Codeine and tramadol analgesic efficacy and respiratory effects are influenced by CYP2D6 genotype

We thank Sudheer and coworkers for their investigation of analgesic efficacy and respiratory effects of morphine, tramadol and codeine [1]. The new aspect of this trial is the study population consisting of patients recovering from craniotomy. On the other hand, several studies have compared tramadol patient-controlled analgesia (PCA) with other analgesics, mainly in patients after abdominal surgery [2–6]. We are interested as to why the results of this study differ from the results of these previous studies. The 10-mg titration increments and PCA bolus doses of tramadol were rather small. Larger doses are frequently used and the poor response in this study might be due insufficient dosing. The authors cite a potency ratio of tramadol to morphine of 10 : 1; however, clinical studies have demonstrated an equi-analgesic ratio of between 11 : 1 and 20 : 1 [2, 3, 7, 8]. One multicentre trial found the loading doses of morphine and tramadol in the recovery room to be 12.3 (SD 5.1) mg and 145 (SD 50) mg, respectively [3]. As Le Roux and Coetze state, the slow onset of tramadol makes it imperative to administer the loading dose well in advance of the emergence from anaesthesia, and doses greater than 200 mg may be necessary [9]. Tramadol loading doses of 2–5 mg.kg−1 administered before the end of surgery enable awakening without severe pain and prevent tramadol-induced nausea and vomiting [2, 5–7, 10]. However, these dosing schemes were not obtained from patients after craniotomy and lower doses might be sufficient in this cohort. In their study Sudheer and colleagues utilised a 4-h PCA limit of morphine 50 mg (50 delivered boluses) whereas in the tramadol group the limit was set to 200 mg, which means only 20 delivered boluses. What was the rationale for this PCA setting? Regrettably, the authors did not include any information on analgesic consumption (such as loading dose, demand : delivered dose ratio, and opioid consumption within 6, 12 and 24 h). These data might have given valuable information on the overall efficacy of the opioids and their equipotency. Although the authors did not indicate a difference in the type of surgery between the groups, frontal craniotomy was under-represented in the tramadol group, with four (20%) patients randomly allocated to this treatment compared with six (30%) and nine (49%) in the morphine and codeine groups, respectively. As the authors stated, these patients tended to have less pain. In contrast, high pain approaches (temporal or posterior fossa craniotomy) were the most frequent in the tramadol group (12 patients). The median satisfaction score provides little information. How many patients were moderately or totally dissatisfied (score 3 or 4)? Was the reason for the dissatisfaction poor pain control, adverse events or other reasons? Sudheer and colleagues discuss the analgesic effect of codeine being subject to genetic polymorphism of cytochrome P4502D6, with 7–10% of a Caucasian population having two poor metaboliser-associated polymorphisms, resulting in an almost complete absence of enzyme activity [10–13]. This is also true for tramadol, which has to be metabolised to (+)-O-demethyltramadol, which is largely responsible for the μ-opioid receptor-mediated analgesic properties of tramadol [11]. In contrast, inhibition of serotonin and noradrenaline reuptake is mediated by the parent enantiomers (+)- and (–)-tramadol. The two patients experiencing no pain relief in the codeine and tramadol groups are likely to be CYP2D6-poor metabolisers and further pain management should have used another opioid, such as morphine. One or two further patients with a poor metaboliser genotype may have been included in the codeine and tramadol groups. We note that in the discussion the authors described five patients (three in the codeine group and two in the tramadol group) with severe pain requiring rescue medication and withdrawal from the study. The influence on respiration of both opioids was negligible, probably due to the low analgesic doses. A difference in respiratory effects will probably only be visible if larger opioid doses, especially morphine, are used. Nevertheless, a tendency to a higher degree of central nervous system-related effects was observed in the morphine group, with a pupil size of 2 mm at some time points compared with 3 mm in the codeine and tramadol groups. Severe respiratory depression with opioids, especially tramadol, is rare. However, the statement that tramadol never causes respiratory depression is not correct. Respiratory depression has been described after both tramadol and codeine [14, 15], and impaired renal clearance of metabolites and genetic background (CYP26 ultra-rapid metaboliser status) have been implicated [15].