What is the mechanism of action and what are the common side effects of tramadol (ultram)?

Tramadol: Mechanism of Action and Side Effects

Mechanism of Action

Tramadol works through a unique dual mechanism: it acts as a weak mu-opioid receptor agonist (approximately one-tenth as potent as morphine) while simultaneously inhibiting the reuptake of norepinephrine and serotonin in the central nervous system. 1, 2

Opioid Component

• Tramadol binds to mu-opioid receptors with 6,000-fold less affinity than morphine 3
• The active metabolite M1 (O-desmethyltramadol), produced by hepatic CYP2D6 metabolism, has 200 times greater affinity for mu-opioid receptors than the parent compound and is up to 6 times more potent in producing analgesia 2, 4
• The opioid effect is only partially antagonized by naloxone, confirming that opioid activity accounts for only part of tramadol's analgesic effect 2, 3

Monoaminergic Component

• The (+) enantiomer stimulates presynaptic serotonin release and inhibits serotonin reuptake 4, 5
• The (-) enantiomer primarily inhibits norepinephrine reuptake 4, 5
• These complementary monoaminergic actions block nociceptive impulses at the spinal level and work synergistically with the opioid mechanism 4, 6

Clinical Pharmacology

• Oral bioavailability is approximately 75% 2
• Peak plasma concentrations occur at 2 hours for tramadol and 3 hours for M1 2
• Analgesia begins within one hour and peaks at 2-3 hours 2, 7
• Elimination half-life is 5-6 hours for tramadol and 7 hours for M1 2, 4

Common Side Effects

The most common adverse effects include nausea, dizziness, drowsiness, constipation, dry mouth, and sweating—similar to other opioids but generally less severe. 2, 5

Gastrointestinal Effects

• Nausea is dose-dependent and more likely with high loading doses 4, 7
• Constipation occurs but is less severe than with traditional opioids 5, 7
• Vomiting (in cancer pain studies, tramadol produced more vomiting than hydrocodone or codeine) 1

Central Nervous System Effects

• Dizziness and somnolence are common 2, 7
• Weakness (particularly noted in cancer pain patients) 1
• Cognitive impairment, especially in elderly patients 8
• Sedation 7

Cardiovascular Effects

• Orthostatic hypotension has been observed 2
• At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function, or cardiac index 2
• Fall risk is particularly concerning in elderly patients due to orthostatic hypotension and dizziness 8

Other Common Effects

• Sweating and pruritus 2
• Dry mouth 5, 7

Critical Safety Warnings

Serotonin Syndrome Risk

Tramadol should be avoided or used with extreme caution in patients receiving serotonergic medications (SSRIs, SNRIs, tricyclic antidepressants, MAOIs) due to the risk of serotonin syndrome. 1, 8, 9

Seizure Risk

• Lower doses are recommended for older adults (age ≥75 years) and those with hepatic and/or renal dysfunction to reduce seizure risk 1
• Seizure risk increases with high doses or in predisposed patients 8

Respiratory Depression

• Respiratory depression can occur but is less severe than with traditional opioids 4, 5

Dependence and Abuse Potential

• Tramadol has low abuse potential compared to traditional opioids 4, 7
• Dependence is rare based on controlled studies and postmarketing surveillance 4

Dosing Considerations

Standard Adult Dosing

• Immediate-release: 50-100 mg every 4-6 hours, maximum 400 mg/day 1, 8, 10
• Extended-release: maximum 300 mg/day 8, 10

Special Populations

• Elderly patients (≥75 years): start at 12.5-25 mg every 4-6 hours or 25 mg every 12 hours (50 mg total daily) 8
• Hepatic impairment: 50 mg every 12 hours (bioavailability increases 2-3 fold in cirrhosis) 8
• Renal dysfunction: reduced dosing required 1, 10

Key Pitfall to Avoid

Starting with high loading doses significantly increases the risk of nausea and other adverse effects; begin with the lowest effective dose and titrate slowly over days to weeks, particularly in elderly patients. 8, 10, 4