At recommended dosages, tramadol generally is well tolerated.1,10,16,17,20,46 Adverse effects usually have been mild10,16,17,20 and similar in incidence to active controls (i.e., acetaminophen 300 mg with codeine phosphate 30 mg and aspirin 325 mg with codeine phosphate 30 mg).1,21 The frequency of some adverse effects may be related to dose and route of administration.4,46 The most common adverse effects observed with tramadol in controlled clinical trials and open-label extension periods enrolling patients with chronic nonmalignant pain were nervous system effects (e.g., dizziness) and GI disturbances.1,3,53,54
Nervous System Effects 
The most frequent adverse nervous system effect of tramadol is dizziness1,3,4,7,8,9,10,11,21,38,43,46,51 or vertigo,1,21,46 which occurred in 26, 31, and 33% of patients receiving tramadol hydrochloride conventional tablets for up to 7, 30, and 90 days, respectively, in clinical studies.1 In patients receiving tramadol hydrochloride as extended-release tablets in clinical studies, dizziness53,54 was reported in about 16, 20, 23, or 28% of patients receiving the drug in a dosage of 100, 200, 300, or 400 mg once daily, respectively.53 In patients receiving tramadol hydrochloride as extended-release capsules in clinical studies, dizziness was reported in about 10, 12, or 14% of patients receiving the drug in a dosage of 100, 200, or 300 mg once daily, respectively.59 The incidence of dizziness may be dose related.46
Headache1,3,4,7,21,38,43,46 occurred in 18, 26, and 32% of patients,1 and somnolence1,3,4,8,9,11,21,38,43,46,51 occurred in 16, 23, and 25% of patients receiving the conventional tablets for up to 7, 30, and 90 days, respectively.1 Headache was reported in up to 16 or 23% of patients receiving tramadol hydrochloride as extended-release tablets or extended-release capsules, respectively, at recommended dosages (100-300 mg daily) in clinical studies.53,59 Somnolence53,54,59 or insomnia53,59 occurred in up to 11 or 9%, respectively, of patients receiving recommended dosages of tramadol hydrochloride extended-release tablets and in up to 16 or 5%, respectively, of patients receiving recommended dosages of tramadol hydrochloride extended-release capsules in clinical studies.53,59 Weakness53,54 has been reported in up to 4% of patients receiving the extended-release tablets in recommended dosages.53
CNS stimulation1,4,21,46 (a composite of nervousness,1,21 anxiety,1,21 agitation,1,21 tremor,1,21 spasticity,1,21 euphoria,1,21 emotional lability,1,21 and hallucinations1,21 ) occurred in 7, 11, and 14% of patients receiving tramadol hydrochloride conventional tablets for up to 7, 30, and 90 days, respectively.1 Asthenia1,21,46 occurred in 6, 11, and 12% of patients, and sweating1,3,4,7,9,10,11,20,21,22,46,51 occurred in 6, 7, and 9% of patients receiving the conventional tablets for up to 7, 30, and 90 days, respectively.1 Sweating may be more common following rapid IV injection.46 Asthenia53 or increased sweating53,54 was reported in up to 7 or 4%, respectively, of patients receiving recommended dosages of tramadol hydrochloride extended-release tablets in clinical studies.53 Asthenia59 or increased sweating59 was reported in up to 9% or 7%, respectively, of patients receiving recommended dosages of the extended-release capsules in clinical studies.59
GI Effects
Constipation14,9,21,22,38,43,46,51 is the most common adverse GI effect of tramadol, occurring in 24, 38, and 46% of patients receiving tramadol hydrochloride conventional tablets for up to 7, 30, and 90 days, respectively, in clinical studies.1 Nausea1,3,4,7,8,9,11,20,21,22,38,43,46,51 occurred in 24, 34, and 40% of patients,1 and vomiting1,3,4,7,8,17,20,21,22,43,46 occurred in 9, 13, and 17% of patients receiving conventional tablets of the drug for up to 7, 30, and 90 days, respectively.1 Nausea,53,54 constipation,53,54 vomiting,53,54 or anorexia53 has been reported in up to 26, 22, 9, or 5%, respectively, of patients receiving recommended dosages of tramadol hydrochloride extended-release tablets (100-300 mg daily) in clinical studies.53 Nausea,59 constipation,59 vomiting,59 or anorexia59 has been reported in up to 25, 21, 10, or 6%, respectively, of patients receiving recommended dosages of the extended-release capsules (100-300 mg daily) in clinical studies.59 Nausea and vomiting may occur more frequently with higher doses and following rapid IV injection.46
Other adverse GI effects reported in patients receiving conventional tablets of the drug include dyspepsia,1,21,43,51 which occurred in 5, 9, and 13% of patients, dry mouth,1,3,4,8,11,17,21,43,46,51 which occurred in 5, 9, and 10%, and diarrhea,1,21,46 which occurred in 5, 6, and 10% of patients receiving tramadol for up to 7, 30, and 90 days, respectively.1 Dry mouth53 or diarrhea53 was reported in up to 10 or 9%, respectively, of patients receiving recommended dosages of tramadol hydrochloride extended-release tablets in clinical studies.53 Dry mouth59 also was reported in up to 13% of patients receiving recommended dosages of the extended-release capsules in clinical studies.59
Sensitivity Reactions
Pruritus1,9,21,22,46,51,53,59 occurred in 8, 10, and 11% of patients receiving tramadol hydrochloride conventional tablets for up to 7, 30, and 90 days, respectively;1 in up to 9% of patients receiving the extended-release tablets in recommended dosages (100-300 mg daily);53 and in up to 7% of patients receiving the extended-release capsules in recommended dosages (100-300 mg daily).59 Rash1,59 or dermatitis53 was reported in 1% to less than 5% of patients receiving the drug in clinical trials.1,53,59 Serious and rarely fatal anaphylactoid reactions, often occurring after the initial dose, have been reported in patients receiving tramadol.1,46,53 (See Cautions: Precautions and Contraindications.) Urticaria,1,53,59 bronchospasm,1,53,59 and angioedema1,53,59 have occurred.1,53,59
