Tramadol (Ultram): Drug Whys

Overdoses of tramadol have been reported, which has led several states to reclassify it as a controlled substance.


Generic Name: Tramadol (multiple generics available)
Common Brand Name: Ultram (Wyeth Pharmaceuticals – U.S.) – multiple generics available
Popularity: 18th most commonly prescribed drug from 2002 – 2012 (U.S.)
Class: Non-narcotic opioid analgesic

Treatment Uses – For treatment of moderate to moderately severe pain, particularly in patients who need round-the-clock treatment for extended periods.  Also used commonly for dental pain.  Used as an adjunct to anesthesia and for treatment of cancer pain.  Tramadol is also abused for its euphoric effects, which has led several states to reclassify it as a controlled substance.

Dosing and Administration – The recommended tramadol dosing for adults is 50 to 100 milligrams immediate release given orally every 4 to 6 hours as needed up to a maximum of 400 milligrams daily.   For chronic pain patients not on immediate release tramadol, extended release tramadol can be started at 100 milligrams once daily and titrated upwards in 100 milligram increments every 5 days as needed up to a maximum of 300 milligrams daily.  To switch a chronic pain patient from immediate release to extended release tramadol, calculate the total daily tramadol dose and start extended release tramadol at a dose rounded down to the nearest 100 milligram increment, not to exceed 300 milligrams daily.

The safety and efficacy of immediate release tramadol in patients under 16 years of age and extended release tramadol in patients under 18 years of age are not established.

Food has no effect on absorption or availability of tramadol; doses can be taken without regard to meals.  Extended release capsules and tablets should not be divided, crushed, chewed or mixed with water.

In renally impaired patients with a creatinine clearance (CrCl) less than 30 mL per minute or patients on dialysis, the dosing interval of immediate release tramadol should be increased to 12 hours and the maximum daily dose decreased to 200 milligrams.  No supplemental dosing of tramadol is needed following hemodialysis.  In patients with hepatic insufficiency, dosing of immediate release tramadol should be reduced to 50 milligrams orally every 12 hours.  Extended release tramadol is not recommended for use in patients with renal or hepatic insufficiency.  In patients over 65-years-old, tramadol should be started at the low end of the dosing ranges and continued at the lowest effective dose.  For patients over 75-years-old, immediate the maximum daily dose of immediate release tramadol should not exceed 300 milligrams.

Overdoses of tramadol have been reported.  Toxicity is related to sedation and respiratory depression and, although rare, serotonin syndrome (hypertension, hyperthermia, myoclonus, altered mental status) and/or seizures may occur.  In mild to moderate overdoses, patients may need only observation and supportive care.  In severe cases, naloxone is the antidote for significant respiratory or CNS depression.  Endotracheal intubation to protect the airway should be promptly performed in patients who do not respond to naloxone.  Seizures should be treated with benzodiazepines.  Activated charcoal may be useful in asymptomatic patients likely to have medication still in their gut or in symptomatic intubated patients.  Gastric lavage may be beneficial in very large (over 2.5 grams) recent ingestions.  Of note, there is some controversy over the use of naloxone in tramadol overdoses for its theoretical potential to precipitate seizures.  When used, larger doses of naloxone may be needed compared to other opioid overdoses.  Dosing (usually 0.4 to 2 milligrams IV, IM, IN, or nebulized) may need to be repeated every 2 to 3 minutes up to 20 milligrams.  Once effective, the duration of naloxone is 1 to 2 hours and the patient should be observed for at least 3 to 4 hours after the last naloxone dose.  For extended release tramadol overdoses, a naloxone infusion may be necessary, started at an hourly rate equal to half the total amount required to reverse the symptoms.  In opioid dependent patients, naloxone can precipitate withdrawal, which, while not life-threatening, can be extremely uncomfortable for the patient.

Hypotension should be treated initially with fluids, followed by pressors if necessary.  Delirium should be treated with liberal doses of benzodiazepines to induce mild sedation.   Serotonin syndrome should be treated aggressively with benzodiazepines, cooling, and consultation with a toxicologist or Poison Control Center.  Hypoglycemia has been reported with tramadol overdoses; glucose should be monitored.  Hemodialysis and hemoperfusion are of no value in tramadol overdose. 

