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Tramadol


Pronunciation

 (TRA ma dole)


U.S. Brand Names

 Ultram®


Synonyms

 Tramadol Hydrochloride


Generic Available

 Yes


Canadian Brand Names

 Ultram®


Use

 Relief of moderate to moderately-severe pain


Use - Dental

 Relief of moderate to moderately-severe dental pain


Pregnancy Risk Factor

 C


Pregnancy Implications

 Tramadol has been shown to cross the placenta. 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/contraindicated


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


Warnings/Precautions

 Should be used only with extreme caution in patients receiving MAO inhibitors. May cause CNS depression and/or respiratory depression, particularly when combined with other CNS depressants. Use with caution and reduce dosage when administered to patients receiving other CNS depressants. An increased risk of seizures may occur in patients receiving serotonin reuptake inhibitors (SSRIs or anorectics), 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, or malignancy, or during ethanol/drug withdrawal) are also at increased risk.

Elderly patients and patients with chronic respiratory disorders may be at greater risk of adverse events. Use with caution in patients with increased intracranial pressure or head injury. Use tramadol with caution and reduce dosage in patients with liver disease or renal dysfunction and in patients with myxedema, hypothyroidism, or hypoadrenalism. Not recommended during pregnancy or in nursing mothers. 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. Safety and efficacy in pediatric patients have not been established.


Adverse Reactions

 Incidence of some adverse effects may increase over time

>10%:

Central nervous system: Dizziness, headache, somnolence, vertigo

Gastrointestinal: Constipation, nausea

1% to 10%:

Cardiovascular: Vasodilation

Central nervous system: Agitation, anxiety, confusion, coordination impaired, emotional lability, euphoria, hallucinations, malaise, nervousness, sleep disorder, tremor

Dermatologic: Pruritus, rash

Endocrine & metabolic: Menopausal symptoms

Gastrointestinal: Abdominal pain, anorexia, diarrhea, dry mouth, dyspepsia, flatulence, vomiting

Genitourinary: Urinary frequency, urinary retention

Neuromuscular & skeletal: Hypertonia, spasticity, weakness

Ocular: Miosis, visual disturbance

Miscellaneous: Diaphoresis

<1%: Abnormal gait, allergic reaction, amnesia, anaphylactoid reactions, anaphylaxis, angioedema, bronchospasm, cognitive dysfunction, concentration difficulty, death, depression, dyspnea, dysuria, hallucinations, menstrual disorder, orthostatic hypotension, paresthesia, seizure, serotonin syndrome, Stevens-Johnson syndrome, suicidal tendency, syncope, taste perversion, tachycardia, toxic epidermal necrolysis, tremor, urticaria, vesicles, weight loss

Postmarketing and/or case reports: Abnormal ECG, cataracts, creatinine increased, deafness, gastrointestinal bleeding, hemoglobin decreased, hepatitis, hyper-/hypotension, liver enzymes elevated, liver failure, migraine, myocardial ischemia, palpitation, proteinuria, pulmonary edema, pulmonary embolism, speech disorders, stomatitis, tinnitus

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.


Overdosage/Toxicology

 Symptoms of overdose include CNS and respiratory depression, lethargy, coma, seizure, cardiac arrest, and death. Treatment may include naloxone 2 mg I.V. (0.01 mg/kg children) with repeat administration as needed up to 18 mg. Naloxone may increase the risk of seizures in tramadol overdose.


Drug Interactions

 Substrate of CYP2D6 (major), 3A4 (minor)

Amphetamines: May increase the risk of seizures with tramadol.

Carbamazepine: Decreases half-life of tramadol by 33% to 50%.

CYP2D6 inhibitors: May decrease the effects of tramadol. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

Digoxin: Rare reports of digoxin toxicity with concomitant tramadol use.

Linezolid: May be associated with increased risk of seizures (due to MAO inhibition)

MAO inhibitors: May increases the risk of seizures.

Naloxone: May increase the risk of seizures (if administered in tramadol overdose)

Neuroleptic agents: May increase the risk of tramadol-associated seizures and may have additive CNS depressant effects.

Opioids: May increase the risk of seizures, and may have additive CNS depressant effects.

Quinidine: May increase the tramadol serum concentrations.

Selegiline: An increased risk of seizures has been associated with MAO inhibitors. It is not clear if drugs with selective MAO type B inhibition are safer than nonselective agents.

SSRIs: May increase the risk of seizures with tramadol. Includes citalopram, fluoxetine, paroxetine, sertraline.

Tricyclic antidepressants: May increase the risk of seizures.

Warfarin: Concomitant use may lead to an elevation of prothrombin times; monitor.


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Does not affect the rate or extent of absorption.

Herb/Nutraceutical: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).


Stability

 Store at controlled room temperature of 25°C (77°F).


Mechanism of Action

 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: ~1 hour

Duration of action: 9 hours

Absorption: Rapid and complete

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

Bioavailability: 75%

Half-life elimination: Tramadol: ~6 hours; Active metabolite: 7 hours; prolonged in elderly, hepatic or renal impairment

Time to peak: 2 hours

Excretion: Urine (as metabolites)


Dosage

 Oral:

Adults: Moderate to severe chronic pain: 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. Dose may then be increased by 50 mg every 3 days as tolerated, to reach dose of 50 mg 4 times/day.

Elderly: >75 years: 50-100 mg every 4-6 hours (not to exceed 300 mg/day); see dosing adjustments for renal and hepatic impairment

Dosing adjustment in renal impairment: Clcr<30 mL/minute: Administer 50-100 mg dose every 12 hours (maximum: 200 mg/day)

Dosing adjustment in hepatic impairment: Cirrhosis: Recommended dose: 50 mg every 12 hours


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.


Patient Education

 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 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, 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.


Nursing Implications

 Driving or operating machinery should be avoided until the effect of drug wears off. Cravings should be reported to physician immediately.


Anesthesia and Critical Care Concerns/Other Considerations

 Tramadol is not any more effective than Tylenol® #3, Darvocet-N® 100, NSAIDs, or Demerol®. It 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).


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


Dosage Forms

 Tablet, as hydrochloride: 50 mg


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," Med Lett Drugs Ther , 2000, 42(1085):73-8.

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

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