Patient‐controlled oral analgesia following cesarean section: tramadol versus a combination of tramadol and acetaminophen

Abstract

Sir, Experimental and clinical data suggest that analgesic and anti-hyperalgesic properties of tramadol can be improved by combination with acetaminophen (1,2). Tramadol alone is an effective analgesic after cesarean section (3), but we planned to investigate whether a commercially available oral combination of 37.5mg tramadol and 325mg acetaminophen (T + A; Zaldiar©; Gruenenthal GmbH, Aachen, Germany) was superior in pain control and anti-hyperalgesia to an equivalent dosage (2) of 50mg of tramadol alone (T; Tramal©; Grünenthal GmbH). We planned to include in a randomized, double-blind trial (clinical.gov identifier NCT00873743) 120 healthy parturients undergoing elective cesarean section without a history of pain syndrome or substance abuse. Following standardized spinal anesthesia containing hyberbaric bupivacaine and fentanyl, women were offered oral analgesia on demand of either A + T or T. We informed our patients about the delay of analgesia after oral administration and instructed them to take two tablets of their assigned medication at the onset of pain, with subsequently one tablet every three hours (maximum daily dose 10 tablets). At four, eight, 24 and 48hours postoperatively, pain at rest, coughing (= primary outcome), leg raising and uterine cramping pains were evaluated using a visual analog pain-rating scale (VAS). Secondary hyperalgesia was measured by pinprick with a 256mN von Frey hair. Overall patient satisfaction was rated at discharge. The CYP-2-D-6 genotypes of women were analysed (Genosense Diagnostics, Vienna, Austria) and poor metabolizers excluded. After enrolling 10 patients, five patients suffered from unexpectedly high pain levels, with VAS > 9, requiring intravenous rescue analgesia and dropping out of the study. As a consequence, the principal investigator interrupted the study and, as a first randomization block was included, an interim data analysis was performed. Unblinding revealed that all patients dropping out were in the T + A group. Furthermore, all pain states at eight hours postoperatively were significantly higher compared with T (Table 1). This was reported to the institutional ethics committee (Medical University Vienna, Ethikkommission Wien, ID-Nr.: 31121976-3) and the Austrian authorities (AGES; ‘Oesterreichische Agentur für Gesundheit und Ernaehrungssicherheit’), and the trial was stopped. Tablet intake in both groups was equal. Total mean drug dosage differed significantly between the groups (262.5mg tramadol + 2275mg acetaminophen vs. 390mg tramadol; p < 0.01). No difference in adverse effects or secondary hyperalgesia could be assessed, and no patient had poor CYP-2-D-6 metabolizer status. This is the first report evaluating pain control 48hours after cesarean section to compare tramadol with a commercially available combination with acetaminophen. Despite promising experimental and clinical data (1,2,4,5) in other settings, we had to abort our investigation for ethical reasons. We conclude that 37.5mg tramadol combined with 325mg acetaminophen is inferior to 50mg of tramadol in this setting and does not control pain sufficiently after cesarean section.