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Medication Safety Issues
Sound-alike/look-alike issues:
Tramadol may be confused with Toradol®, Trandate®, trazodone, Voltaren®
Ultram® may be confused with Ultane®, Ultracet®, Voltaren®
International issues:
Theradol® [Netherlands] may be confused with Foradil® which is a brand name for formoterol in the U.S.
Theradol® [Netherlands] may be confused with Terazol® which is a brand name for terconazole in the U.S.
Theradol® [Netherlands] may be confused with Toradol® which is a brand name for ketorolac in the U.S.
Pronunciation
(TRA ma dole)
U.S. Brand Names
Index Terms
Generic Available
Yes: Excludes extended release tablet
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use
Relief of moderate to moderately-severe pain
Use: Dental
Relief of moderate to moderately-severe dental pain
Pregnancy Risk Factor
C
Pregnancy Implications
Adverse events were observed in animal studies. Tramadol has been shown to cross the human placenta when administered during labor. Postmarketing reports following tramadol use during pregnancy include neonatal seizures, withdrawal syndrome, fetal death and stillbirth. Not recommended for use during labor and delivery.
Lactation
Enters breast milk/not recommended
Breast-Feeding Considerations
Sixteen hours following a single 100 mg I.V. dose, the amount of tramadol found in breast milk was 0.1% of the maternal dose. Use is not recommended by the manufacturer for postdelivery analgesia in nursing mothers.
Contraindications
Hypersensitivity to tramadol, opioids, or any component of the formulation; opioid-dependent patients; acute intoxication with alcohol, hypnotics, centrally-acting analgesics, opioids, or psychotropic drugs
Note: Based on Canadian product labeling:
Tramadol is contraindicated during or within 14 days following MAO inhibitor therapy
Extended release formulations (Ralivia™ ER [CAN], Tridural™[CAN], and Zytram® XL [CAN]): Additional contraindications: Severe (Clcr <30 mL/minute) renal dysfunction, severe (Child-Pugh Class C) hepatic dysfunction
Warnings/Precautions
Concerns related to adverse effects:
• Anaphylactoid reactions: Rare but serious anaphylactoid reactions (including fatalities) often following initial dosing have been reported. Pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome also have been reported with use. Previous anaphylactoid reactions to opioids may increase risks for similar reactions to tramadol.
• 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).
• Seizures: Even when taken within the recommended dosage seizures may occur; risk is increased in patients receiving serotonin reuptake inhibitors (SSRIs or anorectics), other opioids, tricyclic antidepressants, other cyclic compounds (including cyclobenzaprine, promethazine), neuroleptics, MAO inhibitors, or drugs which may lower seizure threshold. 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.
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists.
• Ethanol use: Use with caution in heavy alcohol users.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur.
• Hepatic impairment: Use with caution and reduce dosage in patients with mild-to-moderate hepatic impairment; extended release formulations should not be used in severe hepatic impairment (Child-Pugh Class C)
• Renal impairment: Use with caution and reduce dosage in patients with mild-to-moderate renal impairment; extended release formulations should not be used in severe renal impairment Clcr <30 mL/minute.
• Respiratory disease: Patients with respiratory disorders (eg, significant chronic obstructive pulmonary disease (COPD), cor pulmonale, hypoxia, hypercapnia) may be at greater risk of respiratory depression.
• Suicide risk: Avoid use in patients who are suicidal.
Concurrent drug therapy issues:
• CNS depressants: Use with caution and reduce dosage when administering to patients receiving other CNS depressants; may cause CNS depression and/or respiratory depression.
• Serotonergic agents: Avoid use with serotonergic agents such as TCAs, MAO inhibitors (contraindicated in Canadian product labeling), triptans, venlafaxine, trazodone, lithium, sibutramine, meperidine, dextromethorphan, St John's wort, SNRIs and SSRIs; concomitant use has been associated with the development of serotonin syndrome.
Special populations:
• Debilitated patients: Use with caution in debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.
• Elderly: Extended-release formulation should be used with extreme caution in the elderly (particularly >75 years of age); may be more sensitive to adverse effects. Reduce initial dose.
• Pediatrics: Immediate release formulation: Safety and efficacy have not been established in children <16 years of age. Extended release formulation: Safety and efficacy have not been established in children <18 years of age.
Dosage form specific issues:
• Extended release tablets: Caution patients to swallow tablets whole. Rapid release absorption of tramadol from tablets that are broken, crushed, or chewed may lead to a potentially-lethal overdose.
Other warnings/precautions:
• Withdrawal: Tolerance or drug dependence may result from extended use (withdrawal symptoms have been reported); abrupt discontinuation should be avoided. Tapering of dose at the time of discontinuation limits the risk of withdrawal symptoms.
