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TRAMADOL HCL ORAL
Adverse Effects List & Discussion

The most frequent adverse nervous system effect of tramadol is dizziness or vertigo which occurred in 26, 31, and 33% of patients receiving tramadol for up to 7, 30, and 90 days, respectively, in clinical studies. The incidence of dizziness may be dose related. Headache occurred in 18, 26, and 32% of patients, and somnolence occurred in 16, 23, and 25% of patients receiving the drug for up to 7, 30, and 90 days, respectively. The incidence of headache may be dose related.

CNS stimulation (a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability, and hallucinations) occurred in 7, 11, and 14% of patients receiving tramadol for up to 7, 30, and 90 days, respectively. Asthenia occurred in 6, 11, and 12% of patients, and sweating occurred in 6, 7, and 9% of patients receiving the drug for up to 7, 30, and 90 days, respectively. Sweating may be more common following rapid IV injection. Anxiety, confusion, coordination disturbance, euphoria, nervousness, and sleep disorder each have been reported in 1% to less than 5% of patients receiving tramadol.  Abnormal gait, amnesia, cognitive dysfunction, depression, difficulty in concentration, dysphoria, fatigue, hallucinations, motor system weakness, paresthesia, tremor, suicidal tendencies, and seizures each were reported in less than 1% of patients receiving the drug. (See Cautions: Precautions and Contraindications.) Migraine, restlessness, mania, and speech disorders also have been reported infrequently with tramadol, although a causal relationship to the drug has not been established.

Constipation is the most common adverse GI effect of tramadol, occurring in 24, 38, and 46% of patients receiving tramadol for up to 7, 30, and 90 days, respectively, in clinical studies. Nausea occurred in 24, 34, and 40% of patients, and vomiting occurred in 9, 13, and 17% of patients receiving the drug for up to 7, 30, and 90 days, respectively. Nausea and vomiting may occur more frequently with higher doses and following rapid IV injection.

Other adverse GI effects of tramadol include dyspepsia, which occurred in 5, 9, and 13% of patients, dry mouth, which occurred in 5, 9, and 10%, and diarrhea, which occurred in 5, 6, and 10% of patients receiving tramadol for up to 7, 30, and 90 days, respectively. Abdominal pain, anorexia, and flatulence each were reported in 1% to less than 5% of patients receiving tramadol in clinical trials. Weight loss was reported in less than 1% of patients receiving the drug. GI bleeding, hepatitis, stomatitis, dysphagia, and gastritis have been reported infrequently with tramadol, although a causal relationship to the drug has not been established.

Pruritus occurred in 8, 10, and 11% of patients receiving tramadol for up to 7, 30, and 90 days, respectively. Rash was reported in 1% to less than 5% of patients receiving the drug in clinical trials. Serious and rarely fatal anaphylactoid reactions, often occurring after the initial dose, have been reported in patients receiving tramadol. (See Cautions: Precautions and Contraindications.) Urticaria, bronchospasm, and angioedema have occurred. Anaphylaxis, allergic reaction, Stevens-Johnson syndrome or toxic epidermal necrolysis and vesicles each have been reported in less than 1% of patients receiving tramadol.

Vasodilatation has been reported in 1% to less than 5% of patients receiving tramadol in clinical trials. Orthostatic hypotension syncope, and tachycardia each were reported in less than 1% of patients receiving the drug. Abnormal ECG, hypertension, hypotension, myocardial ischemia, flushing, and palpitation also have been reported infrequently with tramadol, although a causal relationship to the drug has not been established.  

Menopausal symptoms, urinary frequency, and urinary reaction each were reported in 1% to less than 5% of patients receiving tramadol in clinical trials. Dysuria and menstrual disorder each were reported in less than 1% of patients receiving the drug. Increased serum creatinine concentrations and proteinuria also have been reported infrequently with tramadol; however, a causal relationship to the drug has not been established.  

Malaise, hypertonia, and visual disturbance each have been reported in 1% to less than 5% of patients receiving tramadol in clinical trials. Accidental injury, dyspnea, and dysgeusia each were reported in less than 1% of patients receiving the drug. Respiratory depression has been reported rarely. Decreased serum hemoglobin concentrations, cataracts, deafness, tinnitus, and elevated serum hepatic enzymes also have been reported with tramadol, but a causal relationship to the drug has not been established.  

