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TraMADol

Pronunciation

Pronunciation

(TRA ma dole)

Index Terms

  • Ryzolt
  • Tramadol HCl
  • Tramadol Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

ConZip: 100 mg, 200 mg, 300 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake]

Generic: 100 mg, 150 mg, 200 mg, 300 mg

Cream, External, as hydrochloride:

Active-Tramadol: 8% (120 g) [contains chlorocresol (chloro-m-cresol)]

EnovaRX-Tramadol: 5% (60 g, 120 g) [contains cetyl alcohol]

Suspension Reconstituted, Oral, as hydrochloride:

Synapryn FusePaq: 10 mg/mL (500 mL) [contains saccharin sodium, sodium benzoate]

Tablet, Oral, as hydrochloride:

Ultram: 50 mg [scored]

Generic: 50 mg

Tablet Dispersible, Oral, as hydrochloride:

Rybix ODT: 50 mg [DSC] [contains aspartame]

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Ultram ER: 100 mg [DSC], 200 mg [DSC], 300 mg

Generic: 100 mg, 200 mg, 300 mg

Brand Names: U.S.

  • Active-Tramadol
  • ConZip
  • EnovaRX-Tramadol
  • Rybix ODT [DSC]
  • Synapryn FusePaq
  • Ultram
  • Ultram ER

Pharmacologic Category

  • Analgesic, Opioid

Pharmacology

Tramadol and its active metabolite (M1) binds to μ-opiate receptors in the CNS causing inhibition of ascending pain pathways, altering the perception of and response to pain; also inhibits the reuptake of norepinephrine and serotonin, which are neurotransmitters involved in the descending inhibitory pain pathway responsible for pain relief (Grond 2004)

Distribution

Vd: IV: 2.6 L/kg (males); 2.9 L/kg (females)

Metabolism

Extensively hepatic via demethylation (mediated by CYP3A4 and CYP2D6), glucuronidation, and sulfation; has pharmacologically active metabolite formed by CYP2D6 (M1; O-desmethyl tramadol)

Excretion

Urine (~30% as unchanged drug; 60% as metabolites)

Onset of Action

Immediate release: Within 1 hour; Peak effect: 2 to 3 hours

Time to Peak

Immediate release: ~2 hours; active metabolite (M1): 3 hours

Extended release: ~4 to 12 hours; active metabolite (M1): ~5 to 15 hours

Half-Life Elimination

Immediate release: 6.3 ± 1.4 hours; active metabolite (M1): 7.4 ± 1.4 hours; prolonged in elderly

Extended release:

Capsules: ~10 hours; active metabolite (M1): ~11 hours

Tablets: ~7.9 hours; active metabolite (M1): 8.8 hours

Protein Binding

Plasma: ~20%

Special Populations: Renal Function Impairment

Decreased rate and extent of excretion.

Special Populations: Hepatic Function Impairment

Immediate release: Metabolism is reduced in advanced cirrhosis, resulting in increased AUC and increased elimination half-live (13 hours [tramadol], 19 hours [M1]).

Extended release: Exposure is decreased ~50% with increased severity of hepatic impairment.

Special Populations: Elderly

Maximum serum concentration is increased and elimination half-life prolonged.

Special Populations: Gender

Immediate release: Women had a 12% higher peak tramadol concentration and a 35% higher area under the curve (AUC) compared to men.

Extended release: AUC were somewhat higher in females than in males.

Use: Labeled Indications

Moderate to severe pain: Management of moderate to moderately severe pain in adults (immediate release formulations); management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of pain for an extended period of time (extended release [ER] formulations).

Contraindications

Hypersensitivity to tramadol, opioids, or any component of the formulation.

Immediate-release formulations and Ultram ER only: Any situation where opioids are contraindicated, including acute intoxication with alcohol, hypnotics, narcotics, centrally-acting analgesics, opioids, or psychotropic drugs.

ER formulations only (excluding Ultram ER): Significant respiratory depression, acute or severe bronchial asthma, or hypercapnia in the absence of appropriately monitored settings and/or resuscitative equipment.