Adverse Reactions
>10%:
Cardiovascular: Flushing (8% to 16%)
Central nervous system: Dizziness (16% to 33%), headache (12% to 32%), insomnia (7% to 11%), somnolence (7% to 25%)
Dermatologic: Pruritus (6% to 12%)
Gastrointestinal: Constipation (10% to 46%), nausea (15% to 40%), vomiting (5% to 17%), dyspepsia (1% to 13%)
Neuromuscular & skeletal: Weakness (4% to 12%)
1% to 10%:
Cardiovascular: Chest pain (1% to <5%), postural hypotension (2% to 5%), vasodilation (1% to <5%)
Central nervous system: Anxiety (1% to <5%), confusion (1% to <5%), coordination impaired (1% to <5%), depression (1% to <5%), euphoria (1% to <5%), hypoesthesia (1% to <5%), lethargy (1% to <5%), nervousness (1% to <5%), pain (1% to <5%), pyrexia (1% to <5%), restlessness (1% to <5%), malaise (<1% to <5%)
Dermatologic: Dermatitis (1% to <5%), rash (1% to <5%)
Endocrine & metabolic: Hot flashes (2% to 9%), menopausal symptoms (1% to <5%)
Gastrointestinal: Diarrhea (5% to 10%), xerostomia (5% to 10%), anorexia (1% to <6%), abdominal pain (1% to <5%), appetite decreased (1% to <5%), weight loss (1% to <5%), flatulence (<1% to <5%)
Genitourinary: Urinary tract infection (1% to <5%), urinary frequency (<1% to <5%), urinary retention (<1% to <5%)
Neuromuscular & skeletal: Arthralgia (1% to <5%), back pain (1% to <5%), hypertonia (1% to <5%), rigors (1% to <5%), paresthesia (1% to <5%), tremor (1% to <5%), creatinine phosphokinase increased (1% to <5%)
Ocular: Blurred vision (1% to <5%), miosis (1% to <5%)
Respiratory: Bronchitis (1% to <5%), congestion (nasal/sinus) (1% to <5%), cough (1% to <5%), dyspnea (1% to <5%), nasopharyngitis (1% to <5%), rhinorrhea (1% to <5%), sinusitis (1% to <5%), sneezing (1% to <5%), sore throat (1% to <5%), upper respiratory infection (1% to <5%)
Miscellaneous: Diaphoresis (2% to 9%), flu-like syndrome (1% to < 5%), shivering (<1% to <5%)
<1% (Limited to important or life-threatening): Abnormal ECG, abnormal gait, agitation, allergic reaction, amnesia, anaphylactoid reactions, anaphylaxis, angioedema, appendicitis, ALT/AST increased, bronchospasm, cataracts, cellulitis, cholecystitis, cholelithiasis, clamminess, cognitive dysfunction, concentration difficulty, creatinine increased, deafness, disorientation, dreams abnormal, dysuria, ear infection, edema, gastroenteritis, gastrointestinal bleeding, hallucination, hematuria, hemoglobin decreased, hepatitis, hyperglycemia, hyper-/hypotension, irritability, joint stiffness, libido decreased, liver enzymes increased, liver failure, menstrual disorder, MI, migraine, muscle cramps, muscle spasms, muscle twitching, myalgia, myocardial ischemia, night sweats, palpitation, pancreatitis, peripheral edema, peripheral ischemia, pneumonia, proteinuria, pulmonary edema, pulmonary embolism, sedation, seizure, serotonin syndrome, sleep disorder, speech disorder, Stevens-Johnson syndrome, stomatitis, suicidal tendency, syncope, taste perversion, tachycardia, tinnitus, toxic epidermal necrolysis, urticaria, vertigo, vesicles
A withdrawal syndrome may occur with abrupt discontinuation; includes anxiety, diarrhea, hallucinations (rare), nausea, pain, piloerection, rigors, sweating, and tremor. Uncommon discontinuation symptoms may include severe anxiety, panic attacks, or paresthesia.
Drug Interactions
Substrate of CYP2B6 (minor), 2D6 (major), 3A4 (major)
Carbamazepine: Tramadol metabolism is increased by carbamazepine. Avoid concurrent use; increases risk of seizures.
CNS depressants: Concomitant use with tramadol may cause exaggeration of CNS depressant effects. Examples include barbiturates, opioid analgesics, ethanol, and other sedative agents.
Cyclobenzaprine: May enhance the neuroexcitatory and/or seizure-potentiating effect of tramadol.
CYP2D6 inhibitors: May diminish the therapeutic effect of tramadol by preventing the metabolic conversion of tramadol to its active metabolite (M1) that accounts for much of its opioid-like effects. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.
CYP3A4 inducers: May decrease the levels/effects of tramadol. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.
CYP3A4 inhibitors: May increase the levels/effects of tramadol. Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil.