Cardiovascular Effects
Vasodilation1 has been reported in 1% to less than 5% of patients receiving tramadol hydrochloride conventional tablets in clinical trials.1 Postural hypotension53 or flushing53 occurred in up to 4 or 10%, respectively, of patients receiving tramadol hydrochloride extended-release tablets in recommended dosages (100-300 mg daily) in clinical studies.53 53
Genitourinary and Endocrine Effects
Hypoglycemia has been reported very rarely in patients receiving tramadol, mainly in patients with predisposing risk factors (e.g., diabetes mellitus, renal insufficiency) or in geriatric patients.1,53 Increased blood glucose concentrations have occurred in patients receiving tramadol hydrochloride extended-release tablets.53
Adrenal insufficiency has been reported in patients receiving opiate agonists or opiate partial agonists.1,53,59,400 Manifestations of adrenal insufficiency are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.1,53,59,400 The onset generally has occurred after at least 1 month of opiate agonist or partial agonist use, although the time to onset has ranged from within 1 day to more than 1 year.1,53,59,400 In many of the reported cases, patients required hospitalization.400 If adrenal insufficiency is suspected, appropriate laboratory testing should be performed promptly and physiologic (replacement) dosages of corticosteroids provided; therapy with the opiate agonist or partial agonist should be tapered and discontinued to allow recovery of adrenal function.1,53,59,400 If the opiate agonist or partial agonist can be discontinued, follow-up assessment of adrenal function should be performed to determine if corticosteroid replacement therapy can be discontinued.400 In some patients, switching to a different opiate improved symptoms.1,53,59,400
Hypogonadism and androgen deficiency have been reported in patients receiving long-term opiate agonist or opiate partial agonist therapy,400,401,402,403,404 although a causal relationship has not been established.1,53,59,400 Patients receiving long-term opiate agonist or partial agonist therapy who present with manifestations of hypogonadism (e.g., decreased libido, impotence, erectile dysfunction, amenorrhea, infertility) should undergo laboratory evaluation.400
Acute Toxicity
Manifestations
Tramadol taken in excessive doses, either alone or in combination with other CNS depressants, is a cause of drug-related deaths.1,53 Fatalities associated with both intentional and unintentional overdose have been reported.1,21,40,52,53 Estimates of ingested dose in non-US fatalities ranged from 3-5 g.21,52 A 3-g intentional overdose by a patient enrolled in a clinical trial produced emesis and no sequelae.21,52 The lowest tramadol hydrochloride dose 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.21,52 Tramadol is intended for oral use only.1,53,59 Crushing, cutting, breaking, or chewing tramadol hydrochloride extended-release tablets or capsules, “snorting” the powder, or injecting dissolved contents of the tablets or capsules results in uncontrolled delivery of tramadol and poses a risk of a potentially fatal overdose.53,59 The risk of a fatal overdose is increased when tramadol is misused concurrently with other CNS depressants (e.g., alcohol, other opiates).1,53,59 Manifestations of overdosage are similar to those of other opiate agonists, with the most serious potential consequences being respiratory depression, lethargy, skeletal muscle flaccidity, coma, seizure, bradycardia, hypotension, pulmonary edema, partial or complete airway obstruction, cardiac arrest, cardiac collapse, and death.1,3,21,52,53,59 Death may occur within 1 hour of overdosage.53 Other manifestations may include miosis,21 vomiting,21 cold and clammy skin,1,51,53 and atypical snoring.1,53,59 Marked mydriasis (rather than miosis) may be observed in patients with hypoxia.1,53,59
Treatment
When treating tramadol overdosage, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (including administration of oxygen and vasopressors as clinically indicated).1,53,59 Tramadol hydrochloride extended-release tablets or capsules will continue to release the drug for 24-48 hours or longer following ingestion, necessitating prolonged monitoring.53,59 An opiate antagonist should be administered if clinically important respiratory or circulatory depression is present, but should not be administered in the absence of such manifestations.1,53,59 Although an opiate antagonist (e.g., naloxone, nalmefene) will reverse some, but not all, manifestations of tramadol overdosage, the risk of seizures also is increased with naloxone administration.1,3,4,21,53,59 In animals, seizures following the administration of toxic tramadol doses could be suppressed with barbiturates or benzodiazepines but were increased with naloxone.1,53,59 Naloxone administration did not change the lethality of an overdose in mice.1,53,59 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.1,53,59 .
Precautions and Contraindications
General Opiate Agonist Precautions
Administration of tramadol may cause effects similar to those produced by other opiate agonist drugs,1,2,3,4,5,7,8,9,11,53 and the usual precautions of opiate agonist therapy should be observed.1,53,59 (See Description and the manufacturers' labeling.)
