Tramadol

Pharmacologic Category

Analgesic, Opioid

Dosing: Adult

Pain management, moderate to severe:

Note: In general, opioids may be considered a potential component of a comprehensive, multimodal, patient-specific treatment plan for pain. Nonopioid analgesia should be maximized, if appropriate, prior to initiation of opioid analgesia; combination therapy with analgesics with differing mechanisms of action may improve efficacy and reduce the doses and/or frequency required for each agent (APS 2016; Hill 2018). Tramadol doses should be titrated to appropriate analgesic effect; use the lowest effective dose for the shortest period of time. Tramadol is used for a variety of moderate to moderately severe painful conditions and may be of particular benefit for patients with mixed nociceptive and neuropathic pain due to its dual mechanism of action (APS 2016).

Acute pain (eg, postoperative):

Note: In patients who are experiencing acute pain severe enough to require opioids (in addition to appropriate nonopioid analgesia), limit the quantity prescribed to the expected duration of acute pain; a quantity sufficient for ≤3 days is often adequate, whereas >7 days is rarely needed (CDC [Dowell 2016]). Long-acting preparations are not recommended for treatment of acute pain in opioid-naive patients (CDC [Dowell 2016]).

Immediate release: Oral: Initial: 50 mg every 4 to 6 hours as needed (APS 2016); some experts suggest that 25 to 50 mg 3 times per day may be sufficient for patients with moderate acute pain (Isaac 2019; Pino 2018). The dose may be increased as needed and tolerated to 50 to 100 mg every 4 to 6 hours (maximum: 400 mg/day) (APS 2016; manufacturer's labeling).

Chronic pain (alternative agent):

Note: Opioids, including tramadol, are not the preferred therapy for chronic noncancer pain due to insufficient evidence of benefit and risk of serious harm; nonpharmacologic treatment and nonopioid analgesics are preferred with the exception of pain from sickle cell disease and in end-of-life care (CDC [Dowell 2016]; CDC [Dowell 2019]). Opioids, including tramadol, should only be considered in patients who experience clinically meaningful improvement in pain and function that outweighs patient safety risks (CDC [Dowell 2016]). The utility of tramadol in patients with chronic pain due to cancer is questionable, especially considering its dual mechanism of action and dose ceiling (Bandieri 2016; Wiffen 2017).

Opioid-naive patients not currently on tramadol immediate release:

Immediate release: Oral: The ideal dosing regimen has not been established; consider restricting the initial dose to <300 mg tramadol per day (ie, <50 mg morphine equivalents daily) (Busse 2017). An example initial dose is 25 to 50 mg every 6 hours as needed (Rosenquist 2018). The dose may be increased as needed and tolerated to 50 to 100 mg every 4 to 6 hours (maximum: 400 mg/day) (APS 2016; manufacturer's labeling).

Extended release:

Note: Although manufacturer's labeling contains the following directions for initiating extended-release tramadol products in opioid-naive patients with chronic pain, it is recommended that when starting opioid therapy, treatment be initiated with an immediate-release preparation to more accurately determine the daily opioid requirement and decrease the risk of overdose (CDC [Dowell 2016]). The CDC recommends that extended-release opioids be reserved for patients who have received immediate-release opioids daily for ≥1 week yet continue to experience severe, continuous pain (CDC [Dowell 2016]).

Initial: Oral: 100 mg once daily; titrate by 100 mg/day increments every 5 days as needed (maximum: 300 mg/day)

Tridural [Canadian product]: Initial: Oral: 100 mg once daily; titrate by 100 mg/day increments every 2 days as needed (maximum: 300 mg/day)

Zytram XL [Canadian product]: Oral: 150 mg once daily; if pain relief is not achieved, may titrate by increasing dosage incrementally with sufficient time to evaluate effect of increased dosage, generally not more often than every 7 days (maximum: 400 mg/day).

Patients currently on tramadol immediate release for ≥1 week: Calculate 24-hour tramadol immediate-release total dose and initiate total extended-release daily dose (round dose to the next lowest 100 mg increment); titrate as needed and tolerated to desired effect (maximum: 300 mg/day). In patients who experience breakthrough pain, clinicians may consider the addition of an immediate-release rescue analgesic (eg, NSAID or short-acting weak opioid).

Discontinuation of therapy: When discontinuing chronic opioid therapy, the dose should be gradually tapered down. An optimal universal tapering schedule for all patients has not been established (CDC [Dowell 2016]). Proposed schedules range from slow (eg, 10% reductions per week) to rapid (eg, 25% to 50% reduction every few days) (CDC 2015). Tapering schedules should be individualized to minimize opioid withdrawal while considering patient-specific goals and concerns as well as the pharmacokinetics of the opioid being tapered. An even slower taper may be appropriate in patients who have been receiving opioids for a long duration (eg, years), particularly in the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse events (CDC [Dowell 2016]). 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 withdrawal symptoms (Berna 2015; CDC [Dowell 2016]; manufacturer's labeling). Continue to offer nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasm) as needed (Berna 2015; Sevarino 2018).

Premature ejaculation (alternative agent) (off-label use):

Note: Tramadol may be considered in patients who have failed other therapies (eg, SSRIs, topical anesthetics). Consideration should be given to the risk of addiction and adverse effects associated with opioids (ISSM [Althof 2014]); to promote safe use, regular follow-up to monitor for response, toxicity, and misuse is recommended.

Immediate release: Oral: The ideal dosing regimen has not been established; dosage range studied: 25 to 50 mg administered on demand 1 to 3 hours prior to intercourse (Alghobary 2010; Eassa 2013; Gameel 2013; Kaynar 2012; Safarinejad 2006; Salem 2008).

Restless legs syndrome, refractory (alternative agent) (off-label use):

Note: Use of opioids for restless legs syndrome (RLS) is typically restricted to patients with severe symptoms refractory to first-line agents for RLS (Silber 2018). Consideration should be given to the risk of addiction and adverse effects associated with opioids; to promote safe use, regular follow-up to monitor for response, toxicity, and misuse is recommended. Clinicians should note that the adverse effect of RLS augmentation (ie, worsening of symptoms) has been reported with tramadol use (Earley 2006; Vetrugno 2007).

