effects are stable.
Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma tramadol concentrations); may reduce efficacy or precipitate opiate withdrawal. If concomitant therapy required, monitor for opiate withdrawal and consider increasing tramadol dosage until stable drug effects are achieved. If CYP3A4 inducer is discontinued, monitor for seizures, serotonin syndrome, sedation, and respiratory depression, and consider decreasing tramadol dosage until drug effects are stable.
Drugs Metabolized by Hepatic Microsomal Enzymes
Unlikely to inhibit CYP3A4-mediated metabolism of other drugs when administered in usual dosages.
Drugs Associated with Serotonin Syndrome
Risk of serotonin syndrome when used with other serotonergic drugs. May occur at usual dosages. Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases. (See Advice to Patients.)
If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.
If serotonin syndrome is suspected, discontinue tramadol, other opiate therapy, and/or any concurrently administered serotonergic agents.
Specific Drugs
Drug
Interaction
Comments
Amiodarone
May inhibit tramadol metabolism, increasing tramadol concentrations and decreasing M1 concentrations; increased tramadol concentrations may increase or prolong therapeutic effects and increase risk of adverse effects (e.g., seizures, serotonin syndrome); decreased M1 concentrations may reduce therapeutic effects and precipitate withdrawal
Monitor closely for serious adverse effects (e.g., seizures, serotonin syndrome) and opiate toxicity or withdrawal; if amiodarone is discontinued, monitor closely for adverse effects (e.g., respiratory depression, sedation) and consider reducing tramadol dosage until drug effects are stable
Anorectic agents
Increased risk of seizures
Anticholinergic agents
Possible increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus
Monitor for urinary retention or reduced gastric motility
Anticonvulsants (Carbamazepine, phenytoin)
May increase tramadol metabolism, decreasing tramadol concentrations and reducing efficacy or precipitating opiate withdrawal
Carbamazepine: Analgesia is substantially reduced
Phenytoin: Monitor for opiate withdrawal and consider increasing tramadol dosage until drug effects are stable; if phenytoin is discontinued, monitor for seizures, serotonin syndrome, sedation, and respiratory depression, and consider decreasing tramadol dosage until drug effects are stable
Carbamazepine: Concomitant use not recommended
Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), SNRIs (e.g., desvenlafaxine, duloxetine, milnacipran, venlafaxine), tricyclic antidepressants (TCAs), mirtazapine, nefazodone, trazodone, vilazodone
Increased risk of serotonin syndrome
SSRIs, SNRIs, TCAs: Increased risk of seizures
Amitriptyline, fluoxetine, paroxetine: May inhibit tramadol metabolism, increasing tramadol concentrations and decreasing M1 concentrations; increased tramadol concentrations may increase or prolong therapeutic effects and increase risk of adverse effects (e.g., seizures, serotonin syndrome); decreased M1 concentrations may reduce therapeutic effects and precipitate withdrawal
If concomitant use warranted, monitor patient closely, particularly during treatment initiation and dosage increases
If serotonin syndrome suspected, discontinue tramadol, the antidepressant, and/or any concurrently administered opiates or serotonergic agents
Amitriptyline, fluoxetine, paroxetine: Monitor closely for serious adverse effects (e.g., seizures, serotonin syndrome) and opiate toxicity or withdrawal; if antidepressant is discontinued, monitor closely for adverse effects (e.g., respiratory depression, sedation) and consider reducing tramadol dosage until drug effects are stable
Antiemetics, 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron)
Risk of serotonin syndrome
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases
If serotonin syndrome suspected, discontinue tramadol, the 5-HT3 receptor antagonist, and/or any concurrently administered opiates or serotonergic agents
Antifungals, azole (ketoconazole)
May decrease tramadol clearance; increased tramadol concentrations may increase M1 formation; increased risk of adverse effects (e.g., seizures, serotonin syndrome) and opiate toxicity
Monitor closely for serious adverse effects (e.g., seizures, serotonin syndrome) and opiate toxicity, and consider reducing tramadol dosage until drug effects are stable; if antifungal is discontinued, monitor for opiate withdrawal and consider increasing tramadol dosage until drug effects are stable
Antipsychotics (e.g., aripiprazole, asenapine, Cariprazine, chlorpromazine, clozapine, fluphenazine, haloperidol, iloperidone, loxapine, lurasidone, molindone, olanzapine, paliperidone, perphenazine, pimavanserin, quetiapine, risperidone, thioridazine, thiothixene, trifluoperazine, ziprasidone)
Risk of profound sedation, respiratory depression, hypotension, coma, or death
Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy
In patients receiving tramadol, initiate antipsychotic, if required, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response
In patients receiving an antipsychotic, initiate tramadol, if required, at reduced dosage and titrate based on clinical response
Monitor closely for respiratory depression and sedation
Benzodiazepines (e.g., alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, triazolam)
Risk of profound sedation, respiratory depression, hypotension, coma, or death
Whenever possible, avoid concomitant use
Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy
In patients receiving tramadol, initiate benzodiazepine, if required for any indication other than epilepsy, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response
In patients receiving a benzodiazepine, initiate tramadol, if required, at reduced dosage and titrate based on clinical response
Monitor closely for respiratory depression and sedation
Consider prescribing naloxone for patients receiving opiates and benzodiazepines concomitantly
May inhibit tramadol metabolism, increasing tramadol concentrations and decreasing M1 concentrations; increased tramadol concentrations may increase or prolong therapeutic effects and increase risk of adverse effects (e.g., seizures, serotonin syndrome); decreased M1 concentrations may reduce therapeutic effects and precipitate withdrawal
Monitor closely for serious adverse effects (e.g., seizures, serotonin syndrome) and opiate toxicity or withdrawal; if bupropion is discontinued, monitor closely for adverse effects (e.g., respiratory depression, sedation) and consider reducing tramadol dosage until drug effects are stable
Risk of serotonin syndrome
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases
If serotonin syndrome suspected, discontinue tramadol, buspirone, and/or any concurrently administered opiates or serotonergic agents
Cimetidine
Tramadol pharmacokinetics not altered
No dosage adjustment required
CNS depressants (e.g., alcohol, anxiolytics, general anesthetics, tranquilizers, phenothiazines, other opiates)
Additive respiratory and CNS depressant effects; increased risk of profound sedation, respiratory depression, hypotension, coma, or death
Other opiate agonists, phenothiazines: Increased risk of seizures
Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy
In patients receiving tramadol, initiate CNS depressant, if required for any indication other than epilepsy, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response
In patients receiving a CNS depressant, initiate tramadol, if required, at reduced dosage and titrate based on clinical response
Monitor closely for respiratory depression and sedation; with phenothiazines or general anesthetics, also monitor for hypotension
Consider prescribing naloxone for patients receiving opiates and other CNS depressants concomitantly
Avoid alcohol use
Dextromethorphan
Risk of serotonin syndrome
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases
If serotonin syndrome suspected, discontinue tramadol, dextromethorphan, and/or any concurrently administered opiates or serotonergic agents
Digoxin
Digoxin toxicity reported rarely
Monitor for digoxin toxicity; adjust digoxin dosage as needed
Diuretics
Opiates may decrease diuretic efficacy by inducing vasopressin release
Monitor for reduced diuretic and/or BP effects; increase diuretic dosage as needed
HIV protease inhibitors (PIs) (e.g., ritonavir)
May decrease tramadol clearance; increased tramadol concentrations may increase M1 formation; increased risk of adverse effects (e.g., seizures, serotonin syndrome) and opiate toxicity
Monitor closely for serious adverse effects (e.g., seizures, serotonin syndrome) and opiate toxicity, and consider decreasing tramadol dosage until drug effects are stable; if HIV PI is discontinued, monitor for opiate withdrawal and consider increasing tramadol dosage until drug effects are stable
5-HT1 receptor agonists (triptans; e.g., almotriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan)
Risk of serotonin syndrome
If concomitant use warranted, monitor patient closely, particularly during treatment initiation and dosage increases
If serotonin syndrome suspected, discontinue tramadol, the triptan, and/or any concurrently administered opiates or serotonergic agents
Lithium
Risk of serotonin syndrome
If concomitant use warranted, monitor patient closely, particularly during treatment initiation and dosage increases
If serotonin syndrome suspected, discontinue tramadol, lithium, and/or any concurrently administered opiates or serotonergic agents
Macrolides (erythromycin)
May decrease tramadol clearance; increased tramadol concentrations may increase M1 formation; increased risk of adverse effects (e.g., seizures, serotonin syndrome) and opiate toxicity