Extended-release preparations of tramadol should be prescribed only by clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain.53,59
Addiction, Abuse, and Misuse
Tramadol exposes patients and other users to the risks of opiate addiction (opiate use disorder [OUD]), abuse, and misuse, which can lead to overdosage and death.1,53,59 The abuse potential of tramadol is less than that of morphine or oxycodone but similar to that of propoxyphene (see Description).56 Addiction can occur with appropriately prescribed or illicitly obtained opiates, and at recommended dosages or with misuse or abuse.1,53,59 Concurrent abuse of alcohol or other CNS depressants increases the risk of toxicity.1,53,59 Each patient's risk for addiction, abuse, and misuse should be assessed prior to initiating tramadol therapy, and all patients receiving the drug should be monitored for development of these behaviors or conditions.1,53,59 Personal or family history of substance abuse (drug or alcohol addiction or abuse) or mental illness (e.g., major depression) increases risk.1,53,59 The potential for addiction, abuse, and misuse should not prevent opiate prescribing for appropriate pain management, but does necessitate intensive counseling about risks and proper use and intensive monitoring for signs of addiction, abuse, and misuse.1,53,59 Tramadol should be prescribed in the smallest appropriate quantity and the patient should be instructed on secure storage and proper disposal to prevent theft.1,53,59
Extended-release opiates are associated with a greater risk of overdosage and death because of the larger amount of drug contained in each dosage unit.53,59 Abuse or misuse of tramadol extended-release tablets or capsules by splitting, crushing, breaking, cutting, or chewing the tablets or capsules, snorting the contents, or injecting the dissolved contents will result in uncontrolled delivery of tramadol and can result in a fatal overdosage.53,59 IV injection of excipients in these formulations can result in local tissue necrosis, infection, pulmonary granulomas, embolism, and death and increase the risk of endocarditis and valvular heart injury.53,59
Respiratory Depression
Serious, life-threatening, or fatal respiratory depression can occur in patients receiving opiates, even when used as recommended.1,53,59 Although respiratory depression can occur at any time during therapy, the risk is greatest during initiation of therapy and following an increase in dosa therefore, patients receiving tramadol should be monitored closely for respiratory depression, especially during the first 24-72 hours of therapy and following any increase in dosage.1,53,59 Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression.1,53,59 Large initial doses in nontolerant patients, overestimation of the initial tramadol dosage when transferring patients from another opiate analgesic, or accidental ingestion of even one dose of tramadol, especially by a child, can result in respiratory depression and death.1,53,59 For clinically important respiratory depression resulting from tramadol overdosage, an opiate antagonist should be administered.1,53,59 (See Treatment under Cautions: Acute Toxicity.)
Geriatric, cachectic, or debilitated patients are at increased risk of life-threatening respiratory depression.1,53,59 In patients with chronic obstructive pulmonary disease or cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, even recommended doses of tramadol may decrease respiratory drive to the point of apnea.1,53,59 Such patients should be monitored closely, particularly following initiation of therapy, during dosage titration, and during concomitant therapy with other respiratory depressants.1,53,59 Alternatively, use of nonopiate analgesics should be considered in such patients.1,53,59 Use of tramadol in patients with substantial respiratory depression or in those with severe bronchial asthma in unmonitored settings or in the absence of resuscitative equipment is contraindicated.1,53,59
Because of the risks associated with opiate overdosage, clinicians should routinely discuss the availability of the opiate antagonist naloxone with all patients receiving new or reauthorized prescriptions for opiate analgesics, including tramadol.750 Clinicians should consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with a history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose)411,431,750 or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.750 Even if patients are not receiving an opiate analgesic, a naloxone prescription should be considered if the patient is at increased risk of opiate overdosage (e.g., those with a current or past diagnosis of OUD, those who have experienced a prior opiate overdose).750 (See Naloxone Hydrochloride 28:10.)
Drugs Affecting Hepatic Microsomal Enzymes
Because orally administered tramadol undergoes extensive hepatic metabolism, including metabolism by cytochrome P-450 (CYP) isoenzymes 2D6 and 3A4, concomitant use of drugs that inhibit or induce CYP3A4 or inhibit CYP2D6 requires careful consideration of the effects on tramadol and its active O -desmethyl metabolite (M1) (see Description).1,53,59
Because formation of M1 is dependent on CYP2D6 activity, concomitant use of tramadol and CYP2D6 inhibitors (e.g., amiodarone, bupropion, fluoxetine, paroxetine, quinidine) may result in increased plasma concentrations of tramadol and decreased concentrations of M1, particularly when the CYP2D6 inhibitor is initiated after a stable dosage of tramadol has been achieved.1,53,59 The increase in tramadol concentrations can result in increased or prolonged therapeutic effects and an increased risk of serious adverse effects, including seizures and serotonin syndrome, while the decrease in M1 concentrations may result in reduced therapeutic effects and, in patients physically dependent on opiates, manifestations of opiate withdrawal.1,53,59 Discontinuance of the CYP2D6 inhibitor may result in a decrease in plasma concentrations of tramadol and an increase in M1 concentrations, which could increase or prolong therapeutic effects or manifestations of opiate toxicity and potentially cause fatal respiratory depression.1,53,59 If concomitant therapy with tramadol and a CYP2D6 inhibitor is required, patients should be monitored closely for serious tramadol-related adverse effects (including seizures and serotonin syndrome) and manifestations of opiate toxicity or opiate withdrawal.1,53,59 If concomitant therapy with a CYP2D6 inhibitor is discontinued, the patient should be monitored closely for adverse effects, including respiratory depression and sedation, and consideration should be given to reducing the tramadol dosage until stable drug effects are achieved.1,53,59