Immediate release: Oral: Initial: 50 mg once daily at bedtime or during the night; titrate to the lowest effective dose (Silber 2018). Usual effective dosage range: 50 to 100 mg/day (Silber 2013).

Extended release: Oral: Initial: 100 mg once daily at bedtime or during the night; titrate to the lowest effective dose. Usual effective dosage range: 100 to 200 mg/day (Silber 2018). Note: Extended-release formulations may be preferred to decrease end-of-dose rebound; consider conversion to an extended-release formulation after establishment of efficacy and tolerability (≥7 days based on chronic pain recommendations [CDC (Dowell 2016)]) with an immediate-release formulation (Silber 2018).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Elderly >65 years to ≤75 years: Refer to adult dosing; use with caution and initiate at the low end of the dosing range.

Elderly >75 years:

Immediate release: Maximum: 300 mg/day.

Extended release: Use with extreme caution.

Dosing: Renal Impairment: Adult

Immediate release:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

CrCl <30 mL/minute: Increase dosing interval to every 12 hours (maximum: 200 mg/day).

Dialysis: Dialyzable (7%); increase dosing interval to every 12 hours; (maximum: 200 mg/day); administer regular dose on the day of dialysis.

Extended release:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

CrCl <30 mL/minute: Avoid use.

Dosing: Hepatic Impairment: Adult

Immediate release:

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Severe impairment: 50 mg every 12 hours.

Extended release:

Mild to moderate impairment (Child-Pugh class A and B): There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Severe impairment (Child-Pugh class C): Avoid use.

Dosing: Pediatric

Note: Doses should be titrated to appropriate analgesic effect; use the lowest effective dose for the shortest period of time:

Pain management, moderate to severe pain (excluding postoperative tonsillectomy/adenoidectomy pain): Note: The FDA has recommended that tramadol not be used in pediatric patients <12 years of age and all pediatric patients undergoing tonsillectomy and/or adenoidectomy due to increased risk of breathing problems (sometimes fatal). Slowed or difficult breathing has been reported in pediatric patients <18 years of age; risk may be increased in pediatric patients who are obese or have conditions such as obstructive sleep apnea or severe lung disease, or who are ultrarapid metabolizers of the drug (FDA 2015; FDA 2017).

Acute pain: Immediate-release formulations:

Children and Adolescents 4 to ≤16 years: Limited data available: Oral: 1 to 2 mg/kg/dose every 4 to 6 hours; maximum single dose: 100 mg (usual adult starting dose: 50 to 100 mg); maximum daily dose is the lesser of 8 mg/kg/day or 400 mg/day (Finkel 2002; Payne 2002; Rose 2003). Note: Due to potential respiratory complications, tramadol should be avoided in patients <12 years of age and all pediatric patients undergoing tonsillectomy and/or adenoidectomy (FDA 2017).

Adolescents ≥17 years: Oral: 50 to 100 mg every 4 to 6 hours; maximum daily dose: 400 mg/day. For patients not requiring rapid onset of effect, tolerability to adverse effects may be improved by initiating therapy at 25 mg/day and titrating dose by 25 mg every 3 days until 25 mg 4 times daily is reached. Dose may then be increased by 50 mg every 3 days as tolerated to reach 50 mg 4 times daily.

Chronic pain: Extended-release formulations: Adolescents ≥18 years: Oral: Note: For patients requiring around-the-clock pain management for an extended period of time. Opioids, including tramadol, are not the preferred therapy for chronic noncancer pain due to insufficient evidence of benefit and risk of serious harm; nonpharmacologic treatment and nonopioid analgesics are preferred with the exception of pain from sickle cell disease and in end-of-life care (CDC [Dowell 2016]; CDC [Dowell 2019]). Opioids, including tramadol, should only be considered in patients who experience clinically meaningful improvement in pain and function that outweighs patient safety risks (CDC [Dowell 2016]).

Patients not currently on immediate-release tramadol: 100 mg once daily; titrate every 5 days; maximum daily dose: 300 mg/day.

Patients currently on immediate-release tramadol: Calculate 24-hour total immediate-release tramadol dose and initiate total extended-release daily dose (round dose to the next lowest 100 mg increment) once daily; titrate as tolerated to desired effect; maximum daily dose: 300 mg/day.

Dosing: Renal Impairment: Pediatric

Immediate release: Adolescents ≥17 years:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

CrCl <30 mL/minute: Increase dosing interval to every 12 hours; maximum daily dose: 200 mg/day.

Dialysis: Dialyzable (7%); increase dosing interval to every 12 hours; maximum daily dose: 200 mg/day; administer regular dose on the day of dialysis.

Extended release: Adolescents ≥18 years:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

CrCl <30 mL/minute: Avoid use.

Dosing: Hepatic Impairment: Pediatric

Immediate release: Adolescents ≥17 years: There are no dosage adjustments provided in the manufacturer's labeling. In patients with cirrhosis, recommended dose is 50 mg every 12 hours.

Extended release: Adolescents ≥18 years:

Mild to moderate impairment (Child-Pugh class A and B): There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Severe impairment (Child-Pugh class C): Avoid use.

Calculations

• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)

Use: Labeled Indications

Pain management:

Extended release: Management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Immediate release: Management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of use: Reserve tramadol for use in patients for whom alternative treatment options (eg, nonopioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Tramadol ER is not indicated as an as-needed analgesic.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Premature ejaculationLevel of Evidence [B, G]

Data from mostly placebo-controlled clinical trials suggest that tramadol may be beneficial for the treatment of premature ejaculation Ref.

Based on the International Society of Sexual Medicine (ISSM) guidelines for the diagnosis and treatment of premature ejaculation, tramadol may be considered an alternative treatment option in patients who have experienced treatment failure with other therapies due to the risk of addiction and adverse effects associated with use Ref.

Restless legs syndrome, refractoryLevel of Evidence [C, G]

Data from a small noncontrolled trial suggest that tramadol may be beneficial in the treatment of restless legs syndrome (RLS) Ref.

