Influence of CYP2D6 phenotype on the pharmacokinetics and pharmacodynamics of tramadol in patients treated for post-operative pain management

Anaesth Crit Care Pain Med. 2026 Mar 4:101781. doi: 10.1016/j.accpm.2026.101781. Online ahead of print.

ABSTRACT

INTRODUCTION: Tramadol is widely used in post-operative pain management. Concentrations of tramadol and its active metabolite O-demethyl tramadol (O-dT) are influenced by cytochrome P450 2D6 (CYP2D6) genotype.

OBJECTIVES: The objectives of this study were to investigate the relationships between CYP2D6 phenotype and tramadol pharmacokinetics/ pharmacodynamics (PK/PD) in real life setting.

METHODS: CYTRAM was a prospective multicenter study conducted in patients who received post-operative intravenous (IV) tramadol. Patients underwent CYP2D6 genotyping and phenotyping as well as tramadol and O-dT concentration measurements at 24 h and 48 h of therapy. A PK model was used to estimate tramadol and O-dT area under the concentration-time curve (AUC). Pain rating was performed at 24 h and 48 h and evaluated by Numeric Rating Scale (NRS). Patients with NRS < 4 were classified as responders. Variables associated with analgesic response were examined.

RESULTS: PK data from 285 patients and pain scores from 273 and 204 patients were available at 24 h and 48 h, respectively. Mean AUC of O-dT was two-fold lower in CYP2D6 poor metabolizers (PM) compared with subjects with other phenotypes (non-PM). At 48 h, pain scores were significantly higher in PM than in non-PM patients. In addition, PM subjects exhibited a significantly lower rate of response (50% versus 78%) and a higher rate of morphine use (47% versus 17%) at 48 h compared with non-PM subjects. However, CYP2D6 phenotype was not an independent predictor of response in the entire population.

CONCLUSION: Our results support current pharmacogenetic guidelines and suggest avoiding tramadol for postoperative management in patients with known CYP2D6 PM phenotype.

REGISTRATION: ClinicalTrials.gov (NCT00952159).

PMID:41791456 | DOI:10.1016/j.accpm.2026.101781