Discussion
PROM, postoperative pain, NRS, pain
ADVERSE EFFECTS, PID, ADVERSE EFFECTS, DRUG EFFECT
Few clinical trials have been published at present time studying the effect of multimodal postoperative analgesia using a paracetamol/NSAID/codeine combination on acute post-operative/-traumatic pain [Pharmacokinetic interaction has been suggested as an explanation for the prolonged analgesic efficacy for paracetamol/NSAID combinations [The SPI supported by the SPID results in our study showed that ibuprofen 400 mg/paracetamol 1000 mg/codeine 60 mg did not provide general mean analgesic superiority compared to ibuprofen 400 mg/paracetamol 1000 mg in our mixed-sex study population suggesting that the ibuprofen/paracetamol component, and not the codeine component, provides the major analgesic effect. The results from our study and previous studies [We were surprised at the apparently lack of analgesic efficacy of codeine in our ethnically homogenous study. Female participation in clinical trials is advocated [Our sex/drug interaction findings relating to outcome measures regarding drug efficacy are interesting since the patient populations used in the previous trials using triple drug combinations consisted of multi-ethnic patient populations [Sex- and gender-based pharmacological responses to drugs are known, but clinical drug trials comparing analgesic effects of different opioid analgesics in females and males are sparse. Some trials have shown that females experience more analgesia than males when treated with opioid agonists such as pentazocine and butorphanol both more selective for the kappa-receptor than the mu-receptor in acute postoperative pain [Newer studies with positron emission tomography of the human brain using highly selective radiotracers for kappa-receptors and mu-receptors show that males have higher kappa-receptor availability than females, but females have higher mu-receptor availability than males [Metabolic conversion to morphine, and possibly the 6-glucuronide metabolite of morphine, is generally suggested to explain the analgesic efficacy of codeine, while others claim an analgesic contribution from codeine or its 6-glucuronide metabolite based on animal and human experiments [Patients assess their subjective present pain intensity on linear scales such as the 0–10 point NRS used in our study. PID conversion is traditionally used as a measure for drug efficacy (i.e. pain reduction capability) to correct for individual baseline variability, but pain does not increase linearly [Adverse effects in our study were relatively few representing known issues. The NNH value from ibuprofen 400 mg/paracetamol 1000 mg was higher than, but not significantly different from the NNH values from the other active treatment groups. Only paracetamol 1000 mg/codeine 60 mg was significantly different from placebo. All episodes resolved within a short time, but there was a significant majority of complaints from female participants. The study showed a slight majority of adverse effects related to the use of the codeine-containing drugs used by females, something that is well known when using opioid analgesics [It is noteworthy that the PROM appraisal of ibuprofen 400 mg/paracetamol 1000 mg/codeine 60 mg was roughly the same for both sexes contrasting with significant less female preference for paracetamol 1000 mg/codeine 60 mg and a strong female preference trend for ibuprofen 400 mg/paracetamol 1000 mg. This finding may seem paradoxical if the PROM scores are compared with the sex-based incidence (F/M) of adverse effects reported for the paracetamol 1000 mg/codeine 60 mg group (6/2) and the ibuprofen 400 mg/paracetamol 1000 mg/codeine 60 mg (8/1) groups, as they were nearly the same. Our results support PROM as a global assessment of analgesic drug effect during a defined postoperative period and encompass more quality of life parameters than solely a change in pain experience as shown with SPI and SPID scores.We used the well-characterized third molar surgery model [Our study showed very good generalized analgesic outcomes of the combination of paracetamol and ibuprofen with or without codeine versus codeine added to paracetamol alone in a study with a sex-mixed trial population. NNT found in our study for paracetamol 1000 mg/codeine 60 mg was 2.6 compared with current published data (2.2, 95% CI 1.8–2.9) [The paucity of codeine as an analgesic enhancer in our trial for female patients may explain the difficulty in finding a clinically relevant adjuvant analgesic effect of codeine using generalized outcome data. The authors are aware of the overuse of weak opioids in the clinic with a significant potential for drug dependence, but there is a need for analgesics with more analgesic potency than NSAIDs and paracetamol or their combination. Correct clinical cost/benefit assessments including knowledge of analgesic sex-drug interactions are necessary to achieve this purpose. The possibility of an analgesic sex/drug interaction as shown in our study provides an argument for more studies into personalized sex-based differences in OTC analgesics.