American Academy of Sleep Medicine guidelines on the treatment of RLS and periodic limb movement disorder (PLMD) in adults consider opioids effective based on low-level evidence Ref. American Academy of Neurology guidelines on the treatment of RLS in adults recommend that a specific opioid/opioid antagonist combination agent (does not include tramadol) may be considered in patients with RLS that has not responded to other treatments, but note that the benefit of treatment with opioids should be weighed against the known risks of these agents Ref. European Federation of Neurological Societies/European Neurological Society/European Sleep Research Society joint task force guidelines on the management of RLS consider data insufficient to make a recommendation regarding opioids. These guidelines also note the first case report (involving tramadol) of RLS augmentation with opioids Ref. Access Full Off-Label Monograph

Level of Evidence Definitions

Level of Evidence Scale

Class and Related Monographs

Opioid Analgesics

Clinical Practice Guidelines

Diabetic Neuropathy:

Neurology, "Evidence-Based Guideline: Treatment of Painful Diabetic Neuropathy," April 2011

Osteoarthritis:

American College of Rheumatology, “Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and Knee,” 2012

Patient Safety:

“CDC Guideline for Prescribing Opioids for Chronic Pain,” 2016

Administration: Oral

Immediate release: Administer without regard to meals.

Extended release: Swallow whole; do not crush, chew, dissolve, or split.

ConZip: Administer without regard to meals.

Ultram ER: Administer without regard to meals, but administer in a consistent manner of either with or without meals.

Canadian products:

Durela, Ralivia, Zytram XL: Administer without regard to meals.

Tridural: Administer once daily with breakfast.

Bariatric surgery:

Capsule and tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER capsule should be swallowed whole. Do not crush, chew, dissolve, or split as this may result in rapid release and a potentially fatal dose of tramadol. IR and orally disintegrating tablet formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, clinicians are advised to monitor closely for adverse effects and withdrawal symptoms after bariatric surgery. Oral morphine has been shown to have significantly increased Cmax and decreased Tmax in the immediate period (1 to 2 weeks) and long-term (6 months) period after bariatric surgery.

Administration: Pediatric

Oral:

Immediate-release tablet: May administer with or without food, but it is recommended that it be administered in a consistent manner.

Extended-release tablet: Swallow whole with a sufficient amount of liquid. Do not crush, cut, dissolve, or chew extended-release tablet; may be taken without regard to meals; tablet should be taken once daily at approximately the same time each day.

Storage/Stability

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Extemporaneously Prepared

A 5 mg/mL oral suspension may be made with tablets and either Ora-Sweet® SF or a mixture of 30 mL Ora-Plus® and 30 mL strawberry syrup. Crush six 50 mg tramadol tablets in a mortar and reduce to a fine powder. Add small portions of the chosen vehicle and mix to a uniform paste; mix while adding vehicle in incremental proportions to almost 60 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 60 mL. Label "shake well before use". Stable for 90 days refrigerated or at room temperature.

Wagner DS, Johnson CE, Cichon-Hensley BK, et al, "Stability of Oral Liquid Preparations of Tramadol in Strawberry Syrup and a Sugar-Free Vehicle," Am J Health Syst Pharm, 2003, 60(12):1268-70.[PubMed 12845924]

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to ease pain.

Frequently reported side effects of this drug

• Loss of strength and energy

• Flushing

• Diarrhea

• Dry mouth

• Headache

• Sweating a lot

• Itching

• Nausea

• Vomiting

• Trouble sleeping

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Depression like thoughts of suicide, anxiety, emotional instability, agitation, irritability, panic attacks, mood changes, behavioral changes, or confusion

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes

• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea

• Adrenal gland problems like severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss

• Sexual dysfunction (males)

• No menstrual periods

• Decreased sex drive

• Trouble getting pregnant

• Severe dizziness

• Passing out

• Seizures

• Confusion

• Severe constipation

• Severe abdominal pain

• Chest pain

• Fast heartbeat

• Trouble urinating

• Passing a lot of urine

• Trouble breathing

• Slow breathing

• Shallow breathing

• Noisy breathing

• Severe fatigue

• Vision changes

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

Geriatric Patients: High-Risk Medication:

High alert medication:

International issues:

REMS Components

Opioids for analgesic use: Elements to Assure Safe Use; Medication Guide

REMS Programs

• Opioid Analgesic

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:

ConZip: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022370s018lbl.pdf#page=34

Ultram: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020281s045lbl.pdf#page=41

Ultram ER: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021692s015lbl.pdf#page=36

Contraindications

Hypersensitivity (eg, anaphylaxis) to tramadol, opioids, or any component of the formulation; pediatric patients <12 years; postoperative management in pediatric patients <18 years who have undergone tonsillectomy and/or adenoidectomy; significant respiratory depression; acute or severe bronchial asthma in the absence of appropriately monitored settings and/or resuscitative equipment; GI obstruction, including paralytic ileus (known or suspected); concomitant use with or within 14 days following MAO inhibitor therapy.

Canadian products: Additional contraindications (not in US labeling): (Note: Contraindications may differ between product labeling; refer also to product labeling): Severe renal impairment (CrCl <30 mL/minute), severe hepatic impairment (Child-Pugh class C); mild, intermittent or short-duration pain that can be managed with other pain medication; management of perioperative pain; status asthmaticus, chronic obstructive airway, acute respiratory depression, hypercapnia, cor pulmonale, delirium tremens, seizure disorder, severe CNS depression, increased cerebrospinal or intracranial pressure, head injury, suspected surgical abdomen (eg, acute appendicitis or pancreatitis); acute intoxication with ethanol, hypnotics, centrally acting analgesics, opioids, or psychotropic drugs; breastfeeding, pregnancy; use during labor and delivery.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid reactions: Serious anaphylactoid reactions (including rare fatalities) often following initial dosing have been reported. Pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome have also been reported. Previous anaphylactoid reactions to opioids may increase risks for similar reactions to tramadol; avoid use in these patients. If anaphylaxis or other hypersensitivity occurs, discontinue permanently; do not rechallenge.

• 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).

• Hypoglycemia: Hypoglycemia (including severe cases) has been reported (rare) particularly within the first 30 days of tramadol initiation (Fournier 2015).