Canadian product labeling:

Tramadol is contraindicated during or within 14 days following MAO inhibitor therapy

Extended release formulations: Additional contraindications:

Ralivia, Tridural: Severe (CrCl <30 mL/minute) renal dysfunction, severe (Child-Pugh class C) hepatic dysfunction

Durela and Zytram XL: Severe (CrCl <30 mL/minute) renal dysfunction, severe (Child-Pugh class C) hepatic dysfunction; known or suspected mechanical GI obstruction or any disease/condition that affects bowel transit; mild, intermittent or short-duration pain that can be managed with other pain medication; management of peri-operative pain; obstructive airway, acute respiratory depression, cor pulmonale, delirium tremens, seizure disorder, severe CNS depression, increased cerebrospinal or intracranial pressure, head injury, breast-feeding, pregnancy; use during labor and delivery

Dosing: Adult

Moderate to severe pain: Oral: Note: Doses should be titrated to appropriate analgesic effect; use the lowest effective dose for the shortest period of time:

Immediate release: 50 to 100 mg every 4 to 6 hours (maximum: 400 mg/day). For patients not requiring rapid onset of effect, tolerability may be improved by initiating therapy at 25 mg once daily in the morning and titrating dose by 25 mg every 3 days until 25 mg 4 times daily is reached. Dose may then be increased by 50 mg every 3 days as tolerated to reach 50 mg 4 times daily. After titration, 50 to 100 mg may be given every 4 to 6 hours as needed (maximum: 400 mg/day).

Orally-disintegrating tablet (Rybix ODT): 50 to 100 mg every 4 to 6 hours (maximum: 400 mg/day). For patients not requiring rapid onset of effect, tolerability may be improved by initiating with 50 mg/day and titrating dose by 50 mg every 3 days, until reaching 50 mg 4 times daily. After titration, 50 to 100 mg may be given every 4 to 6 hours as needed (maximum: 400 mg/day).

Extended release: Note: For patients requiring around-the-clock pain management for an extended period of time.

US labeling:

Patients not currently on tramadol immediate-release: Initial: 100 mg once daily; titrate by 100 mg increments every 5 days as needed (maximum: 300 mg/day)

Patients currently on tramadol immediate-release: Calculate 24-hour tramadol immediate release total dose and initiate total extended release daily dose (round dose to the next lowest 100 mg increment); titrate as tolerated to desired effect (maximum: 300 mg/day)

Canadian labeling: Note: Patients currently on immediate-release tramadol: When switching to extended release, initiate at the same or lowest nearest total daily tramadol dose. Not to exceed recommended maximum daily dosing.

Durela, Ralivia, Tridural: Patients not currently on immediate-release tramadol or opioids: Initial: 100 mg once daily; titrate every 5 days (Durela, Ralivia) or every 2 days (Tridural) as needed based on clinical response and severity of pain (maximum: 300 mg daily)

Zytram XL: Patients not currently on immediate-release tramadol or opioids: 150 mg once daily; if pain relief is not achieved may titrate by increasing dosage incrementally, with sufficient time to evaluate effect of increased dosage; generally not more often than every 7 days (maximum: 400 mg daily)

Dosing: Geriatric

Elderly >65 years to ≤75 years: Refer to adult dosing; use with caution initiate at the low end of the dosing range.

Elderly >75 years:

Immediate release: Maximum: 300 mg/day.

Extended release: Use with extreme caution.

Dosing: Pediatric

Moderate to severe pain: Oral:

Immediate release: Adolescents ≥17 years: Refer to adult dosing.

Extended release: Adolescents ≥18 years: Refer to adult dosing.

Dosing: Renal Impairment

Immediate release:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

CrCl <30 mL/minute: Increase dosing interval to every 12 hours (maximum: 200 mg/day).

Dialysis: Dialyzable (7%); administer dose on the day of dialysis.

Extended release:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

CrCl <30 mL/minute: Avoid use.

Dosing: Hepatic Impairment

Immediate release: There are no dosage adjustments provided in the manufacturer’s labeling. In patients with cirrhosis, recommended dose is 50 mg every 12 hours.

Extended release:

Mild to moderate impairment (Child-Pugh Class A and B): There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Severe impairment (Child-Pugh class C): Avoid use.

