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Intrathecal Midazolam: An Ethical Editorial Dilemma

Cousins, Michael J. MD*; Miller, Ronald D. MD

doi: 10.1213/01.ANE.0000127033.05715.6E

*Section Editor, Pain Medicine, Anesthesia & Analgesia, and Pain Management Research Institute, Royal North Shore, St. Leonards, NSW, Australia; and †Editor in Chief, Anesthesia & Analgesia, and Department of Anesthesia and Perioperative Care, University of California, San Francisco, California

Accepted for publication February 12, 2004.

Address correspondence and reprint requests to Ronald D. Miller, Editor in Chief, Anesthesia & Analgesia, Department of Anesthesiology, University of California, San Francisco, CA 94143.

Editor's note: Please refer to the editorial by Yaksh and Allen (pp. 1509–11) and the articles by Tucker et al. (pp. 1512–20 and 1521–7), Johansen et al. (pp. 1528–35) and Yaksh and Allen (pp. 1536–45) in this issue.

This issue of the journal features two large clinical studies on the intrathecal administration of midazolam (1,2). The acceptance of these papers has posed a dilemma for the editors. On one hand, intrathecal midazolam was successfully given for postoperative and obstetrical analgesia with local institutional approval; however a proper toxicology study had not been performed. After considerable debate, we decided that, in the end, publication would bring more benefit to patients than any perceived harm resulting from a process of investigation that was less than ideal. Serendipitously, the dilemma was alleviated by the submission of a large-animal toxicology study (appearing in this issue of Anesthesia & Analgesia) (3) that lessens, but does not entirely resolve, previous concerns about two small-animal studies (4,5) reporting neurotoxicity associated with intrathecal midazolam.

Because of this unusual ethical issue, we have commissioned a Special Article by Yaksh and Allen (6) which reviews the following: the rationale for a spinal action of midazolam; preclinical studies of analgesic efficacy, therapeutic ratio, effects other than analgesia, and neurotoxic potential; and clinical studies of efficacy and safety. Yaksh and Allen were also asked to draw on these data to write an editorial (7) that focuses on the lessons to be learned from the evolving clinical use of intrathecal midazolam. We hope that these two articles (6,7) make it clear that we do not condone the process through which the intrathecal use of midazolam has evolved. However, the fortuitous availability of a well-designed animal toxicology study (3) and two large clinical case series (1,2) made it reasonable to publish the three original studies together with the Special Article and Editorial (6,7). There has been much debate about the publication of the two clinical papers (1,2) and some members of our Editorial Board expressed a contrary view to the one that prevailed.

We should emphasize that the original articles, Special Article, and Editorials in this issue of Anesthesia & Analgesia will not end the debate concerning the status of intrathecal midazolam in humans, but we hope they will serve to clarify issues concerning safe use in humans, in appropriate situations and with appropriate formulations of midazolam. Currently, there is no formulation of midazolam prepared specifically for intrathecal use. In Europe midazolam is available as hydrochloride, which is the predominant form that has been studied. Currently in the United States, the commercially available midazolam is the sulfate preparation, which contains benzoate and is not suitable for intrathecal injection. In the United States, compounding pharmacists are permitted to make up intrathecal solutions of single drugs or multiple drugs. They are used to doing this—chemotherapy in cancer treatment is an example. However, with chemotherapy there is usually a detailed protocol for formulation provided by the manufacturer. There are currently no such protocols for midazolam, although data now available may permit their development in the near future. It is crucial that we learn the lessons of formulation and the delivery methods related to neurotoxicity associated with intrathecal chloroprocaine, lidocaine, and large dose morphine. Thus, at a minimum, intrathecal preparations of midazolam, or any other drug, must meet the following criteria: stability of formulation, with no precipitation; availability from a source with confirmed good manufacturing process origins; formulation in a media compatible with intrathecal delivery, avoiding additives such as inappropriate buffers, excipients, solubility enhancers, and antioxidants; and formulations free of microbial contaminants and endotoxins. “Preservative free” does not equate with “safe for intrathecal administration,” since, apart from preservatives, any or all of the foregoing components may or may not be present. In particular, care should be taken to avoid endotoxins, which are not filtered out by “in line” microbial filters. At a minimum, the pharmacist should test each batch of drug powder for endotoxins. Finally, data need to be obtained for using midazolam with other drugs, not only with respect to formulation, but also with regard to efficacy and safety, particularly neurotoxicity.

In conclusion, we decided, with difficulty, that the confirmation of two large clinical series, a toxicology study, a Special Article, and two Editorials will provide an important contribution to the literature. The editors hope that the lessons learned from midazolam will ensure a more logical development of future candidates for intrathecal drug delivery.

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1. Tucker AP, Lai C, Nadeson R, Goodchild CS. Intrathecal midazolam: I. A cohort study investigating safety. Anesth Analg 2004;98:1512–20.
2. Tucker AP, Mezzatesta J, Nadeson R, Goodchild CS. Intrathecal midazolam: II. Combination with intrathecal fentanyl for labor pain. Anesth Analg 2004;98:1521–7.
3. Johansen MJ, Gradert TL, Satterfield WC, et al. Safety of continuous intrathecal midazolam infusion in the sheep model. Anesth Analg 2004;98:1528–35.
4. Malinovsky JM, Cozian A, Lepage JY, et al. Ketamine and midazolam neurotoxicity in the rabbit. Anesthesiology 1991;75:91–7.
5. Erdine S, Yucel A, Ozyalcin S, et al. Neurotoxicity of midazolam in the rabbit. Pain 1999;80:419–23.
6. Yaksh TL, Allen JW. The use of intrathecal midazolam in humans: a case study of process. Anesth Analg 2004;98:1536–45.
7. Yaksh TL, Allen JW. Preclinical insights into the implementation of intrathecal midazolam: in humans: a cautionary tale. Anesth Analg 2004;98:1509–11.
© 2004 International Anesthesia Research Society