• Hypotension: 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). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.

• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely for respiratory depression, especially during initiation or dose escalation. Swallow ER tablets whole; crushing, chewing, or dissolving can cause rapid release and a potentially fatal dose. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

• Seizures: Even when taken within the recommended dosage seizures may occur; risk is increased in patients receiving serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), anorectics, other opioids, tricyclic antidepressants and other tricyclic compounds (eg, cyclobenzaprine, promethazine), neuroleptics, MAO inhibitors, other drugs which may lower seizure threshold, or drugs which impair metabolism of tramadol (eg, 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, TCAs), 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).

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. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).

• 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.

• 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 with caution; extended-release formulations should not be used in severe hepatic impairment (Child-Pugh class C).

• 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 increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2016]).

• Obesity: Use with caution in patients who are morbidly obese.

• 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: Use with caution; reduce dosage of immediate-release formulations in patients with severe renal impairment; extended-release formulations should be avoided in severe renal impairment.

• 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: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2016]).

• 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: [US Boxed Warning]: 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 tramadol and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosage and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation.

• CYP P450 interactions: [US Boxed Warning]: 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 tramadol requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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 "ultrarapid metabolizers": Avoid use in patients who are ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications donated as *1/*1xN or *1/*2xN); these patients may have extensive conversion to its active metabolite and thus increased opioid-mediated effects. The occurrence of this phenotype is seen in approximately 1% to 2% of East Asians (Chinese, Japanese, Korean), 1% to 10% of Caucasians, 3% to 4% of African-Americans, and may be >10% in certain racial/ethnic groups (ie, Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican).

• Elderly: Use opioids for chronic pain with caution in older adults; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (CDC [Dowell 2016]). Consider the use of alternative nonopioid analgesics in these patients.

• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. 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: [US Boxed Warning]: Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases occurred following tonsillectomy and/or adenoidectomy; in at least 1 case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP450 2D6 polymorphism. Tramadol is contraindicated in pediatric patients <12 years and in pediatric patients <18 years following tonsillectomy and/or adenoidectomy. Avoid the use of tramadol in pediatric patients 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol. 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. Deaths have also occurred in breastfeeding infants after being exposed to high concentrations of morphine because the mothers were ultra-rapid metabolizers of codeine.

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 and 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: [US Boxed Warning]: Use exposes patients and other users to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors or conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other risk factors associated with increased risk include a personal or family history of substance use disorder or mental illness (eg, major depression). Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (CDC [Dowell 2016]).

• Accidental ingestion: [US Boxed Warning]: Accidental ingestion of even one dose of tramadol, especially in children, can result in a fatal overdose of tramadol.

• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, NSAIDs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (CDC [Dowell 2016]).

• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), 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: [US Boxed Warning]: To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, a REMS is required. Drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are encouraged to complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist; and consider other tools to improve patient, household, and community safety.

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

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

One study in the elderly found that tramadol 50 mg was similar in efficacy as acetaminophen 300 mg with codeine 30 mg. In Ultram ER trials, elderly patients experienced more adverse effects than younger adults, particularly constipation, fatigue, weakness, postural hypotension, and dyspepsia. In Conzip trials, elderly patients also experienced more side effects than younger adults. For this reason, the extended release formulations should probably be avoided in the elderly, or only used with great caution. Some studies have observed an increased risk of motor-vehicle accidents with tramadol use (Rudisill 2016a; Bachs 2009); in a case-crossover study involving only older adult drivers ≥65 years, risk of motor-vehicle accidents was significantly increased in those exposed to tramadol (Rudisill 2016b).

Warnings: Additional Pediatric Considerations

Tramadol may cause slowed or difficult breathing, including fatal respiratory depression. In April 2017, the FDA announced tramadol use should be avoided in all pediatric patients less than 12 years and all pediatric patients undergoing tonsillectomy or adenoidectomy. Additionally, tramadol should be avoided in pediatric patients 12 to 18 years who are obese or have conditions such as obstructive sleep apnea or severe lung disease, which may increase the risk of serious breathing problems. The FDA is requiring updated manufacturer labeling to include in the following contraindications: Use in patients <12 years to treat pain and use in patients <18 years to treat postoperative tonsillectomy/adenoidectomy pain (FDA 2017). Patients who are ultrarapid metabolizers of CYP2D6 are thought to produce more active opioid metabolites, potentially increasing risk for adverse effects. A case report describes a 5-year old who underwent adenotonsillectomy for obstructive sleep apnea syndrome (OSAS) who experienced severe respiratory depression after taking a single dose of tramadol; the patient was found to be an ultrarapid metabolizer of CYP2D6 which potentially added to the inherent increased risk for opioid-induced respiratory depression that patients with OSAS have (Orliaguet 2015).

Reproductive Considerations

Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility in men and women (Brennan 2013).

Premature ejaculation may contribute to male infertility. Tramadol may be an alternative treatment for this condition; however, due to the risk of addiction and adverse effects associated with opioid use, it should only be used in patients who have experienced treatment failure with other therapies (ISSM [Althof 2014]; Martyn-St. James 2015).

Pregnancy Considerations

Tramadol crosses the placenta.

According to some studies, maternal use of opioids may be associated with birth defects (including neural tube defects, congenital heart defects, and gastroschisis), poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2016]).

[US Boxed Warning]: Prolonged use of tramadol during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur (Chou 2009). Symptoms of neonatal abstinence syndrome (NAS) following opioid exposure may be autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, hyperactivity, increased muscle tone, increased wakefulness/abnormal sleep pattern, irritability, sneezing, seizure, tremor, yawning) (Dow 2012; Hudak 2012). Mothers who are physically dependent on opioids may give birth to infants who are also physically dependent. Opioids may cause respiratory depression and psycho-physiologic effects in the neonate; newborns of mothers receiving opioids during labor should be monitored.

Tramadol is not commonly used to treat pain during labor and immediately postpartum (ACOG 209 2019) or chronic noncancer pain in pregnant women or those who may become pregnant (CDC [Dowell 2016]; Chou 2009).