MAO inhibitors: May increase the neuroexcitatory effects or risk of seizures. Examples of inhibitors include isocarboxazid, linezolid, phenelzine, selegiline, and tranylcypromine. (Concomitant use with tramadol is contraindicated in Canadian labeling).
Selective serotonin reuptake inhibitors (SSRIs) (eg, fluoxetine, paroxetine, sertraline): May increase the neuroexcitatory effects or risk of seizures with tramadol. Tramadol may enhance the serotonergic effect of SSRIs; this may cause serotonin syndrome.
Serotonin modulators: May enhance the adverse/toxic effects of tramadol. The development of serotonin syndrome may occur.
Sibutramine: May enhance the serotonergic effects of tramadol. Avoid concurrent use.
Tricyclic antidepressants: May enhance neuroexcitatory and/or seizure-potentiating effect of tramadol.
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS depression).
Food:
Immediate release: Does not affect the rate or extent of absorption.
Extended release: Reduced Cmax and AUC and Tmax occurred 3 hours earlier when taken with a high-fat meal.
Herb/Nutraceutical: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Storage
Store at controlled room temperature of 25°C (77°F).
Mechanism of Action
Tramadol and active metabolite (M1) binds to ?-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 also modifies the ascending pain pathway
Pharmacodynamics/Kinetics
Onset of action: Immediate release: ~1 hour
Duration of action: 9 hours
Absorption: Immediate release formulation: Rapid and complete; Extended release formulation: Delayed
Distribution: Vd: 2.5-3 L/kg
Protein binding, plasma: 20%
Metabolism: Extensively hepatic via demethylation, glucuronidation, and sulfation; has pharmacologically active metabolite formed by CYP2D6 (M1; O-desmethyl tramadol)
Bioavailability: Immediate release: 75%; Extended release: Ultram® ER: 85% to 90% (as compared to immediate release), Zytram® XL, Tridural™: 70%
Half-life elimination: Tramadol: ~6-8 hours; Active metabolite: 7-9 hours; prolonged in elderly, hepatic or renal impairment; Zytram® XL: ~16 hours; Ralivia™ ER, Tridural™: ~5-9 hours
Time to peak: Immediate release: ~2 hours; Extended release: Ultram® ER: ~12 hours, Tridural™: ~4 hours
Excretion: Urine (30% as unchanged drug; 60% as metabolites)
Dosage
Moderate-to-severe chronic pain: Oral:
Adults:
Immediate release formulation: 50-100 mg every 4-6 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, 50-100 mg may be given every 4-6 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™ ER (Canadian labeling, not available in U.S.): 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 U.S.): 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 U.S.): 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.
Dosing adjustment in renal impairment:
Immediate release: Clcr <30 mL/minute: Administer 50-100 mg dose every 12 hours (maximum: 200 mg/day)
Extended release: Should not be used in patients with Clcr <30 mL/minute
Dosing adjustment in hepatic impairment:
Immediate release: Cirrhosis: Recommended dose: 50 mg every 12 hours
Extended release: Should not be used in patients with severe (Child-Pugh Class C) hepatic dysfunction
Dental Usual Dosing
Moderate-to-severe chronic pain: Oral:
Adults:
Immediate release formulation: 50-100 mg every 4-6 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, 50-100 mg may be given every 4-6 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™ ER (Canadian labeling, not available in U.S.): 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 U.S.): 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 U.S.): 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.
Administration: Oral
Extended release tablet: Swallow whole; do not crush, chew, or split
Monitoring Parameters
Pain relief, respiratory rate, blood pressure, and pulse; signs of tolerance or abuse
Reference Range
100-300 ng/mL; however, serum level monitoring is not required
Dietary Considerations
May be taken with or without food. Extended release formulation: Be consistent; always give with food or always give on an empty stomach.
Patient Education
Extended release tablet must be swallowed whole; do not break, chew, or crush. If self-administered, use exactly as directed; do not increase dose or frequency. Drug may cause physical and/or psychological dependence. While using this medication, do not use alcohol and other prescription or OTC medications (especially pain medications, sedatives, antihistamines, or cough preparations) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience headache, drowsiness, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or loss of appetite (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); or constipation (increased exercise, fluids, fruit, or fiber may help). Report severe unresolved constipation, respiratory difficulty or shortness of breath, excessive sedation or increased insomnia and restlessness, rash or hives, changes in urinary pattern or menstrual pattern, seizures, muscle weakness or tremors, or chest pain or palpitations. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.
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. For this reason, the extended release formulation should probably be avoided in the elderly, or only used with great caution.
Anesthesia and Critical Care Concerns/Other Considerations
Tramadol 50 mg is comparable to codeine 60 mg; tramadol 100 mg is comparable to aspirin 650 mg/codeine 60 mg. Tramadol is 5-10 times less potent than morphine and reported to cause less respiratory depression.
