Tramadol hydrochloride is a centrally acting analgesic. The chemical name for tramadol hydrochloride is (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. The molecular weight of tramadol hydrochloride is 299.8.

Tramadol hydrochloride is a white, bitter, crystalline and odorless powder. It is readily soluble in water and ethanol and has a pKa of 9.41. The water/n-octanol partition coefficient is 1.35 at pH 7.

Ultram tablets contain 50 mg of tramadol hydrochloride and are white in color. Inactive ingredients in the tablet are corn starch, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and wax.

Tramadol hydrochloride has been given in single oral doses of 50, 75, 100, 150 and 200 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars).

In single-dose models of pain following oral surgery, pain relief was demonstrated in some patients at doses of 50 mg and 75 mg. A dose of 100 mg tramadol tended to provide analgesia superior to codeine sulfate 60 mg, but it was not effective as the combination of aspirin 650 mg with codeine phosphate 60 mg. In single-dose models of pain following surgical procedures, 150 mg provided analgesia generally comparable to the combination of acetaminophen 650 mg with propoxyphene napsylate 100 mg, with a tendency toward later peak effect.

Tramadol hydrochloride has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol. Patients with a variety of chronic painful conditions were studied in double-blind trials of 1-3 months duration. Average daily doses of approximately 250 mg of tramadol in divided doses were generally comparable with 5 doses of acetaminophen 300 mg with codeine phosphate 30 mg daily, 5 doses of aspirin 325 mg with codeine phosphate 30 mg daily, or 2-3 doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg daily.

Tramadol is indicated for the management of moderate to moderately severe pain.

Non-FDA Approved Indications 

Tramadol has also been reported to have shown efficacy in the treatment of diabetic neuropathy and restless legs syndrome. However, these uses have not been approved by the FDA.

Tramadol should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids. It is also contraindicated in cases of acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs.

Respiratory Depression 

Administer tramadol HCl cautiously in patients at risk for respiratory depression. When large doses of tramadol HCl are administered with anesthetic medications or alcohol, respiratory depression may result. Treat such cases as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see WARNINGS, Seizure Risk and OVERDOSAGE).

Increased Intracranial Pressure or Head Trauma 

Tramadol should be used with caution in patients with increased intracranial pressure or head injury. Pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving tramadol.

Acute Abdominal Conditions 

The administration of tramadol may complicate the clinical assessment of patients with acute abdominal conditions.

Withdrawal 

Withdrawal symptoms may occur if tramadol HCl is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhoea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience suggests that withdrawal symptoms may be relieved by tapering the medication.

Patients Physically Dependent on Opioids 

Tramadol is not recommended for patients who are dependent on opioids. Patients who have recently taken substantial amounts of opioids may experience withdrawal symptoms. Because of the difficulty in assessing dependence in patients who have previously received substantial amounts of opioid medication, administer tramadol cautiously to such patients.

Use in Renal and Hepatic Disease 

Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 ml/min, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION).

Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION).

With the prolonged half-life in these conditions, achievement of steady state is delayed, so that it may take several days for elevated plasma concentrations to develop.

Information for the Patient 

• Tramadol HCl may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.

• Tramadol HCl should not be taken with alcohol containing beverages.

• Tramadol HCl should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics.

• Patients should be instructed to inform the physician if they are pregnant, think they might become pregnant, or are trying to become pregnant (see Labor and Delivery).

• The patient should understand the single-dose and 24 hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression and seizures.

Carcinogenesis, Mutagenesis, and Impairment of Fertility 

Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.

A slight, but statistically significant, increase in 2 common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice (dosing orally up to 30 mg/kg for approximately 2 years, although the study was not done with the Maximum Tolerated Dose). This finding is not believed to suggest risk in humans. No such finding occurred in a rat carcinogenicity study.

No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats.

Pregnancy, Teratogenic Effects, Pregnancy Category C 

There are no adequate and well-controlled studies in pregnant women. Tramadol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Tramadol has been shown to be embryotoxic and fetotoxic in mice, rats and rabbits at maternally toxic doses 3-15 times the maximum human dose or higher (120 mg/kg in mice, 25 mg/kg or higher in rats and 75 mg/kg or higher in rabbits), but was not teratogenic at these dose levels. No harm to the fetus due to tramadol was seen at doses that were not maternally toxic.

No drug-related teratogenic effects were observed in progeny of mice, rats or rabbits treated with tramadol by various routes (up to 140 mg/kg for mice, 80 mg/kg for rats or 300 mg/kg for rabbits). Embryo and fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit.

In peri- and post-natal studies in rats, progeny of dams receiving oral (gavage) dose levels of 50 mg/kg or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (6-10 times the maximum human dose). No toxicity was observed for progeny of dams receiving 8, 10, 20, 25 or 40 mg/kg. Maternal toxicity was observed at all dose levels, but effects on progeny were evident only at higher dose levels where maternal toxicity was more severe.

Labor and Delivery 

Tramadol should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependance and post-partum withdrawl symptoms in the newborn. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.

The effect of tramadol, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Mothers 

Tramadol is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours postdose was 100 µg of tramadol (0.1% of the maternal dose) and 27 µg of M1.

Pediatric Use 

The pediatric use of tramadol is not recommended because safety and efficacy in patients under 16 years of age have not been established.

Geriatric Use 

In subjects over the age of 75 years, serum concentrations are slightly elevated and the elimination half-life is slightly prolonged. The aged also can be expected to vary more widely in their ability to tolerate adverse drug effects. Daily doses in excess of 300 mg are not recommended in patients over 75 (see DOSAGE AND ADMINISTRATION).