Breast-Feeding Considerations

Tramadol and the active M1 metabolite are present in breast milk. M1 has stronger opioid activity than tramadol. Actual exposure to a breastfeeding infant may depend on the mothers CYP2D6 metabolism (Salman 2011).

Tramadol is not recommended for use in breastfeeding women. Due to the potential for serious adverse events in the breastfed infant (including excess sedation and respiratory depression), use during breastfeeding is not recommended by the manufacturer. Nonopioid analgesics are preferred for breastfeeding females who require pain control peripartum or for surgery outside of the postpartum period (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]). When opioids are needed in breastfeeding women, the lowest effective dose for the shortest duration of time should be used to limit adverse events in the mother and breastfeeding infant. In general, a single occasional dose of an opioid analgesic may be compatible with breastfeeding (WHO 2002). Breastfeeding women using opioids for postpartum pain or for the treatment of chronic maternal pain should monitor their infants for drowsiness, sedation, feeding difficulties, or limpness (ACOG 209 2019). Withdrawal symptoms may occur when maternal use is discontinued or breastfeeding is stopped.

Lexicomp Pregnancy & Lactation, In-Depth

• TraMADol

Briggs' Drugs in Pregnancy & Lactation

• Tramadol

Adverse Reactions

>10%:

Gastrointestinal: Constipation (9% to 46%), nausea (16% to 40%), vomiting (5% to 17%), xerostomia (5% to 13%), dyspepsia (1% to 13%)

Nervous system: Dizziness (≤33%), vertigo (≤33%), headache (12% to 32%), drowsiness (7% to 25%), central nervous system stimulation (7% to 14%)

Neuromuscular & skeletal: Asthenia (≤12%)

1% to 10%:

Cardiovascular: Flushing (8%), chest pain (1% to <5%), hypertension (1% to <5%), vasodilation (1% to <5%), peripheral edema (<5%), orthostatic hypotension (≤4%)

Dermatologic: Diaphoresis (1% to 9%), dermatitis (1% to <5%), skin rash (1% to <5%), pruritus (3%)

Endocrine & metabolic: Hot flash (1% to <5%), hyperglycemia (1% to <5%), weight loss (1% to <5%)

Gastrointestinal: Diarrhea (5% to 10%), anorexia (1% to 6%), abdominal pain (1% to <5%), decreased appetite (1% to <5%), sore throat (1% to <5%), viral gastroenteritis (1% to <5%), flatulence (<1% to <5%)

Genitourinary: Menopausal symptoms (1% to <5%), pelvic pain (1% to <5%), prostatic disease (1% to <5%), urine abnormality (1% to <5%), urinary tract infection (1% to <5%), urinary frequency (<5%), urinary retention (<5%)

Infection: Influenza (1% to <5%)

Nervous system: Anxiety (1% to <5%), apathy (1% to <5%), ataxia (1% to <5%), chills (1% to <5%), confusion (1% to <5%), depersonalization (1% to <5%), depression (1% to <5%), falling (1% to <5%), feeling hot (1% to <5%), hypoesthesia (1% to <5%), lethargy (1% to <5%), nervousness (1% to <5%), pain (1% to <5%), paresthesia (1% to <5%), restlessness (1% to <5%), rigors (1% to <5%), agitation (<5%), euphoria (<5%), hypertonia (<5%), malaise (<5%), sleep disorder (<5%), withdrawal syndrome (<5%), insomnia (2%)

Neuromuscular & skeletal: Arthralgia (≤5%), back pain (1% to <5%), increased creatine phosphokinase in blood specimen (1% to <5%), limb pain (1% to <5%), myalgia (<5%), neck pain (1% to <5%), tremor (<5%)

Ophthalmic: Blurred vision (1% to <5%), miosis (1% to <5%), visual disturbance (1% to <5%)

Respiratory: Bronchitis (1% to <5%), cough (1% to <5%), nasal congestion (1% to <5%), nasopharyngitis (1% to <5%), pharyngitis (1% to <5%), rhinitis (1% to <5%), rhinorrhea (1% to <5%), sinus congestion (1% to <5%), sinusitis (1% to <5%), sneezing (1% to <5%), upper respiratory tract infection (1% to <5%)

Miscellaneous: Fever (1% to <5%), flu-like syndrome (1% to <5%), accidental injury (<5%)

<1%, postmarketing, and/or case reports: Abnormal dreams, abnormal gait, abnormality in thinking, acute myocardial infarction, adrenocortical insufficiency, amnesia, anaphylactoid reaction, anaphylaxis, anemia, angioedema, appendicitis, arthritis, bronchospasm, cataract, cellulitis, cholecystitis, cholelithiasis, cognitive dysfunction, cold and clammy skin, deafness, decreased hemoglobin, decreased libido, delirium, difficulty in micturition, disorientation, diverticulitis of the gastrointestinal tract, dysgeusia, dyspnea, dysuria, ecchymoses, ECG abnormality, emotional lability, eye disease, femoral neck fracture (Wei 2020), gastroenteritis, gastrointestinal hemorrhage, gout, hair disease, hallucination, hematuria, hepatic failure, hepatitis, hyperkinesia, hypersensitivity reaction, hypoglycemia, hypotension, increased blood urea nitrogen, increased gamma-glutamyl transferase, increased liver enzymes, increased serum ALT, increased serum AST, increased serum creatinine, irritability, ischemic heart disease, jitteriness, joint stiffness, lack of concentration, lacrimal dysfunction, lower extremity edema, menstrual disease, migraine, movement disorder, muscle cramps, muscle injury, muscle spasm, muscle twitching, mydriasis, neck stiffness, night sweats, osteoarthritis, otitis, palpitations, pancreatitis, peripheral ischemia, piloerection, pneumonia, prolonged QT interval on ECG, proteinuria, pulmonary edema, pulmonary embolism, sedated state, seizure, serotonin syndrome, sexual difficulty, skin vesicle, speech disturbance, Stevens-Johnson syndrome, stomatitis, suicidal tendencies, syncope, tachycardia, tinnitus, toothache, torsades de pointes, urticaria viral infection, yawning