Concomitant use of tramadol and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole antifungals (e.g., ketoconazole), or HIV protease inhibitors (e.g., ritonavir), can increase plasma concentrations of tramadol, which may result in larger amounts of parent drug being metabolized by CYP2D6 and higher concentrations of M1.1,53,59 If concomitant therapy with tramadol and a CYP3A4 inhibitor is required, patients should be monitored closely for serious adverse effects (including seizures and serotonin syndrome) and for manifestations of opiate toxicity (including sedation and potentially fatal respiratory depression), particularly when the CYP3A4 inhibitor is initiated after a stable dosage of tramadol has been achieved, and consideration should be given to reducing the tramadol dosage until stable drug effects are achieved.1,53,59 If concomitant therapy with a CYP3A4 inhibitor is discontinued, the patient should be monitored for manifestations of opiate withdrawal, and consideration should be given to increasing the tramadol dosage until stable drug effects are achieved.1,53,59
Concomitant use of tramadol and CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin) can decrease plasma concentrations of tramadol, resulting in decreased efficacy and, in patients who are physically dependent on opiates, manifestations of opiate withdrawal.1,53,59 Discontinuance of the CYP3A4 inducer may result in increased plasma concentrations of tramadol, which could increase or prolong both the therapeutic and adverse effects of tramadol and may cause seizures, serotonin syndrome, and potentially fatal respiratory depression.1,53,59 If concomitant therapy with tramadol and a CYP3A4 inducer is required, patients should be monitored for manifestations of opiate withdrawal, and consideration should be given to increasing the tramadol dosage until stable drug effects are achieved.1,53,59 If concomitant therapy with a CYP3A4 inducer is discontinued, patients should be monitored for seizures, serotonin syndrome, sedation, and respiratory depression, and consideration should be given to decreasing the tramadol dosage until stable drug effects are achieved.1,53,59
Concomitant use of tramadol with carbamazepine is not recommended because carbamazepine increases tramadol metabolism and substantially reduces tramadol's analgesic effect, and because tramadol is associated with increased risk of seizures.1,53,59
Concomitant Use with Benzodiazepines or Other CNS Depressants
Tramadol may potentiate the respiratory and CNS depressant effects of other CNS depressants.1,11,21,38,53,59 Concomitant use of tramadol with benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, hypotension, coma, and death.1,53,59,416,417,418,700,701,702,703 (See Cautions: Acute Toxicity.) Concomitant use of such drugs should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.1,53,59,700,703 Concomitant use with alcohol should be avoided.1,53,59,700,703 Clinicians should consider prescribing the opiate antagonist naloxone for patients receiving opiates who are at increased risk of opiate overdosage, including those receiving benzodiazepines or other CNS depressants concomitantly.411,431,750 (See Drug Interactions: Benzodiazepines and Other CNS Depressants, in the Opiate Agonists General Statement 28:08.08.)
If a benzodiazepine or other CNS depressant is required for any indication other than epilepsy in a patient receiving tramadol, the drug should be initiated at a lower dosage than indicated in the absence of opiate therapy and titrated based on clinical response.700,703 In patients receiving a CNS depressant, tramadol, if required, should be initiated at a reduced dosage and titrated based on clinical response.1,53,59,700,703
Serotonin Syndrome
Potentially life-threatening serotonin syndrome may occur with tramadol, particularly with concurrent use of other serotonergic drugs,1,53,59,400 drugs that impair the metabolism of serotonin (e.g., monoamine oxidase [MAO] inhibitors),1,53,59,400 or drugs that impair the metabolism of tramadol (e.g., inhibitors of CYP2D6 and CYP3A4).1,53,59 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1,53,59,400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.1,53,59,400 (See Drugs Associated with Serotonin Syndrome under Cautions: Precautions and Contraindications.)
Seizures
Seizures have occurred during tramadol therapy with recommended dosages.1,21,38,39,43,44,45,46,53,59 Spontaneous postmarketing reports indicate that seizure risk is increased with tramadol doses above the recommended range.1,38,39,43,44,46,53,59 Seizures can occur following the first dose.46,53 The manufacturers warn that tramadol increases the seizure risk in patients taking selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), anorectic agents, tricyclic antidepressants or other tricyclic compounds (e.g., cyclobenzaprine, promethazine), or other opiate agonists.1,43,44,46,53,59 The manufacturers also warn that the drug may enhance the risk of seizure in those receiving MAO inhibitors, antipsychotic agents, or other drugs that decrease the seizure threshold.1,21,43,46,53,59 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.1,21,43,46,53,59 Naloxone administration in patients with tramadol overdose also may increase the risk of seizure.1,43,46,53,59
Suicide
Tramadol should not be prescribed for individuals who are suicidal or prone to addiction.1,53,59 Tramadol should be used with caution in patients with a history of misuse, patients receiving concomitant therapy with CNS-active drugs including tranquilizers or antidepressants, individuals with excessive alcohol consumption, and patients with emotional disturbances or depression.1,53,59 The use of alternative analgesics without opiate agonist activity should be considered in suicidal or depressed patients.1,53,59 (See Cautions: Acute Toxicity.)
