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Anesth Analg 2004;98:1536-1545
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000122638.41130.BF

PAIN MEDICINE

Editor’s note: Please refer to the editorials by Cousins and Miller (pp. 1507–8) and Yaksh and Allen (pp. 1509–11) and the articles by Tucker et al. (pp. 1512–20 and 1521–7) and Johansen et al. (pp. 1528–35) in this issue.

The Use of Intrathecal Midazolam in Humans: A Case Study of Process

Tony L. Yaksh, PhD, and Jeffrey W. Allen, PhD

Department of Anesthesiology, University of California, San Diego, La Jolla, California

Address correspondence and reprint requests to Tony L. Yaksh, PhD, Department of Anesthesiology 0818, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0818. Address e-mail to tyaksh{at}ucsd.edu


   Abstract
Top
 Abstract
Introduction
 Rationale for Spinal Action...
 Conclusions
 References
 
Early preclinical work demonstrated the potential role of spinal benzodiazepine pharmacology in regulating spinal nociceptive transmission. We review this preclinical activity and the evolving implementation of intrathecal midazolam in humans for pain management. Important elements in this development for use in humans are issues pertinent to safety and the preclinical reports that have increased our understanding of intrathecal midazolam toxicity. We seek to emphasize the time course of these studies and how they merged to provide enabling data that drove the clinical implementation. In the case of midazolam, we point to the potential issues that arose when preclinical safety data were unreasonably ignored and how consideration of preclinical safety data can serve to facilitate drug development by demonstrating reasonable safety profiles that document the minimal degree of potential risk to the patient. Issues that are of continuing relevance to the use of intrathecal midazolam, including issues of formulation and kinetics, are considered.

IMPLICATIONS:The intrathecal use of midazolam has evolved over 20 years though a combination of preclinical and clinical investigations. We review the time course of this development to define critical elements that should be pursued in reducing the risk associated with the clinical use of a novel spinal drug.


   Introduction
Top
 Abstract
 Introduction
Rationale for Spinal Action...
 Conclusions
 References
 
In medicine we often consider the etiology of rare events by a detailed review of the events noted in a particular case. Such is the circumstance related to the development of drugs for spinal delivery. We here take the opportunity to consider specifically the development of the clinical use of intrathecal (IT) midazolam. This commentary is occasioned by the joint publication of three articles. The first, by Johansen et al. (1), describes a safety study reporting continuous IT midazolam infusion in sheep and pigs for more than 28 days. The second, by Tucker et al. (2), describes an extensive chart review of the status of patients who had received IT midazolam given as a bolus for postoperative pain management. The third article, by Tucker et al. (3), describes a prospective study performed with IT bolus administration of a mixture of fentanyl and midazolam to manage pain in labor and delivery. These are not the first reports on the use of spinal midazolam, but the current merger of the preclinical and clinical literature may lead to a wider implementation of this drug. Consideration of issues associated with the development of this drug may prove useful in future efforts in this therapeutic area.

We note that midazolam is not a new drug. Reported first around 1978 as a relatively water-soluble benzodiazepine (Bz) (4), midazolam is a widely used systemic adjuvant in critical care medicine and in the operating room, delivered for its sedative, anxiolytic, and amnestic effects (5,6). Its systemic actions and Bz pharmacology are well understood. However, it is evident that the safe and logical development of any drug for spinal delivery raises specific questions that extend beyond those asked regarding a drug aimed at systemic delivery and that should be addressed before spinal delivery is undertaken in humans. Among the issues pertinent to the development of any drug for spinal delivery are 1) appropriate rationale for a spinal action justifying its IT delivery; 2) demonstration of analgesic efficacy and side-effect profile after spinal delivery in validated animal models; 3) compatibility and stability of injectate formulation; 4) consideration of local tissue toxicity after spinal delivery in validated animal models; and 5) clinical delivery of the drug. In the following text, we will consider these issues as they pertain to midazolam. In addition, we assert that the logical development of any therapy should proceed so as to minimize the margin of patient risk. Thus, we are interested in considering not only the existing data, but also the historical sequence of the preclinical research that led to the clinical implementation of IT midazolam. The timeline of relevant events in the published literature related to preclinical efficacy, preclinical safety, and clinical experimentation in humans with IT midazolam is summarized in Table 1.