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Opioid Allergy/Hypersensitivity

Toxicology

• Opioids

Metabolism/Transport Effects

Substrate of CYP2B6 (minor), CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions Open Interactions

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Almotriptan: May enhance the serotonergic effect 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 therapy

Alvimopan: Opioid Agonists may enhance the adverse/toxic effect 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 enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy

Amphetamines: May enhance the serotonergic effect 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 therapy

Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Exceptions: Danazol. Risk C: Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect 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. Exceptions: Ondansetron. Risk C: Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect 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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy

BusPIRone: May enhance the serotonergic effect 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 therapy

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

CarBAMazepine: TraMADol may enhance the CNS depressant effect of CarBAMazepine. TraMADol may diminish the therapeutic effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of TraMADol. Risk X: Avoid combination

Chlormethiazole: May enhance the CNS depressant effect 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 enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

CNS Depressants: May enhance the CNS depressant effect 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

CYP2D6 Inhibitors (Moderate): May diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Exceptions: DULoxetine; Lorcaserin (Withdrawn From US Market). Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May diminish the therapeutic effect of TraMADol. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of TraMADol. CYP2D6 Inhibitors (Strong) may increase the serum concentration of TraMADol. Exceptions: FLUoxetine; PARoxetine. Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

CYP3A4 Inhibitors (Strong): May increase the serum concentration of TraMADol. Exceptions: Nefazodone. Risk C: Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification

Dapoxetine: May enhance the serotonergic effect 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 combination

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Desmopressin: Opioid Agonists may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect 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 therapy

Dextromethorphan: May enhance the serotonergic effect 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 therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk D: Consider therapy modification

DULoxetine: May enhance the adverse/toxic effect of TraMADol. The risk for serotonin syndrome/serotonin toxicity and seizures may be increased with this combination. DULoxetine may diminish the therapeutic effect 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 therapy

Eletriptan: May enhance the serotonergic effect 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 therapy

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Risk D: Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Ergot Derivatives: May enhance the serotonergic effect 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. Exceptions: Lisuride; Nicergoline. Risk C: Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Risk D: Consider therapy modification

Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Iobenguane Radiopharmaceutical Products: TraMADol may diminish the therapeutic effect 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 combination

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect 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 anticonvulsants. Risk D: Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect 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 anticonvulsants. Risk D: Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect 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 anticonvulsants. Risk D: Consider therapy modification

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Lemborexant: May enhance the CNS depressant effect 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

Linezolid: May enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk C: Monitor therapy

Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect 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 therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

Methylene Blue: May enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Risk D: Consider therapy modification

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

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

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of nalmefene and opioid agonists. Discontinue nalmefene 1 week prior to any anticipated use of opioid agonistss. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk D: Consider therapy modification

Nefazodone: May enhance the adverse/toxic effect of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Nefazodone may increase the 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 therapy

Ondansetron: May enhance the serotonergic effect of TraMADol. This could result in serotonin syndrome. Ondansetron may diminish the therapeutic effect of TraMADol. 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 therapy

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect 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 combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect 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 therapy

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect 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

Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Management: Concomitant use of ozanimod with serotonergic agents is not recommended. If combined, monitor patients closely for the development of hypertension, including hypertensive crises. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Risk D: Consider therapy modification

PHENobarbital: May enhance the CNS depressant effect of TraMADol. PHENobarbital may decrease the serum concentration of TraMADol. Management: Avoid use of tramadol and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D: Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Primidone: May enhance the CNS depressant effect of TraMADol. Primidone may decrease the serum concentration of TraMADol. Management: Avoid use of tramadol and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D: Consider therapy modification

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect 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 therapy

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

Ritonavir: May decrease serum concentrations of the active metabolite(s) of TraMADol. Ritonavir may increase the serum concentration of TraMADol. Risk C: Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: TraMADol may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. 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. Exceptions: Dapoxetine; FLUoxetine; PARoxetine. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): May enhance the adverse/toxic effect of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may diminish the therapeutic effect 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 therapy

Serotonergic Agents (High Risk, Miscellaneous): Serotonergic Opioids (High Risk) may enhance the serotonergic effect 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 therapy

Serotonergic Non-Opioid CNS Depressants: May enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. 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 enhance the CNS depressant effect of TraMADol. Serotonergic Opioids (High Risk) may enhance the serotonergic effect of TraMADol. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Exceptions: TraMADol. Risk D: Consider therapy modification

Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect 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. Exceptions: Almotriptan; Eletriptan. Risk C: Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the adverse/toxic effect 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. Exceptions: DULoxetine. Risk C: Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect 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 Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Risk D: Consider therapy modification

St John's Wort: May enhance the serotonergic effect of TraMADol. This could result in serotonin syndrome. St John's Wort may decrease the 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 therapy

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect 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 enhance the serotonergic effect 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 therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Tricyclic Antidepressants: May enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. 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

Vitamin K Antagonists (eg, warfarin): TraMADol may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect 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

Test Interactions

May interfere with urine detection of phencyclidine (false-positive) (Hull 2006).

Gene Testing May Be Considered

• CYP2D6 - Tramadol

Genes of Interest

• Catechol-O-Methyltransferase
• Cytochrome P450 3A4

Monitoring Parameters

Pain relief, respiratory and mental status, blood pressure, heart rate; bowel function; signs/symptoms of tolerance, addiction, abuse, misuse, or suicidal ideation; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013)

Alternate recommendations: Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). 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 2016]).

Reference Range

100 to 300 ng/mL; however, serum level monitoring is not required

Advanced Practitioners Physical Assessment/Monitoring

Assess patient's physical and/or psychological dependence. Discontinue slowly after prolonged use.

Nursing Physical Assessment/Monitoring

Assess patient's physical and/or psychological dependence. Discontinue slowly after prolonged use.

Controlled Substance

C-IV

Dosage Forms Considerations

ConZip extended release capsules are formulated as a biphasic product, providing immediate and extended release components:

100 mg: 25 mg (immediate release) and 75 mg (extended release)

200 mg: 50 mg (immediate release) and 150 mg (extended release)

300 mg: 50 mg (immediate release) and 250 mg (extended release)

EnovaRX-Tramadol and Active-Tramadol creams are compounded from kits. Refer to manufacturer’s labeling for compounding instructions.