Tramadol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single-dose data. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.

Use With Carbamazepine: Concomitant administration of tramadol hydrochloride with carbamazepine causes a significant increase in tramadol metabolism, presumably through metabolic induction by carbamazepine. Patients receiving chronic carbamazepine doses of up to 800 mg daily may require up to twice the recommended dose of tramadol.

Use With Quinidine: Tramadol is metabolized to M1 by the CYP2D6 P-450 isoenzyme. Quinidine is a selective inhibitor of that isoenzyme; so that concomitant administration of quinidine and tramadol results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of this effect have not been fully investigated, and the effect on quinidine concentrations is unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.

Use With Inhibitors of CYP2D6: In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.

Use With Cimetidine: Concomitant administration of tramadol with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the tramadol dosage regimen is recommended.

Use With MAO Inhibitors: Interactions with MAO Inhibitors due to interference with detoxification mechanisms, have been reported for some centrally acting drugs (see WARNINGS, Use With MAO Inhibitors)).

Use With Digoxin and Warfarin: Post-marketing surveillance has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.

Tramadol hydrochloride was administered to 550 patients during the double-blind or open-label extension periods in US studies of chronic nonmalignant pain. Of these patients, 375 were 65 years old or older. TABLE 2 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. Although the reactions listed in the table are felt to be probably related to tramadol administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication. The overall incidence rates of adverse experiences in these trials were similar for tramadol and the active control groups, acetaminophen 300 mg with codeine phosphate 30 mg, and aspirin 325 mg with codeine phosphate 30 mg. (TABLE 2)

Incidence 1% to Less Than 5%, Possibly Casually Related 

The following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a casual relationship with tramadol exists.

Body as a Whole: Malaise.

Cardiovascular: Vasodilation.

Central Nervous System: Anxiety, confusion, coordination disturbance, euphoria, nervousness, sleep disorder.

Gastrointestinal: Abdominal pain, anorexia, flatulence.

Musculoskeletal: Hypertonia.

Skin: Rash.

Special Senses: Visual disturbance.

Urogenital: Urinary retention, urinary frequency, menopausal symptoms.

Incidence Less Than 1%, Possible Causally Related 

The following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials and/or reported in post-marketing experience.

Body as a Whole: Allergic reaction, accidental injury, weight loss, anaphylaxis.

Cardiovascular: Syncope, orthostatic hypotension, tachycardia.

Central Nervous System: Seizure (see WARNINGS), paresthesia, cognitive dysfunction, hallucinations, tremor, amnesia, difficulty in concentration, abnormal gait, depression.

Respiratory: Dyspnea.

Skin: Urticaria, vesicles, Stevens-Johnson syndrome/toxic epidermal necrolysis.

Special Senses: Dysgeusia.

Urogenital: Dysuria, menstrual disorder.

Other Adverse Experiences, Causal Relationship Unknown 

A variety of other adverse events were reported infrequently in patients taking tramadol during clinical trials and/or reported in post-marketing experience. A causal relationship between tramadol and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.

Body as a Whole: Suicidal tendency.

Cardiovascular: Abnormal ECG, hypertension, hypotension, myocardial ischemia, palpitations.

Central Nervous System: Migraine, speech disorders.

Gastrointestinal: Gastrointestinal bleeding, hepatitis, stomatitis.

Laboratory Abnormalities: Creatinine increase, elevated liver enzymes, hemoglobin decrease, proteinuria.

Sensory: Cataracts, deafness, tinnitus.

Skin: Pruritus.

Tramadol HCl has a potential to cause psychic and physical dependence of the morphone-type (µ-opioid). The drug has been associated with craving, drug-seeking behavior and tolerance development. Cases of abuse and dependence on tramadol HCl have been reported. Tramadol HCl should not be used in opioid-dependent patients. Tramadol HCl can reinitiate physical dependence in patients that have been previously dependent or chronically using other opioids. In patients with a tendency to drug abuse, a history of drug dependence, or are chronically using opioids, treatment with tramadol HCl is not recommended.

Cases of overdose with tramadol have been reported. Estimates of ingested dose in foreign fatalities have been in the range of 3-5 g. A 3 g intentional overdose by a patient in the clinical studies produced emesis and no sequelae. The lowest dose reported to be associated with fatality was possibly between 500 and 1000 mg in a 40 kg woman, but details of the case are not completely known.

Serious potential consequences of overdosage are respiratory depression and seizure. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol HCl the risk of seizures is also increased with naloxone administration. In animals convulsions following the administration of toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4 hour dialysis period.

For the treatment of painful conditions tramadol 50-100 mg can be administered as needed for relief every 4-6 hours, not to exceed 400 mg/day. For moderate pain tramadol 50 mg may be adequate as the initial dose, and for more severe pain, tramadol 100 mg is usually more effective as the initial dose.

Individualization of Dose 

Available data do not suggest that a dosage adjustment is necessary in elderly patients 65-75 years of age unless they also have renal or hepatic impairment. For elderly patients over 75 years old, not more than 300 mg/day in divided doses as above is recommended. In all patients with creatine clearance less than 30 ml/min, it is recommended that the dosing interval of tramadol HCl be increased to 12 hours with a maximum daily dose of 200 mg. Since only 7% of an administered dose is removed by hemodialysis, dialysis patients can receive their regular dose on the day of dialysis. The recommended dose for patients with cirrhosis is 50 mg every 12 hours. Patients receiving chronic carbamazepine doses up to 800 mg daily may require up to twice the recommended dose of tramadol HCl.