Combining nonopioid analgesics of different classes 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 . Multimodal analgesic techniques often include the use of acetaminophen, a cyclooxygenase enzyme blocker, ketoprofen, a nonsteroidal anti-inflammatory drug, ketamine, an N-methyl-D-aspartate receptor antagonist, and nefopam, a centrally acting nonnarcotic analgesic, which also inhibits serotonin and norepinephrine reuptake peripherally [2–5]. Stabilities of separated infusions of ketamine, nefopam, acetaminophen and ketoprofen have already been assessed [6–9]. However, we are not aware of any investigations into the chemical and physical interactions among these four routinely coadministered drugs, even though it is well known that mixing two or more chemicals together can lead to physical, chemical or both changes, which may result in a variation in therapeutic properties and undesirable side effects . Therefore, it is recommended that the combination of coadministered drugs is avoided when no data on their compatibility are available . An experimental protocol was designed to investigate the physicochemical compatibility of binary mixtures of acetaminophen, ketoprofen, nefopam and ketamine. In addition, some studies [11,12] have indicated that multimodal analgesia has limited efficacy for certain surgery. Interindividual variations in analgesic drug sensitivity and severity of pain and various times and modalities of drug administration were suggested to have accounted for interstudy discrepancies regarding coadministered nonopioid analgesic drugs [13,14]. We assumed that there is a possibility that these discrepancies may have some origin in an alteration in the therapeutic properties of the combinations of analgesic drugs employed, owing to negative chemical interactions. This study will also discuss this hypothesis.
Binary mixtures of acetaminophen, ketoprofen, nefopam and ketamine were studied. The drugs were studied in the forms used in clinical practice in our institution, collected from ready-to-use bottles. Binary mixtures were chosen because they are the most commonly used combinations of analgesics in our institution. Acetaminophen is available in Europe in a ready-to-use intravenous (i.v.) acetaminophen formulation. Intravenous acetaminophen, 1 g (Perfalgan, Bristol-Myers-Squib Laboratory, Rueil Malmaison, France), is available in 100 ml bottles, which also contain cysteine chlorhydrate, disodium phosphate and isotonic saline. It has a similar effect to propacetamol, 2 g, the prodrug of acetaminophen . Ketoprofen, 100 mg (Profenid, Sanofi-Aventis Laboratory, Paris, France), is available in 2 ml bottles comprising arginine, benzyl alcohol, anhydrous citric acid and water for injection. In our institution, ketoprofen, 50 mg, is dissolved in 100 ml isotonic saline prior to i.v. administration over 30 min. Nefopam, 20 mg (Acupan, Biocodex Laboratory, Beauvais, France), is available in 2 ml ampoules also containing monosodium phosphate, disodium phosphate and water for injection. In our institution, nefopam, 20 mg, is frequently dissolved in 100 ml isotonic saline prior to i.v. administration over 30 min. Ketamine hydrochloride, 50 mg (Ketamine, Panpharma Laboratory, Fougères, France), is available in 5 ml ampoules also containing chlorobutanol and water for injection. Low-dose ketamine is dissolved in isotonic saline prior to intraoperative administration to treat pain, which is expected to be moderate to severe . In our institution, ketamine regimens involve either 0.15 mg kg−1 i.v. administration 1 h prior to the end of surgery or 25–50 mg kg−1 min−1 intraoperative continuous i.v. administration . A solution of ketamine, 15 mg, in 20 ml isotonic saline was considered for this evaluation.
All samples were kept at 25°C throughout the investigation. The stability study involved determining each drug concentration for all binary mixtures by means of a specific high-performance liquid chromatographic (HPLC) technique. Each drug concentration determination was carried out in a single run by means of a chromatographic technique coupled to a diode array detector. The chromatographic parameters were as follows: a stationary phase (Varian Polaris column, 33 × 4.6 mm, dp = 5 μm); the mobile phase was set up with an elution gradient produced by 50 mmol l−1 phosphate buffer pH 2.0 (Sigma–Aldrich, Saint Quentin Fallavier, France) and HPLC grade acetonitrile (VWR, Fontenay aux Roses, France). The chromatographic runs were carried out on Waters instruments (Waters, Guyancourt, France): pump 600 E, injector 717+, detector 996. The optical density was monitored at 220 nm and ultraviolet spectra were recorded between 200 and 400 nm. The method was validated in accordance with the International Conference on Harmonization Guidelines . Three determinations were carried out on each binary solution and at each time. Each sample was determined immediately after mixing and again 1, 2, 4, 6, 12 and 24 h later. A 5% loss of initial concentration was considered to be significant . The changes with time of the concentrations of the drugs in solution were analysed using linear regression analysis. In addition to HPLC, variations in the pH of the binary mixtures were also measured at zero and 24 h. The pH was determined using a glass electrode connected to a pH meter (Mettler Toledo, Viroflay, France). A P value of less than 0.05 was considered to be significant.
Table 1 shows the changes in the concentrations of the various binary combinations of acetaminophen, ketamine, ketoprofen and nefopam at various test times. No loss of concentration (i.e. ≥5%) was observed in any of the binary mixtures. The pH remained stable on measurements performed at zero and 24 h; pH was 7 for mixtures in isotonic saline and 5.5 for mixtures with acetaminophen. Figure 1 shows the linear regression analysis of all binary mixtures (concentration vs. time). No correlation was observed between concentration and time for any of the drug combinations (slope test, P > 0.05).
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.
In conclusion, binary mixtures of acetaminophen, ketoprofen, nefopam and ketamine in clinically relevant concentrations in isotonic saline and at room temperature are stable and compatible for at least 24 h.
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Keywords:© 2009 European Society of Anaesthesiology
acetaminophen; analgesics nonnarcotic; drug interactions; drug stability; ketamine; ketoprofen; nefopam