Synapryn FusePaq is a compounding kit for the preparation of an oral suspension. Refer to manufacturer's labeling for compounding instructions.

Dosage Forms: US

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

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

ConZip: 100 mg, 200 mg, 300 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake]

Generic: 100 mg, 150 mg, 200 mg, 300 mg

Tablet, Oral, as hydrochloride:

Ultram: 50 mg [scored; contains corn starch]

Generic: 50 mg, 100 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Ultram ER: 300 mg [DSC]

Generic: 100 mg, 200 mg, 300 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

Durela: 100 mg, 200 mg, 300 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake]

Tablet, Oral, as hydrochloride:

Ultram: 50 mg

Generic: 50 mg

Tablet Extended Release 24 Hour, Oral:

Zytram XL: 75 mg [contains fd&c blue #2 (indigotine)]

Zytram XL: 150 mg, 400 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Ralivia: 100 mg, 200 mg, 300 mg

Tridural: 100 mg, 200 mg, 300 mg

Zytram XL: 100 mg, 200 mg, 300 mg

Generic: 100 mg, 200 mg, 300 mg

Anatomic Therapeutic Chemical (ATC) Classification

• N02AX02

Generic Available (US)

Yes

Pricing: US

Capsule ER 24 Hour Therapy Pack (ConZip Oral)

100 mg (per each): $13.67

200 mg (per each): $17.92

300 mg (per each): $24.78

Capsule ER 24 Hour Therapy Pack (traMADol HCl ER Oral)

100 mg (per each): $9.57

150 mg (per each): $9.27

200 mg (per each): $12.54

300 mg (per each): $17.34

Tablet, 24-hour (traMADol HCl ER (Biphasic) Oral)

100 mg (per each): $4.71

200 mg (per each): $7.78

300 mg (per each): $10.86

Tablet, 24-hour (traMADol HCl ER Oral)

100 mg (per each): $3.64 - $4.71

200 mg (per each): $6.02 - $7.78

300 mg (per each): $10.14 - $10.86

Tablets (traMADol HCl Oral)

50 mg (per each): $0.80 - $1.80

100 mg (per each): $1.93

Tablets (Ultram Oral)

50 mg (per each): $4.10

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.

Mechanism of Action

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)

Pharmacodynamics/Kinetics

Onset of action: Immediate release: Within 1 hour; Peak effect: 2 to 3 hours

Distribution: Vd: IV: 2.6 L/kg (males); 2.9 L/kg (females)

Protein binding, plasma: ~20%

Metabolism: Extensively hepatic via demethylation (mediated by CYP3A4 and CYP2D6), glucuronidation, and sulfation; has pharmacologically active metabolite formed by CYP2D6 (M1; O-desmethyl tramadol)

Bioavailability:

Immediate release: ~75%

Extended release: ~85% to 95% (as compared to immediate release)

Half-life elimination:

Immediate release: 6.3 ± 1.4 hours; active metabolite (M1): 7.4 ± 1.4 hours; prolonged in elderly

Extended-release:

Capsules: ~10 hours; active metabolite (M1): ~11 hours

Tablets: ~7.9 hours; active metabolite (M1): 8.8 hours.

Time to peak, plasma:

Immediate release: ~2 hours; active metabolite (M1): 3 hours

Extended release: ~4 to 12 hours; active metabolite (M1): ~5 to 15 hours

Excretion: Urine (~30% as unchanged drug; 60% as metabolites)

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Decreased rate and extent of excretion.

Hepatic function impairment:

Immediate release: Metabolism is reduced in advanced cirrhosis, resulting in increased AUC and increased elimination half-life (13 hours [tramadol], 19 hours [M1]).

Extended release: Exposure is decreased ~50% with increased severity of hepatic impairment.

Geriatric: Maximum serum concentration is increased and elimination half-life prolonged.

Gender:

Immediate release: Women had a 12% higher peak tramadol concentration and a 35% higher area under the curve (AUC) compared to men.

Extended release: AUC were somewhat higher in females than in males.

Note: Concentrations of tramadol were ~20% higher in “poor metabolizers” versus “extensive metabolizers,” while M1 concentrations were 40% lower.

Dental Use

Relief of moderate to moderately-severe dental pain

* See Uses in AHFS Essentials for additional information.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Dental Health Professional Considerations

Based on systematic reviews evaluating benefits and harms of analgesics for acute dental pain, opioids or medication combinations containing opioids were associated with greater adverse effects. Adverse effects associated with opioid use include drowsiness, respiratory depression, dizziness, nausea, vomiting, and constipation (Moore 2018). Evidence-based recommendations for analgesic efficacy for dental pain recommend NSAIDS as the drug of choice unless contraindicated or ineffective (ADA 2016; Aminoshariae 2016). The ADA has adopted policy consistent with CDC guidelines regarding pain management; opioid prescriptions should be limited to <7 days for the treatment of acute pain (ADA 2018).

Studies have been conducted in adult patients evaluating efficacy of tramadol in the treatment of dental pain. The combination of tramadol and flurbiprofen may be more beneficial than either drug alone when given for the management of endodontic pain. Doses evaluated were flurbiprofen 100 mg loading dose, followed by 50 mg every 6 hours and tramadol 100 mg loading dose, followed by 100 mg every 6 hours (Doroschak 1999). In a comparison of tramadol/acetaminophen (total dose: 75 mg/650 mg) versus tramadol monotherapy (total dose: 100 mg) for postoperative dental pain, tramadol/acetaminophen had superior analgesic efficacy (Fricke 2004). One study showed that naproxen 500 mg was more effective than tramadol 100 mg when given as a single dose following a root canal (Mehrvarzfar 2012). In a study comparing efficacy of tramadol 100 mg and ketorolac 20 mg for the relief of pain after molar extraction, tramadol was equally effective to ketorolac (Mishra 2012).

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation). See Dental Health Professional Considerations.

