What are the side effects of tramadol?

Side Effects of Tramadol

Common Gastrointestinal and Central Nervous System Effects

Tramadol causes frequent gastrointestinal and CNS side effects, with nausea, dizziness, drowsiness, vomiting, dry mouth, and constipation being the most common adverse events, occurring at rates of 1.6% to 6.1%. 1

• Nausea and vomiting are among the most frequently reported side effects, with tramadol producing significantly higher rates compared to other opioids like hydrocodone and codeine in direct comparison studies 2
• Dizziness and drowsiness occur commonly and may impair mental and physical abilities required for driving or operating machinery 3, 1
• Constipation occurs less frequently than with traditional opioids but still requires prophylactic laxative therapy (combination of stool softener and stimulant laxative) when initiating tramadol 4
• Dry mouth and sweating are reported in 1.6% to 6.1% of patients 1, 5

Serious Neurological Risks

Tramadol carries significant risks of seizures and serotonin syndrome, particularly when combined with serotonergic medications.

• Seizure risk is increased at high doses or in predisposed patients due to tramadol's inhibition of nitric oxide, serotonin reuptake, and inhibitory effects on GABA receptors 2, 6
• Serotonin syndrome can occur when tramadol is combined with MAO inhibitors, SSRIs, SNRIs, or TCAs due to tramadol's dual mechanism of serotonin reuptake inhibition 4, 2, 3
• The FDA label explicitly warns to use tramadol with great caution in patients taking MAO inhibitors or SSRIs, as concomitant use increases the risk of seizure and serotonin syndrome 3
• Cognitive impairment may occur, particularly in elderly patients who are more vulnerable to neurological side effects 4, 6

Respiratory and Cardiovascular Safety Profile

Unlike traditional opioids, tramadol has no clinically relevant effects on respiratory or cardiovascular parameters at recommended doses.

• Respiratory depression is of minor clinical relevance compared to other opioids, though it can occur with overdose or in patients with increased intracranial pressure 3, 7, 1
• Tramadol may prove particularly useful in patients with poor cardiopulmonary function, including the elderly, obese, and smokers 1
• The FDA label warns that respiratory depressant effects may be markedly exaggerated in patients with increased intracranial pressure or head injury 3

Central Nervous System Depression and Drug Interactions

Tramadol has additive CNS depressant effects when combined with alcohol, other opioids, sedatives, tranquilizers, muscle relaxants, or antidepressants.

• The FDA explicitly warns that tramadol should be prescribed with caution for patients requiring concomitant administration of CNS depressant drugs 3
• Excessive doses of tramadol, either alone or in combination with other CNS depressants including alcohol, are a cause of drug-related deaths 3
• Tramadol may impair mental and physical abilities required for potentially hazardous tasks such as driving or operating machinery 3

Abuse Potential and Withdrawal

Tramadol has a low potential for abuse and dependence compared to traditional opioids, but withdrawal symptoms can occur with abrupt discontinuation.

• The tolerance and dependence potential during treatment for up to 6 months appears to be low 5
• Withdrawal symptoms may include anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations 3
• Clinical experience suggests that withdrawal symptoms may be avoided by tapering tramadol at the time of discontinuation 3
• Despite low abuse potential, tramadol has mu-opioid agonist activity and can be sought by drug abusers, requiring consideration of misuse risk when prescribing 3

Long-Term Neurological Consequences

Long-term tramadol utilization is associated with various neurological disorders including potential contributions to Alzheimer's disease and Parkinson's disease.

• Extensive tramadol intake alters redox balance through elevating lipid peroxidation and free radicals, leading to neurotoxicity and neurobehavioral deficits 6
• Tramadol interferes with dopamine synthesis and release, which may produce bradykinesia and tremors similar to Parkinson's disease motor abnormalities 6
• During prolonged use, tramadol affects intracellular signaling molecules like cGMP, cAMP, PKC, and PKA, which can impact learning and memory 6

Special Population Considerations

Elderly patients (≥75 years) are particularly vulnerable to tramadol's side effects and require lower doses and closer monitoring.

• The maximum daily dose should not exceed 300 mg in elderly patients over 75 years 4, 2
• Elderly patients should start at the lower end of the dosing range (50 mg once or twice daily) 2
• For patients with renal impairment (creatinine clearance <30 mL/min), the dosing interval should be increased to 12 hours with a maximum daily dose of 200 mg 2
• Patients with hepatic impairment should receive 50 mg every 12 hours 2

Critical Dosing Ceiling

Tramadol has a dose ceiling beyond which increasing the dose only increases side effects without improving analgesia.

• The maximum recommended daily dose is 400 mg for immediate-release formulations or 300 mg for extended-release formulations 4, 2
• Do not increase tramadol beyond maximum doses hoping for better analgesia—this only increases adverse effects without improving pain control 4
• The effectiveness of tramadol typically wanes after 30-40 days for most patients, at which point transition to stronger opioids becomes necessary 4