Rethinking the Risks: Tramadol’s Distinct Side Effect Profile
by Luiza Kerstenetzky-Brenny, PharmD, BCPS, Timothy S. Yeh, PharmD, BCACP, Joshua P. Vanderloo, PharmD, BS, BCPS, Alexis M. Eastman, MD
Abstract
Purpose and Summary:
Tramadol is often considered an attractive option for moderate-to-severe pain due to its perceived lower risk of side effects compared to other opioids. Tramadol is described as a “pro-drug” whose activation by the CYP2D6 enzyme is necessary for its analgesic effects. The main active metabolite, O-desmethyltramadol (M1), is responsible for tramadol’s analgesic effects, while the tramadol parent drug retains norepinephrine and serotonin reuptake inhibition.
Tramadol carries risks of “classic” opioid side effects including central nervous system (CNS) effects, respiratory depression, and constipation. However, due to its pro-drug nature, serotonin and norepinephrine activity, and pharmacokinetic and pharmacogenomic properties, it has unique side effects that must be carefully considered in certain patient populations. This narrative review evaluates tramadol’s underrecognized side effects and the patient populations most affected. These adverse drug events include serotonin syndrome, seizures, hyponatremia, and hypoglycemia. Drug-drug interactions, an individual’s CYP2D6 phenotyping, and various patient factors may predict whether a patient is at higher risk for side effects from excessive amounts of M1 (opioid-like) or the parent drug (serotonergic-driven).
Conclusion:
Various factors should be considered before initiating tramadol, and caution should be exercised for those with advanced age, CYP2D6 poor or ultrarapid metabolism, concomitant medications with CYP2D6 and/or CYP3A4 interactions, diabetes, renal dysfunction, history of opioid use, and a history of seizures.
Download PDF
2025 November/December Table of Contents
Abstract
Purpose and Summary:
Tramadol is often considered an attractive option for moderate-to-severe pain due to its perceived lower risk of side effects compared to other opioids. Tramadol is described as a “pro-drug” whose activation by the CYP2D6 enzyme is necessary for its analgesic effects. The main active metabolite, O-desmethyltramadol (M1), is responsible for tramadol’s analgesic effects, while the tramadol parent drug retains norepinephrine and serotonin reuptake inhibition.
Tramadol carries risks of “classic” opioid side effects including central nervous system (CNS) effects, respiratory depression, and constipation. However, due to its pro-drug nature, serotonin and norepinephrine activity, and pharmacokinetic and pharmacogenomic properties, it has unique side effects that must be carefully considered in certain patient populations. This narrative review evaluates tramadol’s underrecognized side effects and the patient populations most affected. These adverse drug events include serotonin syndrome, seizures, hyponatremia, and hypoglycemia. Drug-drug interactions, an individual’s CYP2D6 phenotyping, and various patient factors may predict whether a patient is at higher risk for side effects from excessive amounts of M1 (opioid-like) or the parent drug (serotonergic-driven).
Conclusion:
Various factors should be considered before initiating tramadol, and caution should be exercised for those with advanced age, CYP2D6 poor or ultrarapid metabolism, concomitant medications with CYP2D6 and/or CYP3A4 interactions, diabetes, renal dysfunction, history of opioid use, and a history of seizures.
Download PDF
2025 November/December Table of Contents