Effects on Bleeding

No information available to require special precautions

Dental Usual Dosing

Moderate-to-severe chronic pain: Oral:

Adults:

Immediate release formulation: 50 to 100 mg every 4 to 6 hours (not to exceed 400 mg/day)

For patients not requiring rapid onset of effect, tolerability may be improved by starting dose at 25 mg/day and titrating dose by 25 mg every 3 days, until reaching 25 mg 4 times/day. The total daily dose may then be increased by 50 mg every 3 days as tolerated, to reach dose of 50 mg 4 times/day. After titration, 50 to 100 mg may be given every 4 to 6 hours as needed up to a maximum 400 mg/day.

Extended release formulations:

Ultram ER:

Patients not currently on immediate-release: 100 mg once daily; titrate every 5 days (maximum: 300 mg/day)

Patients currently on immediate-release: Calculate 24-hour immediate release total and initiate total daily dose (round dose to the next lowest 100 mg increment); titrate (maximum: 300 mg/day)

Ralivia (Canadian labeling, not available in US): 100 mg once daily; titrate every 5 days as needed based on clinical response and severity of pain (maximum: 300 mg/day)

Tridural (Canadian labeling, not available in US): 100 mg once daily; titrate by 100 mg/day every 2 days as needed based on clinical response and severity of pain (maximum: 300 mg/day)

Zytram XL (Canadian labeling, not available in US): 150 mg once daily; if pain relief is not achieved may titrate by increasing dosage incrementally, with sufficient time to evaluate effect of increased dosage; generally not more often than every 7 days (maximum: 400 mg/day)

Elderly >75 years:

Immediate release: 50 mg every 6 hours (not to exceed 300 mg/day); see dosing adjustments for renal and hepatic impairment.

Extended release formulation: Use with great caution. See adult dosing.

Related Information

• Beers Criteria 2019: Potentially Inappropriate Medication Use in Older Adults ≥65 Years of Age
• Drugs With Actionable Pharmacogenomic Recommendations
• Opioid Conversion Table and Morphine Equivalent Dose Table
• Oral Medications That Should Not Be Crushed or Altered
• Patient Information for Disposal of Unused Medications

Index Terms

Ryzolt; Tramadol HCl; Tramadol Hydrochloride

FDA Approval Date

March 03, 1995

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Brand Names: International

Adamon (AR, CR, DO, GT, HN, NI, PA, PY, SV); Adolonta (ES); Amanda (TH); Analab (LK, MY, TH); Betram (PH); Biodalgic (FR); Bongesic (CR, DO, GT, HN, NI, PA, SV); Calmador (AR); Calmol (UY); Contramal (BE, EG, FR, HU, IN, IT, TR); Contramal LP (FR); Dolodol (ES); Dolonil (BD); Dolotral (PH); Dolpaz (PH); Dolzam (BE, LU); Domadol (ET, ZW); Dromadol (GB); Durodor Retard (MX); Durotram XR (AU); E-Dol (ZW); Eufindol (CL); Kontram XL SR (KR); Koridol (HK); Lucidol (BD); Lumidol (HR); Mabron (AE, BH, CY, ET, IQ, IR, JO, KW, LB, LV, LY, MY, OM, SA, SG, SY, YE); Mabron SR (LV); Mandolgin (DK); Monoalgic LP (FR); Monotramal LP (FR); Newtram (KR); Noax (SI); Nobligan (NO, SE); Nobligan Retard (NO); Nomal (QA); Onetram (JP); Orasic (ID); Paxilfar (PT); Pengesic (SG); Pengesic SR (HK); Pengesic SR 100 (ET); Potendol SR (KR); Predxal (VN); Radol (ID); Ramado Retard (KR); Rivadol (EG); Romadol (BD); Sefmal (HK, SG, VN); Seminac (ID); Seminac Continus (ID); Sensitram (BR); Syndol (LK); Tadol (SI); Takadol (FR); Tamolan (TH); Topalgic (FR); Trabilin (BB, BM, BS, BZ, CR, DO, GT, GY, HN, JM, NI, PA, SR, SV, TT); Tradmin (ZW); Tradol (ET, ZW); Tradol-Puren (DE); Tradolan (AE, BH, CY, IQ, IR, JO, KW, LB, LY, OM, SA, SE, SY, YE); Tradonal (BE, PH); Tradorec XL (GB, IE); Tralgit SR (SK); Trama Inj (IL); Tramada (MY); Tramadex (IL); Tramadol Slovakofarma (HU); Tramadolor (LT); Tramagetic (DE); Tramagit (DE); Tramahexal (ZA); Tramake (IE); Tramal (AE, AT, AU, BF, BH, BJ, CH, CI, CN, CO, CR, CU, CY, CZ, DE, DO, EC, EE, EG, ET, FI, GH, GM, GN, GR, GT, HN, HR, IL, IQ, IR, JO, JP, KE, KW, LB, LR, LU, LY, MA, ML, MR, MT, MU, MW, NE, NG, NI, NL, NZ, OM, PA, PE, PH, PK, PL, PT, QA, RU, SA, SC, SD, SK, SL, SN, SV, SY, TH, TN, TW, TZ, UG, VE, YE, ZA, ZM); Tramal Long (EC); Tramal Retard (AE, BH, KW, LB, NL, QA, SA); Tramal SR (NZ); Tramalgin (BG); Tramazac (BF, BJ, CI, ET, GH, GM, GN, IN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TH, TN, TZ, UG, ZM); Tramaze (PH); Tramcontin (CN); Tramed (TW); Tramedo (AU); Tramedo SR (AU); Tramica (ZW); Tramol (LK); Tramundin Retard (AE, KW); Tramundin retard (BH); Trasic (LK); Trasik (ID); TRD-Contin (IN); Trexol (MX); Tridol (KR); Trol (BD); Ultradol (BD); Unitral (PH); Vesnon-V (TH); Zamadol (BR, GB); Zamudol (FR); Zodol (CL, PY); Zudol (LK); Zydol (AU, GB, IE); Zydol SR (AU); Zydol XL (GB); Zytram BD (NZ); Zytram XL (NZ); Zytram XL SR (KR)

Last Updated 5/6/20