CYP2D6 polymorphisms show large geographical and interethnic differences. Variations in CYP2D6 activity may impact upon a patient's pain level and may contribute to interindividual variations in the response to opioids. This paper reviews the evidence on how CYP2D6 polymorphisms might influence pain sensitivity and clinical response to codeine and tramadol. For example, it is shown that (1) CYP2D6 poor metabolizers (PMs) may be less efficient at synthesizing endogenous morphine compared with other metabolizers. In contrast, ultra-rapid metabolizers (UMs) may be more efficient than other metabolizers at synthesizing endogenous morphine, thus strengthening endogenous pain modulation. Additionally, for codeine and tramadol that are bioactivated by CYP2D6, PMs may undergo no metabolite formation, leading to inadequate analgesia. Conversely, UMs may experience quicker analgesic effects but be prone to higher mu-opioid-related toxicity. The literature suggested the potential usefulness of the determination of CYP2D6 polymorphisms in elucidating serious adverse events and in preventing subsequent inappropriate selection or doses of codeine and tramadol. Notably, even though many studies investigated a possible role of the CYP2D6 polymorphisms on pain sensitivity, pharmacokinetics and pharmacodynamics of these drugs, the results of analgesia and adverse effects are conflicting. More studies are required to demonstrate genetically determined unresponsiveness and risk of developing serious adverse events for patients with pain and these should involve larger numbers of patients in different population types.
The success of major surgery depends partly on providing effective post-operative pain relief, which can be commonly achieved by morphine administration via patient- controlled analgesic (PCA) system. Alternatively, tramadol which is a weak opioid analgesic, can be used for post operative pain relief. The purpose of this study was to evaluate the effectiveness of intravenous PCA tramadol in comparison with PCA morphine in term of analgesic properties, sedation and side effects. A randomized, double-blinded study was conducted on 160 ASA I and II patients who underwent major operations. Eighty of them received a loading dose of intravenous morphine 0.1 mg/kg followed by PCA morphine bolus of 1 mg (1 mg/ml) as required, while the other 80 patients received a loading dose of 2.5 mg/kg of intravenous tramadol followed by PCA infusion of 10 mg (10 mg/ml) as required. Patients were monitored for pain, sedation and side effects as well as respiratory rate, nausea, vomiting, pruritus, blood pressure and pulse rate. Patients were evaluated 30 minutes, 4 hours, 24 hours and 48 hours post operation. There were no differences in the demographic data between the two groups (p > 0.05). The overall mean pain score in tramadol group was 0.70 +/- 0.60 as compared to 0.75 +/- 0.67 for morphine group. The mean pain score for tramadol and morphine groups at 30 minutes, 4 hours, 24 hours and 48 hours post operation were 1.32 +/- 0.79, 104 +/- 0.79, 0.35 +/- 0.48, 0.09 +/- 0.33 and 1.35 +/- 0.99, 1.14 +/- 0.81, 0.40 +/- 0.54, 0.10 +/- 0.34 respectively. The overall mean sedation score in tramadol and morphine group was 0.39 +/- 0.44 as compared to 0.35 +/- 0.43 for morphine group. The mean sedation score for tramadol and morphine group at 30 minutes, 4 hours, 24 hours and 48 hours post operation were 0.90 +/- 0.74, 0.56 +/- 0.59, 0.075 +/- 0.27, 0.025 +/- 0.16 and 0.84 +/- 0.70, 0.46 +/- 0.64, 0.08 +/- 0.27, 0.01 +/- 0.11 respectively. There was no significant difference in the overall mean pain and sedation score between the two groups as well as for each duration assessed (p > 0.05). There were also no significant differences between the two groups with regard to the blood pressure and heart rate. The incidence of nausea, vomiting and pruritus were the same in the two groups. This study indicates that PCA tramadol is as equally effective as PCA morphine control following major surgery. The incidences of sedation, nausea or pruritus were the same in the two groups.
An HPLC system using solid-phase extraction and HPLC with UV detection has been validated in order to determine tramadol and o-desmethyltramadol (M1) concentrations in human plasma. The method developed was selective and linear for concentrations ranging from 50 to 3,500 ng/ml (tramadol) and 50 to 500 ng/ml (M1) with mean recoveries of 94.36 +/- 12.53% and 93.52 +/- 7.88%, respectively. Limit of quantitation (LOQ) was 50 ng/ml. For tramadol, the intra-day accuracy ranged from 95.48 to 114.64% and the inter-day accuracy, 97.21 to 103.24%. Good precision (0.51 and 18.32% for intra- and inter-day, respectively) was obtained at LOQ. The system has been applied to determine tramadol concentrations in human plasma samples for a pharmacokinetic study.