tramadol/acetaminophen (Rx)

1-10%

Abdominal pain

Anxiety

Anorexia

Asthenia

Confusion

Constipation

Diarrhea

Dizziness

Dry mouth

Dyspepsia

Euphoria

Fatigue

Flatulence

Headache

Hot flushes

Insomnia

Nausea

Nervousness

Pruritus

Rash

Somnolence

Sweating

Tremor

Vomiting

<1%

Abnormal hepatic function

Abnormal thinking

Abnormal vision

Aggravated hypertension

Aggravated migraine

Albuminuria

Amnesia

Anemia

Arrhythmia

Ataxia

Chest pain

Convulsions

Depersonalization

Depression

Drug abuse

Dysphagia

Dyspnea

Emotional lability

Hallucination

Hypertension

Hypertonia

Hypotension

Impotence

Involuntary muscle contractions

Melena

Micturition disorder

Migraine

Oliguria

Palpitation

Paresthesias

Paroniria

Rigors

Stupor

Syncope

Tachycardia

Tinnitus

Tongue edema

Urinary retention

Vertigo

Weight decrease

Withdrawal syndrome

Frequency Not Defined

Allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson Syndrome/TENS)

Cognitive dysfunction

Depression

Difficulty concentrating

Gastrointestinal bleeding

Contraindications

Hypersensitivity

Children <12 years

Postoperative management in children <18 years following tonsillectomy and/or adenoidectomy

Significant respiratory depression

Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment

Known or suspected gastrointestinal obstruction, including paralytic ileus

Previous hypersensitivity to tramadol hydrochloride, acetaminophen, any other component of this product, or opioids

Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days

Cautions

Use with caution in hepatitis, liver failure, myocardial ischemia, pulmonary edema, vasodilation

As an opioid, the drug exposes users to risks of addiction, abuse, and misuse; assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing the drug, and monitor all patients for development of addiction behaviors and conditions; reduce risks by prescribing drug in smallest appropriate quantity and advising patient on proper disposal of unused drug risk is greatest during initiation of therapy or following a dosage increase; monitor patients closely for respiratory depression, especially within first 24-72 hours of initiating therapy and following dosage increases; to reduce risk, proper dosing and titration are essential; overestimating; dosage when converting patients from another opioid product can result in fatal overdose with first dose

Monitor for sedation and respiratory depression in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness;. avoid use in patients with impaired consciousness or coma

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; opioid use increases risk of CSA in a dose-dependent fashion; in patients who present with CSA, consider decreasing opioid dosage using best practices for opioid taper

May cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients; there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs; monitor for severe hypotension: during dosage initiation and titration; avoid in patients with circulatory shock

Adrenal insufficiency may occur; if diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid

Monitor closely for life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients, particularly during initiation and titration

As of January 2011, the FDA has mandated a dosage limit for all prescription medications that contain acetaminophen, allowing no more than 325 mg/dosage unit

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplantation or death; risk increases in individuals with underlying liver disease, alcohol ingestion, and/or use of more than 1 acetaminophen-containing product (see Black Box Warnings)

QT prolongation/torsade de pointes; cases of QT prolongation and/or torsade de pointes have been reported with tramadol use; many cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in overdose setting

Acetaminophen may cause rare serious skin reactions (eg, acute generalized exanthematous pustulosis, Stevens-Johnson Syndrome, toxic epidermal necrolysis), which can be fatal; discontinued at the first appearance of skin rash

At least one death reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine; a baby nursing from an ultra-rapid metabolizer mother could potentially be exposed to high levels of M1, and experience life-threatening respiratory depression; for this reason, breastfeeding is not recommended during therapy

Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in tramadol plasma levels and an increase in active metabolite M1 levels, which could increase or prolong adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression

Do not abruptly discontinue therapy in a patient physically dependent on opioids; when discontinuing therapy, in a physically dependent patient, gradually taper the dosage; rapid tapering in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain

Concomitant use with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower tramadol levels; this may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal

Follow patients receiving any CYP3A4 inhibitor or inducer for risk for serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity and opioid withdrawal when used in conjunction with inhibitors and inducers of CYP3A4

If decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with opioid analgesic, prescribe lowest effective dosages and minimum durations of concomitant use; in patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in absence of an opioid, and titrate based on clinical response; if an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response; follow patients closely for signs and symptoms of respiratory depression and sedation