Tramadol did not exhibit mutagenic potential in vitro in the Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, or mouse lymphoma assay (in the absence of metabolic activation). The drug also did not exhibit mutagenic potentialin vivo in dominant lethal mutation tests in mice, a chromosome aberration test in Chinese hamsters, or bone marrow micronucleus tests in mice and Chinese hamsters. Tramadol was weakly mutagenic in vitro with metabolic activation in the mouse lymphoma assay and in vivo in the 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 pulmonary and hepatic murine tumors was observed in a mouse carcinogenicity study, particularly in aged mice who received oral tramadol hydrochloride dosages of up to 30 mg/kg daily for approximately 2 years (the maximum tolerated dose was not studied). This finding is not believed to suggest risk in humans. No evidence of carcinogenicity was observed in a rat carcinogenicity study.

Precautions

Seizures have occurred during tramadol therapy with recommended dosages. Spontaneous postmarketing reports indicate that seizure risk is increased with tramadol doses above the recommended range. Seizures can occur following the first dose. The manufacturer warns that tramadol increases the seizure risk in patients taking selective serotonin-reuptake inhibitors (SSRIs), tricyclic antidepressants or other tricyclic compounds, or other opiate agonists. The manufacturer also warns that the drug may enhance the risk of seizure in those receiving monoamine oxidase (MAO) inhibitors, antipsychotic agents, or other drugs that decrease the seizure threshold. Patients with epilepsy, those with a history of seizures, or patients with a recognized risk for seizure (e.g., head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections) may be at increased risk of seizure. Naloxone administration in patients with tramadol overdose also may increase the risk of seizure.

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving tramadol. These reactions often occur following the first dose. Other reported hypersensitivity reactions include pruritus, urticaria, bronchospasm, and angioedema. The manufacturer warns that patients with a history of anaphylactoid reactions to codeine or other opiate agonists may be at increased risk and therefore should not receive tramadol.

The manufacturer cautions that tramadol is not recommended for use in patients dependent on opiate agonists or in patients who are chronically using opiate agonists. The drug has a potential to cause psychic and physical dependence of the morphine type (µ-opiate agonist). Tramadol has been associated with craving, drug-seeking behavior, and tolerance development. Cases of abuse and dependence have been reported. Tramadol also has been shown to reinitiate physical dependence in some patients who were previously dependent on other opiate agonists or chronically using other opiate agonists. Consequently, in patients with a tendency to opiate agonist abuse or dependence, tendency to drug abuse, or history of drug dependence, treatment with tramadol is not recommended. Patients with a recent history of having received substantial amounts of opiate agonists may experience manifestations of withdrawal if tramadol is initiated. Because of the difficulty in assessing dependence in such patients,tramadol should be used with caution in patients with such a history.

Because tramadol may potentiate the effects of other CNS depressants (e.g., alcohol, anesthetic agents, phenothiazines, sedatives and hypnotics, other centrally acting analgesics, opiate agonists), the drug should be used with caution and in reduced dosage in patients receiving such drugs. Tramadol decreases the synaptic reuptake of the monoamine neurotransmitters norepinephrine and serotonin, and animal studies have shown increased deaths with combined administration of tramadol and MAO inhibitors. Therefore, the drug should be used with great caution in patients receiving MAO inhibitors. Serotonin syndrome (characterized by atypical chest pain, sinus tachycardia, confusion, psychosis, sundowning, agitation, diaphoresis, and tremor) has been reported when tramadol was administered concomitantly with sertraline or paroxetine, which are SSRIs. (See Drug Interactions: Drugs Associated with Serotonin Syndrome, in Sertraline Hydrochloride 28:16.04.) Clinicians should be aware of this potential interaction and closely monitor patients receiving tramadol with any serotonergic drug.

Prolongation of the international normalized ratio (INR) and prothrombin time and extensive ecchymoses have been reported in patients receiving tramadol and warfarin concomitantly. Therefore, the drug should be used with caution in patients receiving warfarin, and the INR should be closely monitored in those receiving tramadol with any serotonergic drug.

Administration of tramadol may cause effects similar to those produced by other opiate agonist drugs, and many of the usual precautions of opiate agonist therapy should be observed. (See Description and the manufacturer’s labeling.)

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 also should maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving tramadol. Tramadol administration also may complicate the clinical assessment of patients with acute abdominal conditions.

Withdrawal symptoms may occur if tramadol is discontinued abruptly. Symptoms may include anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and, rarely, hallucinations. Clinical experiencesuggests that withdrawal symptoms may be relieved by tapering the dosage.

Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. Therefore, dosage reduction is recommended in patients with a creatinine clearance less than 30 mL/minute. Tramadol and M1 metabolism are reduced in patients with advanced hepatic cirrhosis; therefore, dosage reduction also is recommended in these patients. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.) With the prolonged half-life of tramadol in patients with renal or hepatic impairment, achievement of steady-state plasma concentrations is delayed, and it may take several days for elevated plasma concentrations to occur.