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  		Table 1. Preclinical Efficacy/Toxicology and Clinical Trials for Intrathecal (IT) Midazolam
 

   Rationale for Spinal Action of Midazolam
Top
 Abstract
 Introduction
 Rationale for Spinal Action...
Conclusions
 References
 
The impetus to develop a novel approach is typically based on accidental observations, a logical rationale, or a combination thereof. Early work with gamma-aminobutyric acid (GABA) suggested that it may have an important role in regulating primary afferent, as well as dorsal and motor horn, neuron excitability (7,8). Simple block of GABAA receptor activity (as with picrotoxin or bicuculline) led to evident spinal seizures, showing the intrinsic inhibitory role played by this transmitter/receptor system. The rationale for the use of IT midazolam focuses on the awareness that it is an agonist at the Bz binding site on a subunit of the pentameric GABAA receptor (9). Agonist occupancy of the Bz binding site enhances the activity of GABA at the GABAA receptor (10). This receptor is a chloride- ionophore that, when activated, typically stabilizes the transmembrane potential at or near the resting potential. In neurons, this typically serves to decrease excitability. In primary afferent terminals, a modest depolarization is observed that serves, paradoxically, to reduce the transmitter release, e.g., a form of presynaptic inhibition (11). Consistent with these effects and Bz subunit expression in dorsal root ganglia and on spinal neurons (12,13), Bzs tend to suppress afferent evoked excitation in the substantia gelatinosa and motor horn (11,14). There is reasonable logic and extensive preclinical work suggesting that Bz agonists exert an inhibitory effect on spinal sensory and motor excitability.

Preclinical Studies with IT Midazolam
Analgesic Activity and Profile.
Given a rationale suggesting an interactive role for GABA receptors in spinal function and given the water-soluble formulation of midazolam, direct spinal delivery was undertaken in animal models. In the peer-reviewed literature, the first reports of spinal midazolam were by Whitwam et al. (15) and Niv et al. (16), who, in anesthetized dogs, showed a reduction in small afferent evoked somatosympathetic reflexes with no effect on resting arterial blood pressure. These findings were later confirmed by others (17). On the basis of the appreciation of the role of GABA in regulating motor tone, Muller et al. (18), using unanesthetized spinally-catheterized cats, reported an antispasticity effect of IT midazolam with little effect on normal motor function. Targeting pain behavior, Goodchild and Serrao (19) reported that IT midazolam altered electrical thresholds for evoking agitation behavior in rats. This initial report was followed by many others (Table 2). By 1995, more than 20 peer-reviewed articles had appeared wherein IT midazolam was demonstrated to have antinociceptive effects in rats, rabbits, and sheep. Analgesic efficacy had been demonstrated in models of acute (electrical stimulation and acute thermal escape), inflammatory somatic (formalin test), and visceral nociception (Table 2).


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  		Table 2. Summary of the Preclinical Analgesic Profile of Intrathecal (IT) Midazolam
 
Analgesic Efficacy.
An important issue in these analgesic studies is that of apparent efficacy. Inspection of the reported data suggests that in acute reflex models, such as the tail-flick model, there is a dose-dependent increase in latency at doses that are less than those required to produce motor dysfunction. Nevertheless, maximum analgesic effects may not occur until doses are achieved that have degrading effects on motor function. Thus, in the rat, significant motor impairment with IT midazolam is routinely reported at or around 100 µg/10 µL. IT midazolam doses in the range of 10–30 µg will block Phase 2 of the formalin test but will yield only a 50% increase in the tail-flick response latency. (See for example Ref. 20.) Although drugs such as µ-opiate and {alpha}2-adrenergic agonists can produce a significant block on both acute and facilitated pain models at comparable doses, a preclinical profile similar to that reported for midazolam has been noted with other IT drugs, such as adenosine A1, GABAA and GABAB agonists, NK-1 and N-methyl-D-aspartate (NMDA) antagonists, and N-type calcium channel blockers (21,22).

