Ultram - Drug Monograph

Introduction

Ultram (tramadol hydrochloride) is a centrally acting synthetic opioid analgesic used for the management of moderate to moderately severe pain. It possesses unique dual mechanisms of action, combining weak mu-opioid receptor agonism with serotonin and norepinephrine reuptake inhibition. First approved by the FDA in 1995, tramadol occupies a distinct position in the analgesic spectrum between non-opioid analgesics and stronger opioid medications.

Mechanism of Action

Tramadol exerts its analgesic effects through two primary mechanisms: 1. Weak mu-opioid receptor agonist: Binds to opioid receptors with approximately 1/6000th the affinity of morphine 2. Monoamine reuptake inhibition: Inhibits neuronal reuptake of norepinephrine and serotonin, enhancing descending inhibitory pain pathways

The drug requires metabolic activation via CYP2D6 to its primary active metabolite, O-desmethyltramadol (M1), which possesses significantly higher mu-opioid receptor affinity (approximately 200 times greater than the parent compound).

Indications

• Management of moderate to moderately severe pain in adults
• Chronic pain management (extended-release formulations)
• Off-label uses may include neuropathic pain and fibromyalgia (though evidence is limited)

Dosage and Administration

• Adults: 50-100 mg every 4-6 hours as needed for pain
• Maximum daily dose: 400 mg for non-elderly adults; 300 mg for patients >75 years
• Titration: Start with 25 mg daily in opioid-naïve patients, increasing by 25-50 mg every 3 days

• Ultram ER: 100-300 mg once daily
• Must be swallowed whole; not for prn use

• Renal impairment (CrCl <30 mL/min): Increase dosing interval to 12 hours
• Hepatic impairment (Child-Pugh B/C): Maximum 50 mg every 12 hours
• Elderly: Reduced initial doses recommended
• CYP2D6 poor metabolizers: May require alternative analgesia

Pharmacokinetics

• Absorption: Rapid and nearly complete (85-90%) oral bioavailability
• Distribution: Volume of distribution 2.6-2.9 L/kg; 20% protein binding
• Metabolism: Extensive hepatic metabolism via CYP2D6, CYP3A4, and conjugation
• Elimination: Half-life 5-7 hours; renal excretion (30% unchanged, 60% as metabolites)
• Active metabolites: O-desmethyltramadol (M1) half-life 6-8 hours

Contraindications

• Significant respiratory depression
• Acute or severe bronchial asthma
• Known or suspected gastrointestinal obstruction
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days
• Patients with uncontrolled epilepsy
• Known hypersensitivity to tramadol or other opioids
• Suicide attempt or active substance abuse

Warnings and Precautions

• Addiction, abuse, and misuse risk
• Life-threatening respiratory depression
• Neonatal opioid withdrawal syndrome
• Risks from concomitant use with benzodiazepines or other CNS depressants
• Ultra-rapid metabolizer risk (CYP2D6)

• Seizure risk (dose-dependent, increased with SSRIs/SNRIs, TCAs, antipsychotics)
• Serotonin syndrome risk
• Increased intracranial pressure or head injury
• Risk of adrenal insufficiency
• Severe hypotension
• Gastrointestinal conditions
• Withdrawal symptoms upon discontinuation

Drug Interactions

• CNS depressants: Enhanced sedation and respiratory depression (benzodiazepines, alcohol, barbiturates)
• Serotonergic drugs: Increased serotonin syndrome risk (SSRIs, SNRIs, TCAs, MAOIs, triptans)
• CYP2D6 inhibitors: Reduced efficacy (quinidine, fluoxetine, paroxetine)
• CYP3A4 inhibitors/inducers: Altered tramadol exposure (ketoconazole, ritonavir, carbamazepine)
• Opioid antagonists: Precipitated withdrawal (naloxone, naltrexone)

Adverse Effects

• Nausea (30-40%)
• Constipation (25-30%)
• Headache (20-25%)
• Dizziness (15-20%)
• Somnolence (15-20%)
• Vomiting (10-15%)

• Respiratory depression
• Seizures
• Serotonin syndrome
• Anaphylactic reactions
• Adrenal insufficiency
• Severe hypotension
• Withdrawal symptoms
• QT prolongation (high doses)

Monitoring Parameters

• Pain assessment and relief using standardized scales
• Respiratory rate and oxygen saturation
• Mental status and sedation level
• Bowel function and constipation management
• Signs of misuse, abuse, or addiction
• Serotonin syndrome symptoms (agitation, hyperreflexia, clonus)
• Seizure activity in predisposed patients
• Renal and hepatic function (periodically)

Patient Education

• Take only as prescribed; do not increase dose without medical advice
• Avoid alcohol and other CNS depressants
• Do not crush, chew, or break extended-release tablets
• Report any difficulty breathing or excessive drowsiness
• Maintain adequate hydration and fiber intake to prevent constipation
• Do not abruptly stop medication due to withdrawal risk
• Inform all healthcare providers of tramadol use
• Store securely away from others, especially children
• Be aware of potential impairment in driving or operating machinery
• Report any signs of serotonin syndrome (agitation, hallucinations, fever)

References

1. FDA Prescribing Information: Ultram (tramadol hydrochloride) tablets 2. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923 3. Raffa RB, et al. The clinical pharmacology of tramadol. Clin Pharmacokinet. 2018;57(10):1189-1204 4. Dowell D, et al. CDC Clinical Practice Guideline for Prescribing Opioids for Pain. MMWR. 2022;71(3):1-95 5. Beakley BD, et al. Tramadol, pharmacology, side effects, and serotonin syndrome. Pain Physician. 2015;18(4):395-400 6. Micromedex Solutions: Tramadol Drug Monograph 7. Clinical Pharmacogenetics Implementation Consortium Guidelines: CYP2D6 and Tramadol Therapy