Patients should be advised that tramadol may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Patients also should be advised against taking tramadol with alcohol-containing beverages, and to use caution when taking the drug concomitantly with drugs such as tranquilizers, sedatives and hypnotics, or other opiate-containing analgesics that may impair mental abilities. Female patients should be instructed to inform their physician if they are pregnant, think they might become pregnant, or are trying to become pregnant. (See Cautions: Pregnancy, Fertility, and Lactation.) Clinicians should be certain that patients understand the single-dose and 24-hour dose limit for tramadol and the recommended time interval betwen doses, since exceeding these recommendations can result in respiratory depression and seizures.

Tramadol is contraindicated in patients who have previously demonstrated hypersensitivity to the drug, any other component of the formulation, or opiate agonists. Tramadol also is contraindicated in patients who are acutely intoxicated with other CNS depressants (e.g., alcohol, sedatives and hypnotics, other centrally acting analgesics, opiate agonists, psychotropic drugs).

For a more complete discussion of the usual precautions associated with opiate agonist therapy, see the Opiate Agonists General Statement 28:08.08.

The manufacturer states that safety and efficacy of tramadol hydrochloride in children younger than 16 years of age have not been established.

When the total number of patients studied in the double-blind or open-label extension periods in US clinical trials of tramadol for chronic nonmalignant pain is considered, 68% were 65 years of age or older. In patients older than 75 years of age, maximum serum tramadol concentrations are slightly elevated and the elimination half-life is slightly prolonged compared with patients 65—75 years of age. Because geriatric patients generally are at increased risk from adverse effects of drugs, tramadol dosage should not exceed 300 mg daily in patients older than 75 years of age.  

Although there are no adequate and controlled studies to date in humans, 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). Embryo and fetal toxicity included mainly decreased fetal weights, skeletal ossification, and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters also were seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported in only one rabbit study, in which rabbits received tramadol hydrochloride 300 mg/kg, a dose that would cause extreme maternal toxicity in rabbits. No harm to the fetus was observed with tramadol doses that were not maternally toxic.

Tramadol was not teratogenic 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). No drug-related teratogenic effects were observed in progeny of mice, rats, or rabbits receiving tramadol (up to 140 mg/kg, 80 mg/kg, or 300 mg/kg, respectively) by various routes.

In perinatal and postnatal studies in rats, progeny of dams receiving oral (gavage) tramadol hydrochloride doses of 50 mg/kg or higher had decreased weights, and pup survival was decreased early in lactation at tramadol hydrochloride doses of 80 mg/kg (6—10 times the maximum human dose). No toxicity was observed for progeny of dams receiving doses of 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.

Safe use of tramadol in pregnancy has not been established. Tramadol should be used during pregnancy only if the potential benefits justify the possible risks to the fetus. Tramadol also should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Chronic use during pregnancy may lead to physical dependence and postpartum withdrawal symptoms in the neonate. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in theumbilical veins compared with maternal veins was 0.83 for women given tramadol during labor. The effect of tramadol, if any, on the later growth, development, and functional maturation of the child is unknown.

No effects on fertility were observed in male rats receiving oral tramadol hydrochloride doses up to 50 mg/kg or in female rats receiving oral tramadol hydrochloride doses up to 75 mg/kg.

Tramadol is distributed into milk. Following a single IV tramadol dose of 100 mg, the cumulative distribution into milk within 16 hours after dosing was 100 µg of tramadol (0.1% of the maternal dose) and 27 µg of M1. Because the safety of tramadol in infants and neonates has not been evaluated, the drug is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing women.

Overdose & Toxicity

Manifestations

Cases of tramadol overdose have been reported. Estimates of ingested dose in non-US fatalities ranged from 3—5 g. A 3-g intentional overdose by a patient enrolled in a clinical trial produced emesis and no sequelae. The lowest tramadol hydrochloridedose reportedly associated with fatality was possibly between 0.5—1 g in a 40-kg woman, but details of the case are not completely known. Manifestations of overdosage are similar to those of other opiate agonists, with the most serious potential consequences being respiratory depression and seizure. Other manifestations may include miosis, vomiting, coma, and cardiac collapse.

Treatment

When treating tramadol overdosage, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. Although an opiate antagonist (e.g., naloxone) will reverse some, but not all, manifestations of tramadol overdosage, the risk of seizures also is increased with naloxone administration. In animals, seizures following the administration of toxic tramadol doses 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 unlikely to be helpful in a tramadol overdosage because it removes less than 7% of the administered dose in a 4-hour dialysis period. For additional information about overdosage of opiate agonists, see Acute Toxicity in the Opiate Agonists General Statement 28:08.08.