Background and importance Multimodal analgesia is based on the combination of different drugs and analgesic techniques in order to alleviate postoperative pain. One of the limitations of this technique is the lack of evidence about the stability of these mixtures in clinical practice.

Aim and objectives To evaluate the 30-day physicochemical compatibility of four analgesic mixtures of tramadol and ketamine, combined with dexketoprofen or ketorolac, ± methadone, in saline solution bags, for patient-controlled analgesia.

Material and methods Mixtures studied:

V1: tramadol-hydrochloride 7.5 mg/mL + dexketoprofen 2.26 mg/mL + ketamine 0.19 mg/mL

V2: V1 + methadone-hydrochloride 0.075 mg/mL

V3: tramadol-hydrochloride 7.9 mg/mL + ketorolac-trometamine 0.95 mg/mL + ketamine 0.4mg/mL

V4: V3 + methadone-hydrochloride 0.08 mg/mL.

Diluent: 100 mL normal saline (polypropylene bags). Four batches of each mixture were prepared in aseptic conditions using commercially available products. Bags were protected from light, and stored at 2–8°C. The following parameters were evaluated immediately after preparation (t0), 7, 15 and 30 days after preparation (all measures by triplicate) (i) colour change and/or precipitation (visual inspection) and turbidity (nephelometry), (ii) pH (potentiometry), (iii) drug concentration (ultra-high-performance liquid chromatographic-diode array (UHPLC-DAD)) and (iv) preservation of sterility by culture in enriched soybean casein digest broth.

Two chromatographic methods were developed (M1, M2) using two different columns: Acquity-HSS-C18 (100 mm×2.1 mm×1.8 µm) (M1) and Acquity-BEH-C18 (100 mm×2.1 mm×1.7 µm) (M2). The chromatographic method consisted of a gradient with acetonitrile/water. An acidic aqueous phase was also used with a high strength silica (HSS) column (HCOONH₄/HCOOH) and a basic aqueous phase with an ethylene bridged hybrid (BEH) column (HCOONH₄/NH₃), forcing different order of drugs’ elution.

Results Physical parameters and pH remained unchanged during the study; pH range for V1, V2: 7.08–7.28; V3, V4: 6.76–6.91. The chromatographic methods proved to be stable after stress tests and showed good linearity (r²>0.999) and high selectivity, with a detection limit between 0.1 and 0.3 mg/L at 215 nm. The percentage of drug recovery remained in the range 90±110% (97%–103%) of the initial concentration (t0) for all drugs in the four mixtures during the whole study period (coefficient of variation (CV) (%) 0.1–2.4). All samples preserved their sterility during the study.

Conclusion and relevance The four analgesic mixtures of tramadol and ketamine, combined with dexketoprofen or ketorolac, ± methadone, were stable for 30 days at 2–8°C in the conditions described in the study, allowing their centralised preparation at pharmacy service.

Conflict of Interest Corporate sponsored research or other substantive relationships: study financed by the Spanish Government ISCIII FIS PI17/00826.