Tramadol - Drug Monograph

Introduction

Tramadol 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 μ-opioid receptor agonism with monoamine reuptake inhibition. First approved in Germany in 1977 and by the FDA in 1995, tramadol has become widely prescribed worldwide while maintaining a distinct pharmacological profile from traditional opioids.

Mechanism of Action

Tramadol exerts its analgesic effects through two complementary mechanisms: 1. Weak μ-opioid receptor agonist: Binds to opioid receptors with approximately 1/10th the affinity of morphine 2. Monoamine reuptake inhibition: Inhibits neuronal reuptake of norepinephrine and serotonin The active metabolite O-desmethyltramadol (M1) possesses significantly greater μ-opioid receptor affinity (approximately 200 times greater than the parent compound) and contributes substantially to the analgesic effect.

Indications

• Management of moderate to moderately severe pain in adults
• Chronic pain conditions when non-opioid analgesics are inadequate
• 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
• Maximum daily dose: 400 mg (300 mg in patients >75 years)

• Initial dose: 100 mg once daily
• Titrate gradually by 100 mg increments every 5 days
• Maximum daily dose: 300 mg

• Renal impairment (CrCl <30 mL/min): Increase dosing interval to 12 hours
• Hepatic impairment (Child-Pugh Class C): Not recommended
• Elderly: Use lower doses and extended dosing intervals
• Pediatrics: Safety not established below age 17

Pharmacokinetics

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
• History of seizure disorder
• Opioid addiction without adequate monitoring
• Hypersensitivity to tramadol or other opioids

Warnings and Precautions

• Risk of addiction, abuse, and misuse
• Life-threatening respiratory depression
• Accidental ingestion by children can be fatal
• Neonatal opioid withdrawal syndrome
• Cytochrome P450 3A4 interaction risk
• Serotonin syndrome risk
• Risk of medication errors

• Increased seizure risk in patients with epilepsy or seizure predisposition
• Risk of suicide in depressed patients
• Adrenal insufficiency with long-term use
• Severe hypotension in volume-depleted patients
• Withdrawal symptoms with abrupt discontinuation

Drug Interactions

• MAOIs: Risk of serotonin syndrome (contraindicated)
• Other serotonergic drugs (SSRIs, SNRIs, TCAs): Increased serotonin syndrome risk
• CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine): Reduced M1 formation
• CYP3A4 inhibitors/inducers: Altered tramadol metabolism
• CNS depressants (benzodiazepines, alcohol): Additive sedation and respiratory depression
• Carbamazepine: Reduces tramadol efficacy

Adverse Effects

• Nausea (40%)
• Dizziness (33%)
• Constipation (25%)
• Headache (25%)
• Somnolence (25%)
• Vomiting (20%)

• Respiratory depression
• Seizures
• Serotonin syndrome
• Anaphylaxis
• Adrenal insufficiency
• Androgen deficiency
• Severe hypotension

Monitoring Parameters

• Pain intensity and functional assessment
• Respiratory rate, especially during initiation
• Signs of misuse, abuse, or addiction
• Bowel function and need for laxatives
• Mental status changes
• Signs of serotonin syndrome
• Seizure activity in predisposed patients
• Renal and hepatic function periodically

Patient Education

• Take exactly as prescribed; do not increase dose without consultation
• Avoid alcohol and other CNS depressants
• Do not crush, chew, or break extended-release tablets
• Report any difficulty breathing or unusual drowsiness
• Be aware of potential for dizziness/drowsiness affecting driving
• Maintain adequate hydration and consider stool softeners for constipation
• Do not stop abruptly after prolonged use
• Store securely away from children and others
• Dispose of unused medication properly

References

1. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. 2. FDA. Ultram (tramadol) prescribing information. 2021. 3. Raffa RB, et al. The clinical pharmacology of tramadol. Drugs. 1993;46(2):313-340. 4. Adams EH, et al. Tramadol: safety and efficacy. Pain Med. 2005;6(3):201-203. 5. Beakley BD, et al. Tramadol, pharmacology, side effects, and serotonin syndrome. J Emerg Med. 2015;48(4):492-500. 6. CDC Guideline for Prescribing Opioids for Chronic Pain. MMWR. 2016;65(1):1-49. 7. Clinical Pharmacology [database online]. Tampa, FL: Elsevier; 2023.