Preclinical insights into the implementation of intrathecal midazolam: a cautionary tale.

Editor’s note: Please refer to the editorial by Cousins and Miller (pp. 1507–8) 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. I n the present issue of the journal, there are four papers focusing on intrathecal (IT) midazolam: a preclinical assessment of safety in sheep and pigs (1), a population evaluation of postoperative side effects in humans receiving perioperative IT midazolam in combination with local anesthetics and fentanyl (2), a human study examining IT midazolam and fentanyl in labor (3), and a review related to the issues pertinent to the development of the use of spinal midazolam (4). These papers reflect a continuing process that began almost 20 years ago. As reviewed (4), insights in the late 1970s regarding the spinal actions of -aminobutyric acid and the pharmacology of the benzodiazepine receptors led to the initial preclinical work suggesting the activity of spinal midazolam in regulating spasticity and pain processing. These insights, given the zeitgeist of the late 1970s, formed by the appreciation of the clinical benefits arising from the spinal delivery of drugs such as opiates and baclofen provided a foundation for considering the spinal delivery of midazolam as a therapeutic approach to manage pain and spasticity. Tempering the enthusiasm for IT therapy, spinal drugs have long been known for having the potential for producing local injury leading to functional deficits. Accordingly, even early work emphasized that the initial delivery of any drug into the human spinal canal must be preceded by some assessments of safety and the assertion of no toxicity. What justifies this emphasis on preclinical work? First, the preclinical models have been reliable in predicting the analgesic efficacy, physiological effects, and pharmacology of IT delivered drugs ranging from opiates through blockers of N-type calcium channels in humans (5,6). Second, they provide a readout of any potential changes in function that are deleterious. Third, they allow a direct examination of the drug-exposed spinal tissue. Ethical issues aside, the first two aims could be achieved by careful titration of doses in humans. Obtaining normal patient spinal tissue for histopathology poses obvious limitations. Why is the third component so important? The principal concern of a preclinical spinal safety assessment is that the drug therapy induces no deleterious changes in spinal morphology. Whereas persistent changes in behavior and function may indicate underlying events, a lack of change in behavior does not exclude underlying tissue pathology. Normal function is at best only a surrogate marker for the absence of underlying tissue effect. Thus, whereas the lack of deleterious or irreversible effects of a treatment upon autonomic and behavioral function is a required aspect of safety assessment, it is not sufficient. Evolving deficits may not be revealed by functional indices for an extended period of time, whereas histological examination demonstrates a continuing event. How then does the evolution of IT midazolam compare with that of other spinal drugs. IT morphine, frequently used in humans since 1978, initially underwent extensive behavioral investigations in species ranging from the rat through the primate. In all instances, the bolus delivery resulted in predictable, reversible behavioral effects. Although anecdotal comments on tissue pathology were made, it was only later that IT pathology was systematically examined after single dosing in primates (7) and repeated dosing in rats, cats (8), and dogs (9). In each case, the studies provided a convergent assertion that bolus delivery was without evident toxicity. In contrast, the first spinal delivery of many drugs such as clonidine, d-ala2d-leu5-enkephalin, and neostigmine were preceded not only by a host of preclinical studies on behavioral and pharmacological characteristics, but also by systematic studies assessing the histopathological effects of the drug (6). Again, in each instance, although the Accepted for publication January 28, 2004. Address correspondence and reprint requests to Tony L. Yaksh, PhD, Department of Anesthesiology, University of California-San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0818. Address e-mail to [email protected].