Monoamine Oxidase Inhibitors
Concomitant use of opiates with MAO inhibitors (e.g., linezolid, phenelzine, tranylcypromine) may increase the risk of serotonin syndrome, seizures, and opiate toxicity (e.g., respiratory depression, coma).1,53,59 Use of tramadol is contraindicated in patients who are currently receiving or have recently (within 14 days) received an MAO inhibitor.1,53,59
Pharmacogenomics
Tramadol is metabolized by the CYP microsomal enzyme system, principally by CYP2D6 to its active M1 metabolite.59,60 Metabolism of certain drugs, including tramadol, is influenced by CYP2D6 polymorphism.59,60,108,109,110,112,114 Individuals who lack functional alleles of the CYP2D6 gene are described as poor metabolizers, those with one or two functional alleles are described as extensive metabolizers, and those who carry a duplicate or amplified gene are described as ultrarapid metabolizers.108,109,110,114 Population pharmacokinetic analysis of phase 1 studies of tramadol hydrochloride conventional tablets in healthy individuals indicated that concentrations of tramadol were approximately 20% higher and those of M1 were 40% lower in poor metabolizers compared with extensive metabolizers.1,53,59
Genetically determined differences in drug metabolism can affect an individual's response to a drug or risk of having an adverse event.108,109,110,112,114 Individuals who are poor metabolizers may experience reduced analgesic effects of tramadol;60 individuals who are ultrarapid metabolizers are likely to have higher than expected serum concentrations of M1.60,705 To minimize the risk of adverse events in individuals who are ultrarapid metabolizers of CYP2D6, FDA states that tramadol should not be used in such patients.705 Variations in CYP2D6 polymorphism occur at different frequencies among subpopulations of different ethnic or racial origin.107,108,109,110,114 Approximately 1-7% of Caucasians and 10-30% of Ethiopians and Saudi Arabians carry the genotype associated with ultra-rapid metabolism of CYP2D6 substrates.107,108,110,114
Drugs Associated with Serotonin Syndrome
Serotonin syndrome may occur when tramadol is used concurrently with other serotonergic drugs, including serotonin (5-hydroxytryptamine; 5-HT) type 1 (5-HT1) receptor agonists (“triptans”), SSRIs, SNRIs, tricyclic antidepressants, antiemetics that are 5-HT3 receptor antagonists, buspirone, cyclobenzaprine, dextromethorphan, lithium, St. John's wort ( Hypericum perforatum ), tryptophan, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, vilazodone), and MAO inhibitors (both those used to treat psychiatric disorders and others, such as linezolid, methylene blue, and selegiline).1,47,53,59,400 Serotonin syndrome may occur within the recommended dosage ranges for these drugs.1,53,59,400 Serotonin syndrome has been reported during postmarketing experience in patients receiving tramadol concomitantly with MAO inhibitors, SSRIs, SNRIs, or α2-adrenergic blocking agents.1,47,53,59 Tramadol decreases the synaptic reuptake of the monoamine neurotransmitters norepinephrine and serotonin,1,4,11,12,13,14 and animal studies have shown increased deaths with combined administration of tramadol and MAO inhibitors.1,53,59 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1,53,59,400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.1,53,59,400
If concomitant use of other serotonergic drugs is warranted, great caution is advised1,3,8,9,11,38,43,53,59 and patients should be monitored for serotonin syndrome, particularly during initiation of therapy and dosage increases.1,47,53,59,400 If serotonin syndrome is suspected, treatment with tramadol, other opiate therapy, and/or any concurrently administered serotonergic agents should be discontinued.400
For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.
Hypotension
Tramadol may cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients.1,53,59 Because the risk of severe hypotension is increased in patients whose ability to maintain blood pressure has been compromised by blood volume depletion or concomitant use of certain CNS depressants (e.g., phenothiazines, general anesthetics), such patients should be monitored for hypotension following initiation of tramadol therapy or an increase in tramadol dosage.1,53,59 Use of tramadol should be avoided in patients with circulatory shock since the drug may cause vasodilation that can further reduce cardiac output and blood pressure.1,53,59
Increased Intracranial Pressure or Head Injury
The respiratory depressant effects of opiate agonists promote carbon dioxide retention, which can result in elevation of intracranial pressure.1,53,59 Patients who may be particularly susceptible to these effects (e.g., those with evidence of elevated intracranial pressure or brain tumors) should be monitored closely for sedation and respiratory depression, particularly during initiation of therapy.1,53,59 Opiates also may obscure the clinical course in patients with head injuries.1,53,59 Use of tramadol should be avoided in patients with impaired consciousness or coma.1,53,59
GI Conditions
Opiates may increase serum amylase concentrations and cause spasm of the sphincter of Oddi.1,53,59 Patients with biliary tract disease, including those with acute pancreatitis, should be monitored for worsening symptoms.1,53,59 Tramadol is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.1,53,59
Sensitivity Reactions
Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving tramadol.1,46,53,59 These reactions often occur following the first dose.1,46,53,59 Other reported hypersensitivity reactions include pruritus, urticaria, angioedema, bronchospasm, toxic epidermal necrolysis, and Stevens-Johnson syndrome.1,53,59 The manufacturers warn 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.1,46,53,59 If anaphylaxis or other hypersensitivity reaction occurs, tramadol should be discontinued immediately and permanently.1,53,59
Dependence and Tolerance
Both tolerance and physical dependence can develop during long-term opiate therapy.1,53,59 Tolerance may not develop uniformly to all opiate effects.1,53,59
In patients who are physically dependent on opiates, abrupt discontinuance of tramadol or a substantial reduction in dosage may result in manifestations of withdrawal (e.g., restlessness, lacrimation, rhinorrhea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increases in blood pressure, respiratory rate, or heart rate).1,53,59 When tramadol therapy is discontinued in a patient who may be physically dependent on opiates, the dosage should be tapered gradually.1,53,59 Infants born to women who are physically dependent on opiates also will be physically dependent.1,53,59 (See Cautions: Pregnancy, Fertility, and Lactation.)
