Impact of CYP2D6 genotype on postoperative tramadol analgesia

Abstract

Genetic polymorphisms result in absent enzyme activity of CYP2D6 (poor metabolizers, PM) in about 10% of the Caucasian population. This study investigates whether the PM genotype has an impact on the response to tramadol analgesia in postoperative patients. A prospective study design was used and 300 patients recovering from abdominal surgery were enrolled. After titration of an individual loading dose, patients could self-administer 1 ml bolus doses of the drug combination tramadol 20 mg/ml, dipyrone 200 mg/ml and metoclopramide 0.4 mg/ml via patient-controlled analgesia (PCA). Patients' genotype was analyzed considering the most prevalent PM associated CYP2D6 mutations using a real-time PCR and hybridization based genotyping method. Demographic data, surgery related variables, pain scores, analgesic consumption and need for rescue medication were compared between extensive metabolizers (EM) and PM. The primary outcome criterion 'response' was defined as responder or non-responder status by the need for rescue medication and patients' satisfaction at the final interview. Demographic and surgery related data were comparable between EM (n=241) and PM (n=30). The percentage of non-responders was significantly higher in the PM group (46.7%) compared with the EM group (21.6%; p=0.005). Tramadol loading dose amounted to 108.2+/-56.9 and 144.7+/-22.6 mg (p<0.001) in EM and PM, respectively. More patients displaying the PM genotype needed rescue medication in the recovery room and during PCA period than patients with at least one wild type allele (21.6 versus 43.3%, p=0.02). PM for CYP2D6 showed a lower response rate to postoperative tramadol analgesia than EM. Therefore, CYP2D6 genotype has an impact on analgesia with tramadol. Pharmacogenetics may explain some of the varying response to pain medication in postoperative patients.

Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications

“…This is a concern for cancer patients being given pain relief, with a lower analgesic effect of codeine seen in PMs, as conversion of the drug to morphine is CYP2D6-dependent [58,59]. This could also be an issue for the antiemetic dolasetron, as CYP2D6 is also required for its conversion to the active metabolite hydrodolasetron.…”

Pharmacogenetics and Metabolism: Past, Present and Future

“…Second, phenotype status directly affects clinical response. Analgesic effects of some prodrugs, such as tramadol, codeine and oxycodone are CYP2D6-dependent, and PMs present low analgesic efficacy (Poulsen et al 1996;Stamer et al 2003;Stamer & Stuber 2007;Zwisler et al 2009). On the other hand, loss of therapeutic efficacy at standard doses can also be observed in UMs since the drug metabolization occurs at a fast rate (Davis & Homsi 2001).…”

The Role of Opioid Analgesics in the Treatment of Pain in Cancer Patients

“…The starting dose of immediate-release (IR) tramadol is 25 to 50 mg every 4 to 6 hour and that of controlled-release (CR) tablets or capsules is 50 to 100 mg twice daily; the daily dose should not exceed 400 mg (Dickman, 2007). Patients devoid of CYP2D6 activity (poor metabolizers) need a tramadol dose higher by 30% than those with normal CYP2D6 activity (extensive metabolizers) (Stamer et al, 2003). Tramadol analgesia depends on CYP2D6 genotype, with less analgesia in poor metabolizers being associated with lack of (+)-M1 formation (Stamer et al, 2007).…”