Effects on End-Points Other Than Analgesia.
The earliest work emphasized that IT midazolam had no evident effect on spontaneous autonomic outflow at the doses examined (15). IT midazolam in the rat produced a limited increase in the apneic threshold, presumably reflecting a supraspinal redistribution (23). Sedation has typically been reported with larger doses and also reflects a nonspinal action. The most evident functional deficit secondary to a spinal action is the reversible degradation of motor coordination and strength (16,20,24). The effect on other spinal systems, such as those regulating micturition or gastrointestinal motility, has not been reported. Importantly, all observed effects reported after IT midazolam showed reversibility consistent with the time course of drug action.

Therapeutic Ratio.
The therapeutic ratio reflects the dose required to produce a significant analgesic effect versus that which produces a side effect. The absolute ratio depends on the analgesic test stimulus strength and the side effect examined. Thus, the analgesic therapeutic ratios for the formalin test (at a near maximally effective inhibitory dose)—namely, motor effects in rodent models for IT midazolam (100 versus 30 µg = 3)—are somewhat less than those which might be seen with IT morphine (60 versus 10 µg = 6) but are similar to those observed for clonidine (60 versus 30 µg = 2) (25); NMDA antagonism (MK801, 30 versus 10 µg = 3) (26) or superior to that noted with N-type calcium channel blockers (ziconotide, 1 versus 1 µg = 1) (27) or baclofen (1 versus 1 µg = 1) (24). Alternately, by a spinal action, IT clonidine yields hypotension (28), and morphine can inhibit the volume-evoked micturition reflex (29). In those spinal end-points, the preclinical therapeutic ratio may be somewhat better for midazolam. Note that this analysis of the side-effect profile does not reflect the effects of IT drugs if and when they undergo extraspinal redistribution.

Analgesic Pharmacology.
Importantly, these preclinical effects on analgesia and motor function in rats, rabbits, cats, dogs, and sheep have displayed reversal with Bz antagonists such as flumazenil (16,30–32) and not typically by naloxone (but see Ref. 33), suggesting that IT midazolam acts on the Bz binding site of the GABAA receptor. Drug interaction studies have shown potentiation of the antinociceptive effects of midazolam with IT local anesthetics (34), morphine (35,36), and clonidine (20). Interestingly, the nature of the interaction between midazolam and opiates has been reported to be dose-dependent, with inhibitory effects being observed at larger doses, consistent with a reported suppression of opiate binding (37). Countering actions of spinal and supraspinal midazolam on morphine interactions have also been reported (38). The significance of these several studies is not known. In addition, the positive synergy noted above for midazolam is not likely limited to its analgesic actions. Although there are no systematic IT studies, preclinical systemic data support the enhanced respiratory depression and lethality associated with midazolam in combination with an opiate (39–41). The interactive effects of midazolam with other analgesic drug classes on various autonomic and motor functions are largely uncharacterized at present.

By 1986–1987, the preclinical literature had shown that IT midazolam had analgesic effects in a variety of species and models (Table 1). These effects were dose-dependent and displayed a Bz pharmacology. In terms of therapeutic ratio, these drugs at analgesic doses had no evident effects on normal autonomic or behavioral (motor) function, and side effects at slightly larger doses were similar to those observed after systemic delivery, e.g., sedation and reduced motor tone. These profiles and therapeutic ratios compared favorably with the side-effect profiles for other classes of spinally-delivered drugs, some of which, such as opiates, {alpha}2 agonists, and N-type calcium channel blockers, were shown to be effective in human pain states. The analgesic and nonanalgesic effects of IT midazolam over the doses examined showed a reversal, the time course of which suggested a loss of pharmacological effects with clearance of the drug, e.g., an absence of any irreversible effect after bolus delivery.