Concomitant use of opiate partial agonists (e.g., buprenorphine, butorphanol, nalbuphine, pentazocine) should be avoided since they may reduce the analgesic effect of tramadol and/or precipitate withdrawal symptoms.1,53,59
CNS Depression
Tramadol may impair mental alertness and/or physical coordination required to perform potentially hazardous activities such as driving or operating machinery; patients should be warned about possible adverse CNS effects of the drug.1,53,59
Warfarin
Prolongation of the international normalized ratio (INR)48,49,50 and prothrombin time1,49,53,59 and extensive ecchymoses49 have been reported in patients receiving tramadol and warfarin concomitantly.1,48,49,50,53,59 Therefore, tramadol should be used with caution in patients receiving warfarin;49 the INR should be closely monitored in those receiving the combination,48,49,50 and the warfarin dosage should be adjusted as needed.1,53,59
Digoxin
Digoxin toxicity has been reported rarely during postmarketing experience in patients receiving digoxin and tramadol concomitantly.1,53,59 Patients receiving such concomitant therapy should be monitored for digoxin toxicity, and digoxin dosage should be adjusted as needed.1,53,59
Renal and Hepatic Impairment
Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active O -desmethyl metabolite (M1).1,43,53,59 Therefore, in patients with creatinine clearance less than 30 mL/minute, the manufacturers recommend dosage reduction when tramadol is used alone as conventional tablets or in fixed combination with acetaminophen.1,9,43,51 Tramadol hydrochloride extended-release tablets and capsules should not be used in patients with severe renal impairment (i.e., creatinine clearance less than 30 mL/minute); the available tablet and capsule strengths and once-daily dosing do not provide sufficient dosing flexibility for safe use in these patients.53,59 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)
Tramadol and M1 metabolism are reduced in patients with advanced hepatic cirrhosis.1,9,43,53 When tramadol hydrochloride conventional tablets are used in adults with cirrhosis, dosage adjustment is recommended.1 Tramadol hydrochloride extended-release tablets and capsules should not be used in patients with severe hepatic impairment (Child-Pugh class C); the available tablet and capsule strengths and once-daily dosing do not provide sufficient dosing flexibility for safe use in these patients.53,59 The manufacturers state that pharmacokinetics and safety of tramadol in fixed combination with acetaminophen have not been studied in patients with impaired hepatic function.51 Therefore, because both tramadol and acetaminophen are extensively metabolized by the liver, the fixed-combination preparation should not be used in patients with hepatic impairment.51 (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.1
Advice to Patients
Patients should be advised to read the manufacturer's patient information (e.g., medication guide) for tramadol before initiating therapy with the drug and each time the prescription is refilled.1,53,59 Patients should be informed that use of tramadol, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdosage and death.1,53,59 Patients also should be informed that accidental ingestion of tramadol, especially by a child, may result in respiratory depression or death.1,53,59 Patients should be instructed not to share the drug with others, to take steps to protect the drug from theft or misuse, to securely store the drug, to keep the drug out of reach of children, and to properly dispose of any unused drug.1,53,59
Patients should be advised of the risk of life-threatening respiratory depression and instructed to seek immediate medical attention if manifestations of respiratory depression occur.1,53,59 Patients receiving tramadol and/or their caregivers should be advised that concomitant therapeutic or illicit use of benzodiazepines or other CNS depressants, including alcohol, can result in potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma); patients should be advised to avoid concomitant use of alcohol and to avoid concomitant use of other CNS depressants unless such use is supervised by a clinician.1,53,59,700 Patients should be advised of the benefits of naloxone administration following an overdose and of their options for obtaining the drug.750
Patients should be informed of the risk of opiate toxicity in children, especially those who are obese, have respiratory diseases, or have evidence of ultrarapid metabolism of tramadol60,705 and advised that tramadol should not be given to children younger than 12 years of age for pain relief or to children younger than 18 years of age for pain relief following tonsillectomy or adenoidectomy.705 (See Cautions: Pediatric Precautions.)
Patients should be advised that tramadol may cause seizures and/or serotonin syndrome, particularly when used concurrently with serotonergic drugs or drugs that substantially decrease the metabolism of tramadol.1,53,59,400 (See Drugs Associated with Serotonin Syndrome and also Drugs Affecting Hepatic Microsomal Enzymes under Cautions: Precautions and Contraindications.) 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.1,53,59 Patients should be advised of the importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses; patients should be advised that tramadol should not be used concomitantly with MAO inhibitors.1,53,59 Patients also should be advised that severe hypersensitivity reactions have occurred and that the drug may cause orthostatic hypotension and syncope.1,53,59 Because opiates can cause severe constipation, patients should be advised on appropriate management of constipation.1,53,59 Because of the potential risk of adrenal insufficiency, patients should be advised to immediately contact a clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.1,53,59,400 Although a causal relationship between hypogonadism or androgen deficiency and long-term opiate agonist use has not been established, patients should be advised of this potential risk and instructed to inform their clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs.400
Women of childbearing potential should be instructed to inform their clinician if they are or plan to become pregnant1,53,59 and should be advised that use of tramadol is not recommended in nursing women.1,53,59,705 Women of childbearing potential should be advised that tramadol may cause fetal harm and that prolonged use of opiates during pregnancy may result in neonatal opiate withdrawal syndrome, which can be life-threatening if not recognized and treated.1,53,59 (See Cautions: Pregnancy, Fertility, and Lactation.)