Extemporaneously Prepared

A 5 mg/mL oral suspension may be made with tablets and either Ora-Sweet® SF or a mixture of 30 mL Ora-Plus® and 30 mL strawberry syrup. Crush six 50 mg tramadol tablets in a mortar and reduce to a fine powder. Add small portions of the chosen vehicle and mix to a uniform paste; mix while adding vehicle in incremental proportions to almost 60 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 60 mL. Label "shake well before use". Stable for 90 days refrigerated or at room temperature.

Wagner DS, Johnson CE, Cichon-Hensley BK, et al, "Stability of Oral Liquid Preparations of Tramadol in Strawberry Syrup and a Sugar-Free Vehicle," Am J Health Syst Pharm, 2003, 60(12):1268-70.12845924

Administration

Immediate release: Administer without regard to meals.

Extended release: Swallow whole; do not crush, chew, dissolve, or split. Note: Durela, Ralivia, and Tridural: Canadian availability; products not available in US:

ConZip, Zytram XL, Durela: Administer without regard to meals.

Ultram ER, Ralivia, Tridural: Administer without regard to meals, but administer in a consistent manner of either with or without meals.

Orally-disintegrating tablet: Remove from foil blister by peeling back (do not push tablet through the foil). Place tablet on tongue and allow to dissolve (may take ~1 minute); water is not needed, but may be administered with water. Do not chew, break, or split tablet.

Dietary Considerations

Some products may contain phenylalanine.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Consider therapy modification

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Monitor therapy

Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Antiemetics (5HT3 Antagonists): May diminish the analgesic effect of TraMADol. Monitor therapy

Anti-Parkinson Agents (Monoamine Oxidase Inhibitor): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity if selegiline or rasagiline is combined with a serotonin modulator. Use of transdermal selegiline with serotonin modulators is contraindicated. Consider therapy modification

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CarBAMazepine: TraMADol may enhance the CNS depressant effect of CarBAMazepine. TraMADol may diminish the therapeutic effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of TraMADol. Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

CYP2D6 Inhibitors (Moderate): May diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Monitor therapy

CYP2D6 Inhibitors (Strong): May diminish the therapeutic effect of TraMADol. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of TraMADol. CYP2D6 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of TraMADol. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Diuretics: Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics. Analgesics (Opioid) may diminish the therapeutic effect of Diuretics. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Eluxadoline: Analgesics (Opioid) may enhance the constipating effect of Eluxadoline. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Linezolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Due to a risk of serotonin syndrome/serotonin toxicity, discontinue serotonin modulators 2 weeks prior to the administration of linezolid. If urgent initiation of linezolid is needed, discontinue serotonin modulators immediately and monitor closely. Consider therapy modification

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of Analgesics (Opioid). Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Avoid combination

Moclobemide: TraMADol may enhance the serotonergic effect of Moclobemide. This could result in serotonin syndrome. Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nalmefene: May diminish the therapeutic effect of Analgesics (Opioid). Management: Avoid the concomitant use of nalmefene and opioid analgesics. Discontinue nalmefene 1 week prior to any anticipated use of opioid analgesics. If combined, larger doses of opioid analgesics will likely be required. Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Analgesics (Opioid). Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Ramosetron: Analgesics (Opioid) may enhance the constipating effect of Ramosetron. Monitor therapy

Ritonavir: May decrease serum concentrations of the active metabolite(s) of TraMADol. Ritonavir may increase the serum concentration of TraMADol. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Vitamin K Antagonists (eg, warfarin): TraMADol may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

May interfere with urine detection of phencyclidine (false-positive) (Hull 2006).

Adverse Reactions

>10%:

Cardiovascular: Flushing (8% to 16%)

Central nervous system: Dizziness (10% to 33%), headache (4% to 32%), drowsiness (7% to 25%), central nervous system stimulation (7% to 14%), insomnia (2% to 11%)

Dermatologic: Pruritus (3% to 12%)

Gastrointestinal: Constipation (9% to 46%), nausea (15% to 40%), vomiting (5% to 17%), xerostomia (3% to 13%), dyspepsia (1% to 13%)

Neuromuscular & skeletal: Weakness (4% to 12%)

1% to 10%:

Cardiovascular: Orthostatic hypotension (2% to 5%), chest pain (1% to <5%), hypertension (1% to <5%), peripheral edema (1% to <5%), vasodilation (1% to <5%)