Midazolam Formulation
At present, it is generally conceded that a water-based formulation is a minimum criterion for spinal compatibility (42). Midazolam is a weak water-soluble base. Its solubility in water is pH dependent, such that at pH 3.5–3.9, concentrations of approximately 5 mg/mL are achieved. This solubility decreases rapidly to less than 1 mg/mL at pH 4.5–5 (43). Accordingly, commercial formulations of this product are provided as midazolam HCl in stock concentrations of 5 mg/mL titrated to pH 3.4–3.6. These solutions are then diluted in relatively large volumes of slightly less acidic (pH 5–7) preservative-free sterile saline or water for injection. Early formulations of midazolam contained benzyl alcohol, although current formulations are routinely preservative-free. Given this pH-dependent solubility, initial reports, not surprisingly, pointed to cloudiness when the stock drug was dissolved in human cerebrospinal fluid (CSF) (44). It is reasonable to expect that mixing of stock midazolam 5 mg/mL into CSF-like solutions buffered at approximately 7.3 could also lead to precipitation (cloudiness) (45) if the resulting concentrations are incompatible with the resulting less acidic pH. It should be further stressed that the use of multiple adjuvants can have untoward interactions regarding formulation stability (46). Drug admixtures with midazolam in general have not been well studied, and the likelihood of unfavorable interactions must be anticipated until proven otherwise.

Safety Evaluation of IT Midazolam
The spinal delivery of drugs requires an assessment of whether the formulation has any effect on spinal function secondary to local pathology—e.g., is it safe for the local tissue? This issue is distinct from events that are secondary to changes in physiological function, such as respiratory depression. Definition of such a lack of toxicity is based on the absence of irreversible changes in function after removal of the drug and no evident changes in spinal morphology. Five principal points constitute a robust preclinical safety assessment. These are as follows: 1) the route of delivery must match that to be used in humans; 2) the test article must match the human formulation; 3) the concentrations to which the cord is exposed and the duration of drug exposure (e.g., exposure factor) must equal or exceed those to which the human spinal cord will be exposed; 4) the preclinical model must have kinetics that produce local drug concentration exposures that resemble those obtained in humans; and 5) the preclinical model must have the demonstrated ability to distinguish drug treatments in producing pathology. Because toxicity is generally considered to be proportional to the local concentration of the drug and the duration of exposure, the certainty of the lack of toxicity in the animal model is enhanced by the use of the largest available concentration of the formulation to be used in humans along with repeated or continuous delivery (47,48). With regard to the animal model, the enabling studies may require a chronic catheter that invites a spinal reaction on its own. Accordingly, the assertion of an absence of drug effect depends on the lack of difference in histology observed after treatment with the drug or vehicle. When vehicles other than saline or a normal CSF-like infusate are used, additional studies must be undertaken to demonstrate a lack of effect of the vehicle versus a true control (e.g., saline). Finally, in the course of work with the model, it should be possible to have shown at some point that the model can indeed display a relevant toxic reaction. These criteria are particularly important when the respective studies report no difference between a given drug and the vehicle. To the degree that these several attributes are met, we can assert that there has been a robust assessment of toxicity for that treatment.

Behavioral Indices of Toxicity.
As reviewed above in the preclinical literature, all changes in measured sensory and motor function after IT delivery of up to 0.1 mg of midazolam in the rat have all been reported to be reversible by Bz antagonism or over kinetically expected time intervals, e.g., approximately three times the dose required to produce analgesia. These effects are thus representative of reversible changes in motor function consistent with an inhibitory effect on spinal motor neurons. In rabbits (0.3 mg) and dogs (1–2 mg), the respective doses yield a time-dependent reversible antinociception, but extensive supraanalgesic test dosing has not been reported.