Clinicians should be certain that patients understand the single-dose and 24-hour dose limit, and the recommended interval between doses of tramadol administered alone or in fixed combination with acetaminophen, since exceeding these recommendations can result in respiratory depression, seizures, acetaminophen-associated hepatic toxicity, and death.1,51,53,59 Patients receiving therapy with tramadol hydrochloride extended-release tablets or capsules should be advised that the tablets or capsules should be swallowed whole and should not be crushed, chewed, broken, split, or dissolved.53,59 Because of the risk of withdrawal syndrome, patients should be advised not to abruptly discontinue therapy with the drug without consulting their clinician.1,53,59
Contraindications
Tramadol is contraindicated in patients with substantial respiratory depression; acute or severe bronchial asthma in unmonitored settings or in the absence of resuscitative equipment; known or suspected GI obstruction, including paralytic ileus; or known hypersensitivity (e.g., anaphylaxis) to the drug, other opiates, or any ingredient in the formulation.1,53,59 Tramadol also is contraindicated during or within 14 days following treatment with an MAO inhibitor.1,53,59
Tramadol is contraindicated in children younger than 12 years of age for the management of pain and in those younger than 18 years of age for the management of postoperative pain following tonsillectomy and/or adenoidectomy.705 (See Cautions: Pediatric Precautions.)
Pediatric Precautions
Children receiving tramadol for the management of pain, especially those who are obese, have obstructive sleep apnea or severe lung disease, or have evidence of ultrarapid metabolism of CYP2D6 substrates, are at increased risk of respiratory depression.705 Between January 1969 and May 2016, the FDA Adverse Event Reporting System (AERS) received 9 reports of respiratory depression, including 3 deaths, worldwide that were associated with tramadol use in children younger than 18 years of age.705 Respiratory depression generally occurred within the first 24 hours of dosing and required medical intervention (e.g., naloxone).705 All 3 of the fatal cases occurred outside of the US in children younger than 6 years of age receiving tramadol hydrochloride oral solution for postoperative analgesia or management of fever.705 One 5-year-old child with obstructive sleep apnea experienced severely slowed and difficult breathing requiring emergency intervention and hospitalization after receiving a single 20-mg dose of tramadol hydrochloride oral solution (approximately 1 mg/kg) for pain relief following tonsillectomy and adenoidectomy.57,58,705 The child was resuscitated and later found to be a CYP2D6 ultra-rapid metabolizer and to have a high concentration of the active O -desmethyl metabolite (M1).57,58,705 In the other 8 reported cases, the CYP2D6 metabolizer status was unknown.705
To minimize the risk of serious adverse events in children, FDA states that tramadol-containing preparations must not be used for the management of pain in children younger than 12 years of age or for the management of postoperative pain following tonsillectomy and/or adenoidectomy in children younger than 18 years of age.705 FDA also states that use of tramadol for the management of pain is not recommended in children 12-18 years of age who are obese or have conditions such as obstructive sleep apnea or compromised respiratory function (because of potentially greater susceptibility to the respiratory depressant effects of the drug).705 If tramadol is used for the management of pain in children 12-18 years of age, caregivers should closely monitor the child for clinical manifestations of opiate toxicity (e.g., slow, shallow, difficult, or noisy breathing; confusion; unusual sleepiness) and seek immediate medical treatment for the child if such manifestations occur.705
The manufacturers state that safety and efficacy of tramadol hydrochloride conventional tablets have not been established in children younger than 16 years of age.1 Safety and efficacy of tramadol hydrochloride extended-release tablets and capsules and of tablets containing tramadol hydrochloride in fixed combination with acetaminophen have not been established in children younger than 18 years of age.51,53,59 The manufacturers state that use of tramadol in pediatric patients is not recommended.1,51,53,59
Geriatric Precautions
In general, tramadol dosage should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range, considering the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly. 51 (See Dosage and Administration: Dosage.) Because respiratory depression is the chief risk for geriatric patients receiving opiates, dosage should be titrated slowly and geriatric patients should be monitored closely for CNS and respiratory depression.1,53,59 Tramadol is substantially excreted by the kidneys, and the risk of adverse effects may be increased in patients with impaired renal function.1,53,59 Because geriatric patients may have decreased renal function, dosage should be selected carefully; it may be useful to monitor renal function in such patients.1,53,59
In controlled clinical trials of tramadol hydrochloride conventional tablets, 455 patients who received the drug were 65 years of age or older, while 145 patients were 75 years of age or older.1 In patients older than 75 years of age receiving conventional tablets of the drug, maximum serum tramadol concentrations are elevated (208 ng/mL) and the elimination half-life is prolonged (7 hours) compared with patients 65-75 years of age (162 ng/mL and 6 hours, respectively).1,9,43 In clinical studies including geriatric patients receiving tramadol hydrochloride conventional tablets, treatment-limiting adverse GI effects occurred in 30% of patients older than 75 years of age compared with 17% of those younger than 65 years of age, and constipation resulted in discontinuance of treatment in 10% of those older than 75 years of age.1
In clinical trials of tramadol hydrochloride extended-release tablets, 901 patients who received the drug were 65 years of age or older, while 156 patients were 75 years of age or older.53 In these studies, the incidence of adverse effects was higher in patients older than 65 years of age compared with younger adults; adverse effects reported more frequently in older adults include constipation, fatigue, weakness, postural hypotension, and dyspepsia.53 Tramadol hydrochloride extended-release tablets should be used with caution in patients older than 65 years of age and with even greater caution in those older than 75 years of age.53