Central nervous system: Agitation (1% to <5%), anxiety (1% to <5%), apathy (1% to <5%), ataxia (1% to <5%), chills (1% to <5%), confusion (1% to <5%), depersonalization (1% to <5%), depression (1% to <5%), euphoria (1% to <5%), hypertonia (1% to <5%), hypoesthesia (1% to <5%), lethargy (1% to <5%), malaise (<1% to <5%), nervousness (1% to <5%), pain (1% to <5%), paresthesia (1% to <5%), restlessness (1% to <5%), rigors (1% to <5%), sleep disorder (1% to <5%) withdrawal syndrome (1% to <5%), fatigue (2%), vertigo (2%)

Dermatologic: Diaphoresis (2% to 9%), dermatitis (1% to <5%), skin rash (1% to <5%)

Endocrine & metabolic: Hot flash (1% to <5%), hyperglycemia (1% to <5%), weight loss (1% to <5%)

Gastrointestinal: Diarrhea (5% to 10%), anorexia (1% to 6%), abdominal pain (1% to <5%), decreased appetite (1% to <5%), flatulence (<1% to <5%), sore throat (1% to <5%)

Genitourinary: Menopausal symptoms (1% to <5%), pelvic pain (1% to <5%), prostatic disease (1% to <5%), urine abnormality (1% to <5%), urinary tract infection (1% to <5%), urinary frequency (<1% to <5%), urinary retention (<1% to <5%)

Neuromuscular & skeletal: Arthralgia (1% to 5%), back pain (1% to <5%), increased creatine phosphokinase (1% to <5%), myalgia (1% to <5%), neck pain (1% to <5%), tremor (1% to <5%)

Ophthalmic: Blurred vision (1% to <5%), miosis (1% to <5%), visual disturbance (1% to <5%)

Respiratory: Bronchitis (1% to <5%), cough (1% to <5%), dyspnea (1% to <5%), nasopharyngitis (1% to <5%), pharyngitis (1% to <5%), respiratory congestion (1% to <5%), rhinitis (1% to <5%), rhinorrhea (1% to <5%), sinusitis (1% to <5%), sneezing (1% to <5%), upper respiratory tract infection (1% to <5%)

Miscellaneous: Accidental injury (<5%), fever (1% to <5%), flu-like syndrome (1% to <5%)

<1% (Limited to important or life-threatening): Abnormal gait, anemia, appendicitis, bradycardia, cataract, cellulitis, cholecystitis, cholelithiasis, cognitive dysfunction, deafness, dysphagia, dysuria, ECG abnormality, edema, fecal impaction, gastroenteritis, gastrointestinal hemorrhage, gout, hematuria, hepatic failure, hypersensitivity reaction, hypoglycemia, increased blood urea nitrogen, increased gamma-glutamyl transferase, increased liver enzymes, increased serum creatinine, ischemic heart disease, menstrual disease, migraine, muscle spasm, mydriasis, night sweats, otitis, palpitations, pancreatitis, peripheral ischemia, pneumonia, proteinuria, pulmonary edema, pulmonary embolism, sedation, seizure, serotonin syndrome, skin vesicle, speech disturbance, Stevens-Johnson syndrome, stomatitis, suicidal tendencies, syncope, tachycardia, thrombocytopenia

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid reactions: Serious anaphylactoid reactions (including rare fatalities) often following initial dosing have been reported. Pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome also have been reported with use. Previous anaphylactoid reactions to opioids may increase risks for similar reactions to tramadol; avoid use in these patients.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

•Hypoglycemia: Hypoglycemia (including severe cases) has been reported (rare) particularly within the first 30 days of tramadol initiation (Fournier 2015).

• Seizures: Even when taken within the recommended dosage seizures may occur; risk is increased in patients receiving serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), anorectics, other opioids, tricyclic antidepressants and other tricyclic compounds (eg, cyclobenzaprine, promethazine), neuroleptics, MAO inhibitors, other drugs which may lower seizure threshold, or drugs which impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors). Patients with a history of seizures, or with a risk of seizures (head trauma, metabolic disorders, CNS infection, malignancy, or during alcohol/drug withdrawal) are also at increased risk.