Abusers may snort, inject or smoke tramadol in order to rapidly achieve a high serum level of the drug —  quickly producing euphoria.  Chronic opioid users develop tolerance to the analgesic and euphoric effects, but not to the respiratory depression.  Fatalities in adults have been reported with overdoses of tramadol ranging from 2.65 to 8.2 grams, without coingestion of other drugs.  One adult survived an overdose of 10 grams with mild brain injury.  Severe toxicity occurred in infants who received 100 milligrams rectally while older children have tolerated tramadol ingestions of 300 milligrams with mild toxicity.   

Pharmacology/Pharmacokinetics/Stability – Following oral administration, time to peak concentration in the bloodstream for immediate release preparations is 2 to 3 hours.  Steady state plasma levels are seen within 2 days of four times daily dosing with immediate release tramadol.  The half-life (time for half of a dose of tramadol to be eliminated from the body) is approximately 7 hours.

Tramadol is extensively metabolized in the liver and those metabolites are excreted primarily by the kidneys (60%).  Elimination is significantly diminished in patients with liver or kidney dysfunction.

Tramadol is not recommended during pregnancy unless potential benefits outweigh risks, which include neonatal seizures, withdrawal syndrome and fetal death.  There are no well-controlled studies of tramadol in pregnant women or on the growth and development of unborn children exposed to tramadol in utero.   Tramadol is excreted in human breast milk and is not recommended for nursing mothers, as there is insufficient nursing infant safety data.

Tramadol’s mechanism of action in the body is not completely understood, but is believed to be associated with binding of the parent drug metabolite to the mu-opioid receptors and through the weak inhibition of norepinephrine and serotonin reuptake. 

Tramadol comes in multiple strengths, depending on manufacturer.  Size, shape and color also vary; immediate release tablets typically come in 50 milligram strength, extended release tablets and capsules commonly come in 100, 200 and 300 milligram strengths.  There is at least one manufacturer making a tramadol oral suspension of 10 milligrams per milliliter.  Tramadol is also available in combination with acetaminophen.  Tramadol tablets should be stored at room temperature (between 68 and 77°F).

Cautions and Warnings – Tramadol is, as previously mentioned, a drug with abuse, misuse and diversion potential.  Abusers or prolonged users may develop physiologic and psychologic dependence.  Abrupt discontinuation may induce withdrawal symptoms; tapering tramadol when discontinuing therapy is advised.  Tramadol is an opioid; users may experience impairment of mental or physical abilities and should be advised not to perform potentially hazardous tasks such as driving a car or operating machinery.  Seizures have been reported in patients taking tramadol and this risk increases with higher doses.  Seizure risk is also greater in patients taking tramadol with SSRIs (selective serotonin reuptake inhibitors), tricyclics, other opioids, MAOIs (monoamine oxidase inhibitors), neuroleptics or other drugs that reduce the seizure threshold.  Risk of seizures is also greater in patients with a history of seizures or those with recognized risk for seizure.  In tramadol overdose, administration of naloxone may increase the seizure risk.  The same agents associated with increased seizure risk also increase the risk of serotonin syndrome in patients taking tramadol.  This potentially fatal syndrome resembles malignant hyperthermia with rigidity, extremely high fevers and a constellation of other physical effects resulting from excessive levels of serotonin in the brain.  Some patients have experienced severe allergic reactions to tramadol, almost always following the first dose.  Often these individuals have an allergy to codeine or other opioids.

Obviously, respiratory depression is a concern with tramadol and this risk increases when used with other CNS depressants. 

Important Side Effects and Interactions – The most commonly reported side effects in patients taking tramadol are dizziness and vertigo (26%), nausea and/or constipation (24%), headache (18%), somnolence (drowsiness 16%), vomiting (9%), pruritus (itching  8%), and CNS stimulation consisting of restlessness, tremors, euphoria, hallucinations, and emotional lability (7%). 

Currently, there are 89 drugs reported to interact with tramadol.  Of these, none are significant to prehospital and emergency medicine providers. 

Average Costs – U.S.

  • 50 mg tablet (generic)*
  • Patient cost: $0.57 each
  • Large Hospital cost: $0.04 each
  • 100 mg ER (Extended Release – brand name Ultram)*
  • Patient cost: $4.43 each

*Wal Mart® and Target don’t include this med in their $4/month programs

References

  1. MICROMEDEXÒ Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed June, 2013).
  2. Albany Medical Center Pharmacy, Albany, New York.

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