Anesth Analg 2002;94:898-900
© 2002 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
The Stability of a Ketamine-Morphine Solution
Roger Schmid, MD*,
Gideon Koren, MD, FACMT, FRCPC
,
Julia Klein, MS
, and
Joel Katz, PhD*
*Department of Anesthesia and Pain Management, Toronto General Hospital; Departments of Pediatrics, Pharmacology, Pharmacy, Medicine, and Medical Genetics, University of Toronto and The Research Institute, Division of Clinical Pharmacology/Toxicology, Hospital for Sick Children; Departments of Anesthesia and Public Health Sciences, University of Toronto, and Department of Anesthesia and Pain Management, Mount Sinai Hospital, Toronto, Canada
Address correspondence and reprint requests to Joel Katz, Department of Anesthesia and Pain Management, Toronto General Hospital, 200 Elizabeth St., EN 3-440, Toronto, ON, Canada M5G 2C4. Address e-mail to jkatz{at}uhnres.utoronto.ca
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Abstract
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Recent advances in acute pain mechanisms and management have implicated the N-methyl D-aspartate receptor-ion channel complex in the development of postoperative hyperalgesia and acute opioid tolerance. N-methyl D-aspartate receptor antagonists such as ketamine have been used increasingly in clinical studies in an effort to minimize acute postoperative pain and reduce opioid requirements. A mixture of ketamine and an opioid administered in the same solution and syringe would be a practical and useful technique for postoperative epidural analgesia, continuous IV infusion, or patient-controlled IV analgesia. We investigated the stability of a morphine sulfate and racemic ketamine solution in saline at pH 5.5–7.5 over a period of 4 days. Our study demonstrates that the ketamine-morphine mixture at a clinically relevant concentration seems to be stable at room temperature, at a wide range of pH values, for at least 4 days.
IMPLICATIONS: Small-dose ketamine is used with increasing frequency in the acute postoperative setting as an adjunct to traditional opioid analgesics. We show that a racemic ketamine and morphine solution at a clinically relevant concentration seems to be stable at room temperature at a wide range of pH values for at least 4 days.
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Introduction
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Advances in the understanding of acute pain mechanisms have led to a renaissance of the use of ketamine hydrochloride because of its actions as an N-methyl D-aspartate receptor antagonist (1). Clinical studies have reported improved pain relief using ketamine as an adjunct to various analgesics in the treatment of acute postoperative pain (2–5) and cancer pain (6).
Of particular interest is the combination of small-dose ketamine with opioids, the most commonly used drugs for postoperative pain relief. In the clinical setting, subanesthetic doses of ketamine administered with opioids reduced opioid requirements and opioid-related adverse effects (2,7,8) perhaps because of the ability of small-dose N-methyl D-aspartate antagonists to interfere with the development of acute opioid tolerance (9) and opioid-induced hyperalgesia (10,11).
A mixture of ketamine and an opioid administered in the same solution and syringe would be a practical and useful technique for postoperative epidural analgesia, continuous IV infusion, or patient-controlled IV analgesia. However, to administer such a mixture of drugs safely to the patient over a period of several days, one must ensure that the mixture demonstrates physical and chemical stability. Because morphine is the most frequently used opioid for the treatment of acute and chronic pain, we investigated the stability of a morphine sulfate and racemic ketamine solution in saline at pH 5.5–7.5 over a period of 4 days.
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Materials and Methods
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To prepare the stock solutions, the following materials were used: 1 20-mL vial of ketamine hydrochloride (Ketalar®; Parke-Davis, Scarborough, ON, Canada) containing 10 mg/mL ketamine; 2 1-mL vials of morphine sulfate 15 mg/mL (Abbott Laboratories, Ltd., Saint-Laurent, QC, Canada); 2 1-mL vials of morphine sulfate 10 mg/mL (Abbott Laboratories); 1 1-mL vial of morphine sulfate 2 mg/mL (Abbott Laboratories); NaCl, NaOH 10 N, HCl 6 N (Fisher Scientific Ltd., Nepean, ON, Canada).
A stock solution of 0.9% NaCl was prepared in water; 50 mL was aliquoted, and the pH of each aliquot was adjusted to 5.5, 6.0, 6.5, 7.0, and 7.5. The ketamine and morphine were mixed together in the saline at pH 5.5–7.5 at a final concentration of 1.33 mg/mL for ketamine and 2.0 mg/mL for morphine. The total volume of the solution was 25 mL. As soon as the mixtures were ready, 6 1.0-mL aliquots were taken and kept at -20°C in Falcon polystyrene tubes until analysis. The remaining solution was kept at room temperature, also in Falcon polystyrene tubes, for the subsequent 4 days. Each day, the same exercise was repeated: 1.0 mL was aliquoted in 6 small vials. They were placed immediately at -20°C and kept there until analysis.
For ketamine analysis, a high-pressure liquid chromatography (HPLC) method (12) was used with some modifications. Briefly, the mobile phase was 0.1 M sodium dihydrogen phosphate buffer pH 2.1 (adjusted with phosphoric acid) containing 1 mM dodecyl sulfate and 22% acetonitrile. The flow rate was 0.8 mL/min and the column was ProdigyTM ODS (3) 5 µm, 150 x 4.6 mm (Phenomenex, Torrance, CA). We used a Shimadzu HPLC system equipped with a spectrophotometric detector set at 215 nm (Mandel Scientific, Guelph, ON, Canada). For quantitation, a standard solution in saline was prepared from the same Ketalar vial that was used for sample preparation.
For morphine analysis, the same HPLC method was used. For quantitation, an aliquot from a new vial of morphine sulfate 2 mg/mL was used. In addition, morphine was also measured in each sample by using an enzyme-linked immunosorbent assay method.
The StatView® SE program (SAS Institute Inc., Cary, NC) was used for statistical analysis. The mean concentration of ketamine and morphine was calculated each day. Within-the-day and between-the-days coefficient of variation was calculated for each compound.
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Results and Discussion
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Our study demonstrates that the ketamine-morphine mixture at a clinically relevant concentration seems to be stable at room temperature, at least for four days at a wide range of pH (Table 1). Initially, we examined the stability of the solution at pH 5.5 only; however, although the ketamine seemed to be very stable, the morphine results were more erratic. There was no clear pattern of concentration decrease in time, but the coefficient of variation was rather high. The same pattern was observed using both methods of analysis: HPLC and enzyme-linked immunosorbent assay.
In the present stability study, we therefore modified the original HPLC method (12) by adding an ion pairing agent to the mobile phase; the ketamine results were unchanged, but the coefficient of variation for morphine decreased considerably, from 11.04 to 2.18 at this particular pH (Table 1).
There is some indication in the literature (13) that, at pH higher than 5.9, the mixture is no longer stable. However, in that study, much larger concentrations (i.e., ketamine 41.2 mg/mL and morphine 17.6 mg/mL) were used and the pH was adjusted with sodium bicarbonate. We conclude that a ketamine-morphine solution can be used at physiologic pH, at the above-mentioned concentrations and that it is stable for up to four days at room temperature.
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Acknowledgments
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Supported by an Investigator Award from the Canadian Institutes of Health Research (CIHR) and CIHR Grant MCT-38144 (to J. Katz).
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Footnotes
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The present address for RS is Zentrum für Diagnostik und Therapie, Köln, Rodenkirchen, Anästhesie und Schmerztherapie, Ringstr.2b, 50996 Köln, Germany.
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Accepted for publication December 11, 2001.
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Abstract
Introduction