Tissue Toxicity.
With respect to the effects of IT midazolam on spinal morphology, there have been relatively few articles, and the effects have been controversial. Published evaluations of IT midazolam safety are presented in Table 3. The first systematic safety evaluation was reported by Muller et al. (18) and Gerlach et al. (49) in cats, where bolus delivery of concentrations of 1.35 mg/mL was undertaken. Although little detail is provided, the authors indicated that this approach was without deleterious histological effects, and thus the study provided the safety data for their subsequent human investigations with IT midazolam infusions. Five years later, Malinovsky et al. (50) reported the effects of midazolam given by a single percutaneous puncture intracisternally in rabbits. Midazolam (1 mg/mL) produced histological pathology that exceeded that resulting from lidocaine or saline. Erdine et al. (51), using rabbits, delivered lumbar midazolam (1 mg/mL) and also observed pathology that exceeded that in the saline group. Importantly, in subsequent studies, Malinovsky et al. (52,53) demonstrated with this rabbit model that other drugs (ketamine and bupivacaine) were, in contrast to the midazolam effects, without toxicity. Also important in these later studies is the absence of toxicity despite hypotension, a point often raised in criticism of the earlier midazolam investigations (54). These observations indicate that the model as used by these investigators can detect differences between drug treatments other than saline vehicle. Bozkurt et al. (55) delivered midazolam epidurally in neonatal rabbits. In those studies, an acidic saline vehicle control (matching the pH of the midazolam) was used, and pathology was observed with the acidic vehicle formulations that exceeded the pathology observed with a nonacidified vehicle. A single rat study by Bahar et al. (56) was a rigorously controlled assessment wherein daily dosing of several drugs was undertaken for 15 days. Importantly, the midazolam-, fentanyl-, and lidocaine-treated groups were not different from saline, whereas pathology was observed in a group that received IT phenol. This study is notable because, although it failed to observe any toxicity with several drugs, it did demonstrate the ability of the model to show pathology with the phenol exposure. Accordingly, this was also judged to be a robust and controlled investigation.


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  		Table 3. Summary of Preclinical Intrathecal (IT) Midazolam Toxicology
 
Aside from the early cat study, no systematic investigation of safety in large-animal models was undertaken until this year. A cat study used an acute exposure of a cord with an open dura and did not provide interpretable data. Johansen et al. (1) reported the effect of continuously infused midazolam at the rate of 3 mL/d in concentrations of 1.6 or 5 mg/mL in sheep and 5 mg/mL in pigs, producing a total daily dose of 5 or 15 mg of midazolam. This exposure occurred over 43 days in chronically catheterized sheep and in a smaller cohort of pigs. In these studies, multiple midazolam concentrations up through the maximum available concentration (5 mg/mL) were without toxicity as compared with normal saline vehicle controls (pH 5.4; range, 4.5–7) when assessed by behavior and systematic histopathology. It is important to note that the vehicle animals displayed a moderate reaction, which was attributed to the catheter and not to the drug infusate.

Through 1999, aside from the initial cat study by Muller et al. (18), which is often not cited, there were two well defined single-injection rabbit studies that reported evident toxicity in excess of vehicle and a multiple bolus study in the rat (50,51). In the present issue, we now see the report with chronic infusion in the sheep and pig, in which treatment effects were not different from an appropriate vehicle. The failure of IT midazolam, in concentrations up to that which is commercially available, to initiate tissue toxicity in three species with extended exposure now provides substantive support for the assertion of safety within the range of the experimental designs. Nevertheless, caution must be used, because the rabbit studies cannot be simply discarded out of hand. Thus, while the rabbit data in general, and the Malinovsky et al. study (50) in particular, are dismissed because of the unique intracisternal approach (2,3), consider the following: 1) toxicity was observed in the context of an appropriate vehicle treatment; 2) unlike studies with a catheter, the Malinovsky et al. studies had no chronic reaction in their vehicle-treated animals, as is the common case with chronic delivery studies; 3) the intracisternal model in that laboratory has been shown to be capable of showing no toxicity with other treatments; and 4) the midazolam effects in rabbit were replicated by Erdine et al. (51). Perhaps not incidentally, Malinovsky et al.’s work in the rabbit with cisternal delivery leading to hypotension likely points to physiological events that may yet transpire with unintended supraspinal redistribution.