Monitor closely for serious adverse effects (e.g., seizures, serotonin syndrome) and opiate toxicity, and consider decreasing tramadol dosage until drug effects are stable; if macrolide is discontinued, monitor for opiate withdrawal and consider increasing tramadol dosage until drug effects are stable
MAO inhibitors (e.g., isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, tranylcypromine)
Increased risk of adverse effects (e.g., serotonin syndrome, seizures, opiate toxicity)
Do not use tramadol in patients who are receiving or have recently (within 14 days) received MAO inhibitors
If serotonin syndrome suspected, discontinue tramadol, the MAO inhibitor, and/or any concurrently administered opiates or serotonergic agents
Neuromuscular blocking agents
Possible enhanced neuromuscular blocking effect resulting in increased respiratory depression
Monitor for respiratory depression; reduce dosage of one or both agents as necessary
Opiate partial agonists (butorphanol, Buprenorphine, nalbuphine, pentazocine)
Possible reduced analgesic effect and/or withdrawal symptoms
Avoid concomitant use
Quinidine
Inhibits tramadol metabolism, increasing tramadol concentrations by 50–60% and decreasing M1 concentrations by 50–60%; increased tramadol concentrations may increase or prolong therapeutic effects and increase risk of adverse effects (e.g., seizures, serotonin syndrome); decreased M1 concentrations may reduce therapeutic effects and precipitate withdrawal
Clinical importance of altered tramadol and M1 concentrations not fully established
Monitor closely for serious adverse effects (e.g., seizures, serotonin syndrome) and opiate toxicity or withdrawal; if quinidine is discontinued, monitor closely for adverse effects (e.g., respiratory depression, sedation) and consider reducing tramadol dosage until drug effects are stable
Rifampin
May increase tramadol metabolism, decreasing tramadol concentrations and reducing efficacy or precipitating opiate withdrawal
Monitor for opiate withdrawal and consider increasing tramadol dosage until drug effects are stable; if rifampin is discontinued, monitor for seizures, serotonin syndrome, sedation, and respiratory depression, and consider decreasing tramadol dosage until drug effects are stable
Sedative/hypnotic agents (e.g., Butabarbital, eszopiclone, pentobarbital, ramelteon, secobarbital, suvorexant, zaleplon, zolpidem)
Risk of profound sedation, respiratory depression, hypotension, coma, or death
Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy
In patients receiving tramadol, initiate sedative/hypnotic, if required, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response
In patients receiving a sedative/hypnotic, initiate tramadol, if required, at reduced dosage and titrate based on clinical response
Monitor closely for respiratory depression and sedation
Skeletal muscle relaxants (e.g., Baclofen, Carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone, methocarbamol, orphenadrine, tizanidine)
Risk of profound sedation, respiratory depression, hypotension, coma, or death
Cyclobenzaprine: Increased risk of adverse effects (e.g., seizures, serotonin syndrome)
Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy
In patients receiving tramadol, initiate skeletal muscle relaxant, if required, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response
In patients receiving a skeletal muscle relaxant, initiate tramadol, if required, at reduced dosage and titrate based on clinical response
Monitor closely for respiratory depression and sedation
Cyclobenzaprine: If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases
If serotonin syndrome suspected, discontinue tramadol, cyclobenzaprine, and/or any concurrently administered opiates or serotonergic agents
St. John’s wort (Hypericum perforatum)
May increase tramadol metabolism, decreasing tramadol concentrations and reducing efficacy or precipitating opiate withdrawal
Risk of serotonin syndrome
Monitor for opiate withdrawal and consider increasing tramadol dosage until drug effects are stable; if St. John’s wort is discontinued, monitor for seizures, serotonin syndrome, sedation, and respiratory depression, and consider decreasing tramadol dosage until drug effects are stable
If concomitant use warranted, monitor for serotonin syndrome, particularly during treatment initiation and dosage increases
If serotonin syndrome suspected, discontinue tramadol, St. John’s wort, and/or any concurrently administered opiates or serotonergic agents
Tryptophan
Risk of serotonin syndrome
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases
If serotonin syndrome suspected, discontinue tramadol, tryptophan, and/or any concurrently administered opiates or serotonergic agents
Warfarin
Increased PT and INR and extensive ecchymoses reported
Use with caution; closely monitor INR; adjust warfarin dosage as needed
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