In clinical trials of tramadol hydrochloride extended-release capsules, 812 patients who received the drug were 65 years of age or older, while 240 patients were 75 years of age or older.59 In these studies, the incidence of adverse effects was higher in patients older than 65 years of age compared with younger adults; adverse effects reported more frequently in older adults include nausea, constipation, somnolence, dizziness, dry mouth, vomiting, asthenia, pruritus, anorexia, sweating, fatigue, weakness, postural hypotension, and dyspepsia.59 Tramadol hydrochloride extended-release capsules should be used with great caution in geriatric patients older than 75 years of age.59
Limited data from a study of patients with chronic pain receiving tramadol in fixed combination with acetaminophen indicated that there were no substantial changes in pharmacokinetics of tramadol or acetaminophen in patients 65 years of age and older with normal renal and hepatic function compared with younger adults.51
Pregnancy, Fertility, and Lactation
Pregnancy
Prolonged maternal use of opiate agonists during pregnancy can result in neonatal opiate withdrawal syndrome with manifestations of irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.1,53,59 In contrast to adults, the withdrawal syndrome in neonates may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.1,53,59 Women who require prolonged opiate agonist therapy during pregnancy should be advised of the risk of neonatal opiate withdrawal syndrome, and availability of appropriate treatment should be ensured.1,53,59 The onset, duration, and severity of the syndrome vary depending on the specific opiate agonist used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.1,53,59 Neonatal seizures, neonatal withdrawal syndrome, fetal death, and stillbirth have been reported with tramadol during postmarketing experience.1,53,59 The effect of tramadol, if any, on the later growth, development, and functional maturation of the child is unknown.1,53,59
Use of opiates in pregnant women during labor can result in neonatal respiratory depression.1,53,59 Use of tramadol is not recommended immediately before or during labor, when other analgesic techniques may be more appropriate.1,53,59 Opiate agonists may prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions.1,53,59 However, this effect is inconsistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.1,53,59 Neonates exposed to opiates during labor should be monitored for excessive sedation and respiratory depression.1,53,59 An opiate antagonist must be available for reversal of opiate-induced respiratory depression.1,53,59
Tramadol has been shown to cross the placenta.1,53,59 The mean ratio of serum tramadol in the umbilical veins compared with maternal veins was 0.83 for women given tramadol during labor.1,53,59
Analysis of data from the National Birth Defects Prevention Study, a large population-based, case-control study, suggests that therapeutic maternal use of opiate agonists during the period of organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis.61,62 The manufacturers state that available data regarding use of tramadol in pregnant women are insufficient to establish the risk of major birth defects and spontaneous abortion with the drug.1,53,59
Based on animal data, women of childbearing potential should be advised of the potential for tramadol to cause fetal harm.1,53,59
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 1.4, 0.6, and 3.6 times, respectively, the maximum daily human dosage (120 mg/kg in mice, 25 mg/kg in rats, and 75 mg/kg in rabbits).1 Embryo and fetal toxicity consisted mainly of decreased fetal weights, decreased skeletal ossification, and increased supernumerary ribs at maternally toxic dose levels.1 Transient delays in developmental or behavioral parameters also were seen in pups from rat dams allowed to deliver.1 Embryo and fetal lethality was 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.1
Embryotoxicity and fetotoxicity have been demonstrated in rats when tramadol and acetaminophen were administered in fixed combination at maternally toxic doses of 50 and 434 mg/kg, respectively, or 1.6 times the maximum daily human dosages of these drugs.51 Embryonic and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs.51
Tramadol was not teratogenic in mice, rats, and rabbits at maternally toxic doses 1.4, 0.6, and 3.6 times, respectively, the maximum human daily dosage (120 mg/kg in mice, 25 mg/kg in rats, and 75 mg/kg in rabbits).1 No drug-related teratogenic effects were observed in progeny of mice, rats, or rabbits receiving tramadol (up to 140, 80, or 300 mg/kg or 1.7, 1.9, or 14.6 times, respectively, the maximum daily human dosage) by various routes.1
Tramadol and acetaminophen in fixed combination was not teratogenic in rats at a maternally toxic dose of 50 and 434 mg/kg, respectively, or 1.6 times the maximum daily human dosages of these drugs.51
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 (1.2-1.6 or 1.9-2.6 times, respectively, the maximum human dose).1,51 No toxicity was observed for progeny of dams receiving doses of 8, 10, 20, 25, or 40 mg/kg.52 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.52
Fertility
Long-term use of opiates may reduce fertility in females and males of reproductive potential.1,53,59 It is not known whether these effects are reversible.1,53,59 (See Cautions: Genitourinary and Endocrine Effects.)
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 or 1.2 or 1.8 times, respectively, the maximum daily human dosage based on body surface area.1,53,59
Lactation
Tramadol is distributed into milk.1,53 Following a single IV tramadol dose of 100 mg, the cumulative distribution into milk within 16 hours after dosing was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1.1,53
Because the safety of tramadol in infants and neonates has not been established, the drug is not recommended for obstetrical preoperative medication or for use in nursing women, including use for post-delivery analgesia.1,53 FDA review of available medical literature did not reveal evidence of an increased frequency of adverse effects in nursing infants of women receiving tramadol; however, because the drug is distributed into milk and has similar risks as codeine in ultrarapid metabolizers of CYP2D6 substrates, FDA recommends that tramadol not be used in nursing women.705 (See Pharmacogenomics under Cautions: Precautions and Contraindications. Also see Cautions: Precautions and Contraindications, in Codeine Phosphate and Codeine Sulfate 28:08.08.) Infants exposed to tramadol through breast milk should be monitored closely for clinical manifestations of opiate toxicity (e.g., sedation, difficulty breast-feeding or breathing, hypotonia).705 If clinical manifestations of opiate toxicity occur, caregivers should seek immediate medical treatment for the infant.705
Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped.1,53,59
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