The present study demonstrates the physicochemical compatibility of all binary mixtures of acetaminophen, ketoprofen, nefopam and ketamine at clinically relevant concentrations and at room temperature. The concentrations of all the active drugs remained higher than 95% of their expected values for at least 24 h. There was no evidence of interaction, degradation products, or both for the binary mixtures of drugs, and the chromatograms did not reveal any other substances.
The present study was warranted. Combining nonopioid analgesics of different classes such as acetaminophen, ketoprofen, nefopam and ketamine has become an accepted method in reducing the doses of individual drugs, in providing superior pain relief and in reducing opioid analgesic-related side effects . Mixing of two or more chemicals together can lead to physical, chemical or both changes, which may result in alteration in therapeutic properties and in having undesirable side effects . This must be avoided by respecting a simple compounding procedure and sometimes an order of dilution . Ketamine, nefopam, acetaminophen and ketoprofen were previously demonstrated to remain stable when separately infused [6–9]. However, we are not aware of any investigations into the chemical and physical interactions of acetaminophen, ketoprofen, ketamine and nefopam combinations, though routine combined delivery is recommended to improve analgesic care . The aim of this study was to fulfil this lack of information. Actually, few studies have looked at the stability aspect of each of these drugs combined with anaesthetic and analgesic agents. For example, ketoprofen and tramadol have been shown to be physicochemically compatible for up to 7 days at room temperature, protected from light, at all mixing ratios . Ketamine in binary mixtures with dexamethasone, fentanyl, droperidol, morphine, meperidine, bupivacaine, lidocaine and tetracaine is stable for 24–192 h under normal conditions [8,19–21]. Finally, the stability of acetaminophen has only been studied with excipients used in commercially available pharmaceutical formulations and shown to have good compatibility with polyvinylpyrrolidone, magnesium stearate, nitric acid, aspartame, cellulose and starch but not with mannitol . We are not aware of any published data concerning the stability of nefopam in combination.
The present study has direct relevance to clinical practice. The experimental protocol followed in this study had previously been validated for such investigations and all parameters were assessed at clinically relevant intervals [8,10,18,20–27]. Guidelines for the combined administration of binary mixtures of nonopioid analgesic drugs are empirical in nature. In our institution, acetaminophen, nefopam, ketoprofen and ketamine are usually coadministered in separate bottles; however, this is often via a single venous line in which an interaction might occur. No adsorption of these molecules on the plastic bags for infusion or the i.v. lines could be found. Indeed, 100% of baseline concentrations of each drug remained in solution throughout the 24 h follow-up. Coadministration of binary mixtures of acetaminophen, nefopam, ketoprofen and ketamine from the same bottle or infusion bag using the same venous line has now been demonstrated to be feasible. This will considerably facilitate preparation and dispensing of these drugs.
Furthermore, the present study provides support for some of the reasons postulated for the contrary results reported in some investigations regarding the benefit of multimodal analgesia [13,14]. For example, a ketoprofen–acetaminophen combination has been associated with lower pain scores than acetaminophen alone at rest and on movement after disc surgery . In contrast, in the immediate postoperative period after thyroid surgery, the concomitant use of acetaminophen and ketoprofen did not improve analgesia compared with ketoprofen alone . On the basis of opioid requirement and pain scores, the combination of acetaminophen and ketoprofen provided better analgesia than acetaminophen or ketoprofen alone after orthopaedic, but not soft-tissue, surgery in children . Aubrun et al.  investigated a large patient sample and reported that reduction in morphine need associated with acetaminophen administration could vary from zero to 50%. Our findings rule out physicochemical drug alteration as a reason for these interresult discrepancies and support data suggesting that the time of drug administration, type of surgery, sex ratio and genetic factors could account for these discrepancies [13,14].
When mixing drugs taken from ampoules of sterile solutions, there is also the potential issue of bacterial contamination. We did not examine any of our solutions for such contamination but it must be emphasized that solutions that may support bacterial growth should not be prepared more than a few minutes in advance of their administration.
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