Introduction
Ultracet is a combination analgesic medication containing tramadol hydrochloride (37.5 mg) and acetaminophen (325 mg) per tablet. This fixed-dose combination product is designed to provide multimodal pain relief through complementary mechanisms of action. Ultracet is classified as a Schedule IV controlled substance due to its tramadol component, which has opioid-like properties.
Mechanism of Action
Ultracet exerts its analgesic effects through two distinct mechanisms:
- Tramadol: A centrally-acting synthetic opioid agonist that binds to μ-opioid receptors while also inhibiting the reuptake of norepinephrine and serotonin, providing dual analgesic action
- Acetaminophen: Acts primarily through central inhibition of prostaglandin synthesis with minimal peripheral anti-inflammatory effects
This combination provides synergistic pain relief through both opioid and non-opioid pathways while allowing lower doses of each component compared to monotherapy.
Indications
Ultracet is FDA-approved for the short-term (five days or less) management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
Dosage and Administration
Standard adult dosing: Two tablets every 4-6 hours as needed for pain relief Maximum daily dose: Not to exceed 8 tablets (300 mg tramadol/2600 mg acetaminophen) in 24 hours Duration: Limited to 5 days or less due to acetaminophen hepatotoxicity risk Special populations:- Renal impairment: Not recommended for creatinine clearance <30 mL/min
- Hepatic impairment: Use with caution in mild to moderate impairment; contraindicated in severe impairment
- Elderly: Consider reduced doses due to increased sensitivity
- Pediatric: Safety and effectiveness not established
Pharmacokinetics
Absorption: Rapidly absorbed after oral administration with peak concentrations occurring at approximately 1.6-1.9 hours Distribution:- Tramadol: Volume of distribution ~2.6-2.9 L/kg; 20% protein bound
- Acetaminophen: Volume of distribution ~0.9 L/kg; 10-25% protein bound
- Tramadol: Extensive hepatic metabolism via CYP2D6 and CYP3A4 to active metabolite O-desmethyltramadol
- Acetaminophen: Primarily hepatic glucuronidation and sulfation; minor CYP2E1 metabolism to hepatotoxic NAPQI
- Tramadol: Half-life ~6-7 hours; renal excretion (30% unchanged)
- Acetaminophen: Half-life ~2-3 hours; renal excretion (primarily conjugated metabolites)
Contraindications
- Significant respiratory depression
- Acute or severe bronchial asthma in unmonitored settings
- Known or suspected gastrointestinal obstruction
- Concurrent monoamine oxidase inhibitor use or within 14 days
- Hypersensitivity to tramadol, acetaminophen, or any component
- Severe hepatic impairment
Warnings and Precautions
Boxed Warning:- Addiction, abuse, and misuse (can lead to overdose and death)
- Life-threatening respiratory depression
- Accidental ingestion (especially in children)
- Neonatal opioid withdrawal syndrome
- Cytochrome P450 3A4 interaction
- Risks from concomitant use with benzodiazepines or other CNS depressants
- Serotonin syndrome risk (especially with other serotonergic drugs)
- Seizure risk (lowered threshold)
- Adrenal insufficiency reports
- Androgen deficiency with long-term use
- Acetaminophen hepatotoxicity (dose-dependent)
Drug Interactions
Major interactions:- CNS depressants: Enhanced sedation and respiratory depression (benzodiazepines, alcohol, barbiturates)
- Serotonergic drugs: Increased serotonin syndrome risk (SSRIs, SNRIs, MAOIs, triptans)
- CYP2D6 inhibitors: Reduced tramadol efficacy (quinidine, fluoxetine, paroxetine)
- CYP3A4 inducers/inhibitors: Altered tramadol metabolism (carbamazepine, rifampin, ketoconazole)
- Warfarin: Possible increased INR with chronic acetaminophen use
Adverse Effects
Common (≥5%):- Nausea (38%)
- Constipation (20%)
- Dizziness (19%)
- Somnolence (15%)
- Vomiting (12%)
- Headache (10%)
- Respiratory depression
- Seizures
- Anaphylaxis
- Serotonin syndrome
- Hepatotoxicity
- Adrenal insufficiency
- Severe skin reactions
Monitoring Parameters
- Pain assessment: Regular evaluation of pain relief and functional improvement
- Respiratory status: Especially during initiation and dose titration
- Mental status: Assessment for sedation, cognitive impairment
- Bowel function: Monitor for constipation; implement bowel regimen
- Hepatic function: Baseline and periodic LFTs with prolonged use
- Renal function: In patients with renal impairment
- Abuse/misuse behaviors: Regular assessment during therapy
Patient Education
- Take only as prescribed; do not exceed recommended dose or duration
- Avoid alcohol and other CNS depressants during therapy
- Do not crush, chew, or break tablets
- Report any signs of allergic reaction, difficulty breathing, or extreme drowsiness
- Be aware of acetaminophen content and avoid other acetaminophen-containing products
- Store securely away from children and others
- Dispose of unused medication properly
- Inform all providers of Ultracet use, especially before procedures
- Understand risks of dependence and withdrawal with prolonged use
References
1. FDA Prescribing Information: Ultracet (tramadol hydrochloride/acetaminophen) tablets 2. Grond S, et al. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923 3. Raffa RB, et al. The basic science aspect of tramadol hydrochloride. Pain Res Manag. 2014;19(4):217-221 4. Dart RC, et al. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2006;44(1):1-18 5. Nelson EM, et al. Combination analgesics. Am J Health Syst Pharm. 2018;75(17):1293-1304 6. Micromedex Solutions: Tramadol/Acetaminophen Drug Monograph 7. Clinical Pharmacology [Internet]: Tramadol/Acetaminophen monograph