Initiation of Clinical Studies with Spinal Midazolam
In humans, early work after the preclinical literature focused on the management of spasticity. Here, Muller et al. (18), in animals and then in clinical studies, observed that spinal midazolam could exert a favorable regulation of spasticity. In a well controlled clinical case series, 12 patients showed significant management of spinal spasticity after epidural infusion of midazolam. Importantly, there were no adverse clinical signs. In the following year, Goodchild and Noble (57) performed a clinical study in anesthetized patients to study the effects of IT midazolam on perioperative evoked autonomic responses. As with the results reported by Whitwam et al. (15) in dogs with approximately 1 mg IT, there was a block of the autonomic responses to surgical manipulation, with no effect on resting variables. Since the initial reports, there has been a continual increase in published clinical work with IT midazolam. In a PubMed search for IT midazolam, there have been 18 peer-reviewed reports with an estimated total of 797 patients having received bolus injections of spinal midazolam and 17 having received continuous infusions since 1986. Of these studies, 6 represented controlled trials. Most of these perioperative reports typically involved the admixture of midazolam in doses first reported in the dog work of 1–2 mg delivered in volumes of up to several milliliters with an opiate and/or bupivacaine (Table 1). As outlined in Table 1, midazolam delivered to humans has been reported to have significant positive actions on acute (postoperative) and chronic (cancer and neuropathic) pain, as well as spasticity, in humans. Importantly, these studies suggested, as did the preclinical literature, that there were proanalgesic interactions between the Bz and other analgesics, including spinal anesthetics and opiates, and that the combination of midazolam with IT drugs, such as morphine and clonidine, in humans appeared to have a greater analgesic efficacy.

The overall perusal of this clinical literature emphasizes that the typical effects are characterized by an increased duration of motor and sensory block, an increased time to first analgesic request, and/or a decrease in the postoperative analgesic requirement. Importantly, as in the preclinical literature, there appeared to be no reported increase in adverse signs, such as hypotension, bradycardia, time to micturition, or altered incidence of nausea/vomiting, as compared with the groups not receiving midazolam. Tucker et al. (3), in the article published in this issue of the journal, considering the postoperative incidence of neurological signs (e.g., pain/weakness or bowel and bladder function) in 547 patients receiving IT midazolam as an admixture, could find no differences between treatments. It is argued that the study was so powered as to be able to detect the incidence of dysfunction that would occur with spinal lidocaine. Hence, it can be argued that in this case review, midazolam does not exceed the potential clinical toxicity associated with IT lidocaine.

The clinical literature emphasizes that the addition of midazolam in doses of approximately 1–2 mg IT has positive effects on perioperative and chronic pain therapy. Current reports suggest that the use of midazolam in a dose not exceeding 1–2 mg at concentrations not exceeding 1 mg/mL, delivered either alone or as an IT adjuvant, is not accompanied by an increase in the incidence of adverse events. Consideration of the sequelae of the experience of a large population of patients over an interval after the use of perioperative midazolam suggests no evident deleterious neurological effects under these conditions.


   Conclusions
Top
 Abstract
 Introduction
 Rationale for Spinal Action...
 Conclusions
References
 
Utility of Preclinical Models
The evolution of spinally-delivered drugs in humans has arisen because of the insights provided by systematic preclinical studies. These studies, examining the effects of IT administered drugs in rats with chronic catheters and studied in well defined behavioral models, have permitted us to define the role of the spinal cord in the encoding of nociceptive information and to define the pharmacology of spinal pain processing. This approach has served to efficiently identify the analgesic characteristics, the side effect profile, and the pharmacology of all drugs currently used IT in humans, including µ and {delta} opiates, {alpha}2-adrenergic and adenosine A1 agonists, N-type calcium channel blockers, cyclooxygenase (COX) inhibitors, and Bzs (22,48,58). Larger-animal models (dog and sheep) have similarly been useful in defining the kinetics of these spinally-delivered drugs (88). Finally, preclinical models focusing on safety have effectively defined deleterious IT drug-induced changes that occur in humans (e.g., granulomas and demyelination) (89–91). The present cumulative experience with IT midazolam across species broadly confirms the predictive utility of the preclinical approach to define prospectively the analgesic activity of the molecule and its Bz pharmacology, the lack of prominent autonomic and motor side effects, and the lack of irreversible effects.

Missteps in IT Midazolam Development
Where, then, were the missteps in this development of midazolam, and where, accordingly, was the patient placed at unnecessary risk? We see three technical points.