Life-threatening respiratory depression and death have occurred in children who received tramadol; tramadol is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to active metabolite M1; children < 12 years appear to be more susceptible to respiratory depressant effects of tramadol, particularly if there are risk factors for respiratory depression; many reported cases of death occurred in postoperative period following tonsillectomy and/or adenoidectomy, and many of children had evidence of being ultra-rapid metabolizers of tramadol

Avoid use in adolescents 12-18 years of age who have other risk factors that may increase sensitivity to respiratory depressant effects of tramadol unless benefits outweigh risks; risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression; when prescribing tramadol for adolescents, healthcare providers should choose lowest effective dose for shortest period of time and inform patients and caregivers about risks and the signs of opioid overdose

Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range

Do not prescribe therapy to patients who are suicidal or addiction-prone; consideration should be given to use of non-narcotic analgesics in patients who are suicidal or depressed

Contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus; drug may cause spasm of sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms

Avoid use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic; in these patients, mixed agonist/antagonist and partial agonist analgesics may reduce analgesic effect and/or precipitate withdrawal symptoms

May impair mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery; warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of opioid and know how they will react to the medication

Serotonin syndrome (potentially life-threatening) may develop

Opioid analgesic risk evaluation and mitigation strategy (REMS)

• To ensure that benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed; use the following link to obtain the Patient Counseling Guide (PCG): www.fda.gov/OpioidAnalgesicREMSPCG
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities
• To obtain further information on opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com; the FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint

Off-label use in children

• Severe respiratory depression reported with off-label use in children
• Tramadol undergoes extensive hepatic metabolism; it is metabolized by CYP2D6 to the active metabolite O-desmethyltramadol (M1), which has a 200-fold greater affinity for opioid receptors than does tramadol
• CYP2D6 poor metabolizers have shown a 20% increase in tramadol levels and a 40% decrease in O-desmethyltramadol (M1)

Pregnancy

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome; available data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage

Labor and delivery

• Use of tramadol during labor may lead to respiratory depression in the neonate
• Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate; use is not recommended in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate; opioid analgesics, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions; however, this effect is not consistent and may be offset by increased rate of cervical dilation, which tends to shorten labor; monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression

Lactation

Tramadol and its active metabolite, O-desmethyltramadol (M1), are present in human milk; there are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to M1 via breast milk; women who are ultra-rapid metabolizers of tramadol achieve higher than expected serum levels of opioids, potentially leading to higher levels of M1 in breast milk that can be dangerous in their breastfed infants; in women with normal tramadol metabolism (normal CYP2D6 activity), the amount of tramadol secreted into human milk is low and dose-dependent

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Tramadol: Nonopioid-derived synthetic opioid, centrally acting analgesic, but may act at least partially by binding to opioid mu receptors

Acetaminophen: Acts on the hypothalamus to produce antipyresis and analgesia

Absorption

Bioavailability: 75%

Peak plasma time: 2-3 hr

Distribution

VD: 2.6-2.9 L/kg

Protein bound: 20%

Metabolism

Tramadol

• Undergoes extensive hepatic metabolism; it is metabolized by CYP2D6 to the active metabolite O-desmethyltramadol (M1), which has a 200-fold greater affinity for opioid receptors than does tramadol
• CYP2D6 poor metabolizers have shown a 20% increase in tramadol levels and a 40% decrease in O-desmethyltramadol (M1)

Acetaminophen

• Undergoes glucuronide and sulfate conjugation

Elimination

Half-life

• Tramadol: 5-7 hr
• Acetaminophen: 2-4 hr

Excretion

• Tramadol: Primarily renal excretion
• Acetaminophen: Less than 9% excreted unchanged in urine

Pharmacogenomics

Genetic testing laboratories

• The Roche Cytochrome AmpliChip P450 2D6/2C19 Genotyping and Phenotyping Assay can be used to identify 26 different alleles of CYP2D6
• The following companies offer testing for CYP2D6 variants
• DxS (http://www.dxsdiagnostics.com/)
• Genelex (http://www.genelex.com)
• LabCorp (http://www.labcorp.com/)
• Luminex (http://www.luminexcorp.com)