• Serotonin syndrome: May occur with concomitant use of serotonergic agents (eg, SSRIs, SNRIs, triptans, TCAs), lithium, St. John’s wort, agents that impair metabolism of serotonin (eg, MAO inhibitors), or agents that impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors). Monitor patients for serotonin syndrome such as mental status changes (eg, agitation, hallucinations, coma); autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia); neuromuscular changes (eg, hyperreflexia, incoordination); and/or GI symptoms (eg, nausea, vomiting, diarrhea).

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Drug abuse: Use opioids for chronic pain with caution in patients at increased risk for misuse; factors associated with increased risk include previous substance use disorder, younger age, concomitant depression (major), and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]).

• Adrenal insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan 2013).

• Biliary tract impairment: Use caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may cause spasm of the sphincter of Oddi.

• Ethanol use: Use with caution in heavy alcohol users.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur.

• Hepatic impairment: Use with caution and reduce dosage in patients with mild-to-moderate hepatic impairment; extended release formulations should not be used in severe hepatic impairment (Child-Pugh class C).

• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]).

• Renal impairment: Use with caution and reduce dosage in patients with mild-to-moderate renal impairment; extended release formulations should not be used in severe renal impairment CrCl <30 mL/minute.

• Respiratory disease: Patients with respiratory disorders (eg, significant chronic obstructive pulmonary disease (COPD), cor pulmonale, hypoxia, hypercapnia) may be at greater risk of respiratory depression; use with caution.

• Sleep-disordered breathing: Use opioids with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

• Suicide risk: Avoid use in patients who are suicidal; use with caution in patients taking tranquilizers and/or antidepressants, or those with an emotional disturbance including depression.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Sedatives: Effects with other sedative drugs or ethanol may be potentiated. In the setting of chronic pain, avoid prescribing opioids and benzodiazepines concurrently whenever possible; epidemiologic studies suggest there is an increased risk for potentially fatal overdose with concurrent use (Dowell [CDC 2016]).

Special populations:

• Debilitated patients: Use with caution in debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.

• Elderly: Use opioids for chronic pain with caution in older adults; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (Dowell [CDC 2016]). Extended-release formulation should be used with extreme caution in the elderly (particularly >75 years); may be more sensitive to adverse effects. Reduce initial dose.

• Neonates: Neonatal withdrawal syndrome: After chronic maternal exposure to opioids, neonatal withdrawal syndrome may occur in the newborn; monitor neonate closely. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. Onset, duration and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn. Opioid withdrawal syndrome in the neonate, unlike in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts.

Dosage form specific issues:

• Extended-release tablets: Caution patients to swallow tablets whole. Rapid release absorption of tramadol from tablets that are broken, crushed, or chewed may lead to a potentially-lethal overdose.

• Phenylalanine: Some products may contain phenylalanine.

Other warnings/precautions:

• Abuse/misuse/diversion: Health care provider should be alert to problems of abuse, misuse, and diversion.

• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, NSAIDs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and non-opioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (Dowell [CDC 2016]).

• Withdrawal: Tolerance or drug dependence may result from extended use (withdrawal symptoms have been reported); abrupt discontinuation should be avoided. Tapering of dose at the time of discontinuation limits the risk of withdrawal symptoms.

Monitoring Parameters

Pain relief, respiratory rate, blood pressure, and pulse; signs of tolerance, abuse, or suicidal ideation

Alternate recommendations: Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC 2016]).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Tramadol has been shown to cross the human placenta when administered during labor. Postmarketing reports following tramadol use during pregnancy include neonatal seizures, withdrawal syndrome, fetal death, and stillbirth. Tramadol is not recommended for use prior to or during labor and delivery. Some Canadian products are contraindicated for use in pregnant women.

If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur; monitoring of the neonate is recommended (Chou 2009). Neonatal abstinence syndrome following opioid exposure may present with autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, increased muscle tone, irritability, seizure, tremor) symptoms (Dow 2012; Hudak 2012).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation, diarrhea, dry mouth, headache, itching, nausea, vomiting, or insomnia. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking, signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, arrhythmia, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), signs of adrenal gland problems (severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss), severe dizziness, passing out, seizures, severe loss of strength and energy, angina, difficult urination, polyuria, difficulty breathing, slow breathing, shallow breathing, noisy breathing, severe fatigue, or vision changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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