Dental Health: 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 Comment.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Dental Comment
Literature reports suggest that the efficacy of tramadol in oral surgery pain is equivalent to the combination of aspirin and codeine. One study (Olson et al 1990) showed acetaminophen and dextropropoxyphene combination to be superior to tramadol and another study showed tramadol to be superior to acetaminophen and dextropropoxyphene combination. Tramadol appears to be at least equal to if not better than codeine alone. Seizures have been reported with the use of tramadol.
Mental Health: Effects on Mental Status
May cause dizziness, drowsiness, or restlessness
Mental Health: Effects on Psychiatric Treatment
Contraindicated with opioid-dependent patients, MAO inhibitors, psychotropics; carbamazepine may decrease the effects of tramadol; concurrent use with MAO inhibitors and TCAs may produce seizures; tramadol has MAO inhibitor activity and should be used cautiously with other antidepressants
Nursing: Physical Assessment/Monitoring
Assess other medications patient may be taking for additive or adverse interactions. Monitor therapeutic effectiveness and adverse reactions or overdose at beginning of therapy and periodically during therapy. May cause physical and/or psychological dependence. Taper dose when discontinuing to avoid withdrawal symptoms. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [CAN] = Canadian brand name
Tablet, as hydrochloride: 50 mg
Ultram®: 50 mg
Tablet, extended release, as hydrochloride:
Ultram® ER: 100 mg, 200 mg, 300 mg
Ralivia™ ER [CAN]: 100 mg, 200 mg, 300 mg [not available in the U.S.]
Tridural™ [CAN]: 100 mg, 200 mg, 300 mg [not available in the U.S.]
Zytram® XL [CAN]: 150 mg, 200 mg, 300 mg, 400 mg [not available in the U.S.]
Pricing: U.S. (www.drugstore.com)
Tablet, 24-hour (Ultram ER)
100 mg (30): $95.29
200 mg (30): $168.36
300 mg (30): $207.56
Tablets (Tramadol HCl)
50 mg (30): $16.99
Tablets (Ultram)
50 mg (30): $59.84
References
Collins M, Young I, Sweeney P, et al, “The Effect of Tramadol on Dento-Alveolar Surgical Pain,” Br J Oral Maxillofac Surg, 1997, 35(1):54-8.
Dayer P, Collart L, and Desmeules J, “The Pharmacology of Tramadol,” Drugs, 1994, 47(Suppl 1):3-7.
“Drugs for Pain,” Treat Guidel Med Lett, 2004, 2(23):47-54.
Kahn LH, Alderfer RJ, and Graham DJ, “Seizures Reported With Tramadol,” JAMA, 1997, 278(20):1661.
Lewis KS and Han NH, “Tramadol: A New Centrally Acting Analgesic,” Am J Health Syst Pharm, 1997, 54(6):643-52.
Mehlisch DR, Minn F, and Brown P, “Tramadol Hydrochloride: Efficacy Compared to Codeine Sulfate, Acetaminophen With Dextropropoxyphene and Placebo in Dental Extraction Pain,” Clin Pharmacol Ther, 1992.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
Olson NZ, Sunshine A, O'Neill, et al, Tramadol Hydrochloride: Oral Efficacy in Postoperative Pain, American Pain Society 9th Annual Scientific Meeting, St Louis, MO, October, 1990.
Rauck RL, Ruoff GE, and McGillen, “Comparison of Tramadol and Acetaminophen With Codeine for Long-Term Pain Management in Elderly Patients,” Curr Ther Res, 1994, 556:1417-31.
Riedel F and von Stockhausen HB, “Severe Cerebral Depression After Intoxication With Tramadol in a 6-Month-Old Infant,” Eur J Clin Pharmacol, 1984, 26(5):631-2.
Ruoff GE, “Slowing the Initial Titration Rate of Tramadol Improves Tolerability,” Pharmacotherapy, 1999, 19(1):88-93.
Sunshine A, Olson NZ, Zighelboim I, et al, “Analgesic Oral Efficacy of Tramadol Hydrochloride in Postoperative Pain,” Clin Pharmacol Ther, 1992; 51(6):740-6.
Sunshine A, “New Clinical Experience With Tramadol,” Drugs, 1994, 47(Suppl 1):8-18.
Voorhees F, Leibold DG, Stumpf, et al, “Tramadol Hydrochloride: Efficacy Compared to Codeine Sulfate, Aspirin With Codeine Phosphate, and Placebo in Dental Extraction Pain,” Clin Pharmacol Ther, 1992, 51:122.
Wynn RL, “Tramadol (Ultram) - A New Kind of Analgesic,” Gen Dent, 1996, 44(3):216-8,220.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2008
Content last modified May 2008
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