1. Assessment of Safety.
The principal fallacy pertains to the lack of an adequate assessment of safety. No one knowingly seeks to deliver a therapy that leads to unintended morbidity. However, the work with IT midazolam in humans has largely depended on the lack of an untoward behavioral effect in the numerous animal studies. We recognize that persistent deterioration of behavior may indicate a toxic parallel, but the converse is not invariably true. The partial convergence between persistent deterioration of physiological function and indices of spinal injury emphasizes the importance of assessing spinal histopathology in defining safety. This lack of absolute convergence emphasizes why functional observation alone in humans or animals is a necessary, but inadequate, index of safety. That this fallacy persists is evident in the very title of the article by Tucker et al. (2), implying the safety of IT midazolam. Although it is possible that the absence of behavioral change may imply an absence of tissue effects, the only definitive proof of this is in the examination of tissue.

The current development of midazolam’s safety depending on behavior also suffered from the fact that these pharmacological studies are inadequate definers of safety, because they have as their aim defining pharmacology and not drug toxicity. Aside from the absence of systematic examination of the spinal tissues, these studies, whether in animals or in humans, are not adequate as safety evaluations for several reasons. 1) Pharmacological studies seek to address drug actions over the linear range of the dose-response curve. and larger doses or concentrations are not frequently assessed. 2) Chronic or multiple exposures over a short interval are not routinely undertaken. 3) A pharmacological investigation may not use the formulation that is being targeted for human use. Accordingly, targeted safety evaluations, such as those undertaken by Malinovsky et al., Bahar et al., Erdine et al., and, more recently, Johansen et al., are essential. They should be seen not as an obstacle to the evolution of therapy nor dismissed as irrelevant to the human condition, but rather as an important component necessary for safe and rational drug development.

2. Clinical Trials and Preclinical Observations of Toxicity.
Although performing a clinical trial with a novel drug without safety data may be wrong, ignoring data asserting toxicity is absolutely irresponsible. This, however, is the scenario that played out with the rabbit toxicity work (50,51). Had the clinical proponents of IT midazolam been so inclined, should they have attempted to provide countering experimental data rather than simply to mount verbal dismissals? It is sophistry to argue that because the model was inadequate, its results should be ignored. If the results should be ignored, then that still leaves no study asserting safety, and alternate studies should have been undertaken. Until the present work in sheep and pigs (1), the Bahar et al. (56) rat data notwithstanding, one could reasonably assert that every one of the 800 patients reported to have received midazolam, not to mention those not reported, was a true experiment presenting a scenario entailing needless risk to the patient. This limitation has now been in part rectified with the Johansen et al. (1) study. Happily, it seems that, at the concentrations examined, midazolam alone indeed has no distinguishing pathology. We must still puzzle out the implications of the rabbit studies. Are the rabbits really showing an unusual, model-dependent effect, or is there something representative of an underlying property of the injectate that is yet to play out in the human condition? The important message here is that the benefits to patient safety accrue in full only when the preclinical safety evaluation precedes the clinical trial.

3. Limitations of the Current Data Set.
The safety studies examine midazolam alone, yet considering the studies outlined in Table 1, the routine application of this drug is invariably in combination with other drugs. We still have no certainty as to potential drug interactions. Our concerns may be somewhat assuaged, as it is for other drugs such as morphine, by the fact that the IT mixtures involve drugs that are widely used (e.g., fentanyl and bupivacaine). However, let us be reminded that admixtures with midazolam, unlike morphine, involve a drug with an extreme pH dependency. The likelihood of precipitates and altered bioavailability (e.g., kinetics) has yet to be addressed. This issue may emerge when, as will inevitably occur, admixtures in large concentrations are placed in infusion pumps.

Given the above caveats, we must conclude that, save for the several missteps, the progression of the data has led us to the present collection of observations that support the assertion of a degree of safety for this modality within the doses and concentrations examined. Let there be no mistake, however. This approach remains one with which a great deal of experience remains to be garnered, and considerable vigilance should be exercised. We again remind the practitioner of the words of Paracelsus: "There is no safe drug, only safe doses."


   References
Top
 Abstract
 Introduction
 Rationale for Spinal Action...
 Conclusions
 References
 

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Accepted for publication February 2, 2004.




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