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EDITORIAL

Intrathecal Nalbuphine After Cesarean Delivery: Are We Ready?

Tony Yaksh, PhD^*, and David J. Birnbach, MD

Departments of Anesthesiology, *University of California, San Diego, California; and St. Luke’s Roosevelt Hospital Center, New York, New York

Address correspondence and reprint requests to David J. Birnbach, MD, Department of Anesthesiology, St. Luke’s Roosevelt Hospital Center, 100 Tenth Ave., New York, NY 10019.

This issue of Anesthesia and Analgesia contains an article by Culebras et al. (1) reporting on the effects of intrathecal nalbuphine plus bupivacaine for cesarean delivery. While we applaud the study of novel drugs and techniques, the issue of the safety of this and other new intrathecally administered drugs, especially in the obstetric population, is of concern. Although the authors have included a disclaimer about the relative lack of safety data about intrathecal nalbuphine, one reviewer has suggested that any article that investigates an intrathecal drug before it has adequate safety data should be automatically rejected for publication. Ultimately, the decision was made to publish this article along with an accompanying editorial so that the relevant issues of neurotoxicity and ethical concerns could be brought into perspective. Although the publication of this paper might be considered by some as condoning safety lapses, we believe that this publication will provide an important forum for alerting the clinical community to several important issues. This editorial will stress two areas of concern with the Culebras et al. (1) article. First, do we know enough about the safety of intrathecal nalbuphine to study it in humans? Second, what information needs to be available before we study new spinal drugs in pregnant patients?

Nalbuphine the Drug

Nalbuphine is an opioid (393 Da) structurally related to oxymorphone. It is a highly lipid soluble opioid with activity that suggests an agonist action at the opioid receptor and activity as an antagonist at the µ-opioid receptor (2,3). Nalbuphine and other agonists have provided reasonably potent analgesia in certain models of visceral nociception (4). They demonstrate complicated interactions with µ opiates that suggest dose-dependent synergies and significant antagonisms at larger doses (5), but they have a short duration of action, consistent with their lipid solubility and rapid clearance. Initially, the advantage of such drugs given systemically was considered to be a reduced likelihood of respiratory depression. Later, their utility as adjuvant therapy was considered in terms of their ability to produce an antagonism of the side effects attendant to spinal opiates, e.g. respiratory depression, pruritus and urinary retention—events that were considered to be reflective of the actions of spinal µ-opioids (6–8). More recently, the exciting possibility has been offered that agonists may show an unexpected activity in female patients, suggesting a clinically relevant sex difference toward efficacy (9).

Spinal Nalbuphine Studies in Human: An Historical Perspective

It has been reasoned that spinal nalbuphine should demonstrate an improved therapeutic ratio, consistent with that seen after systemic administration. There have been a few studies (10,11), of varying quality, that have supported the utility of neuraxially administered nalbuphine in managing postoperative pain. The general trend of these reports is that epidural or intrathecal delivery of nalbuphine produces a significant analgesia accompanied by minimal pruritus and respiratory depression.

The Culebras et al. (1) Study

Because nalbuphine has been studied in orthopedic patients (11), why not use it for obstetric patients undergoing operative delivery? This question presumably led Culebras et al. (1) to address the analgesic action of nalbuphine after cesarean delivery as reported in this blinded, randomized and well designed study. Several indices of efficacy were reported, and side effects were appropriately considered. Although the addition of bupivacaine to the nalbuphine produced an inherent complication of interpretation, this local anesthetic was administered equally in all groups. Unfortunately, no group received local anesthetic alone for comparison. The results of this study suggested that bolus injection of an optimal dose of intrathecal nalbuphine (0.8 mg) produces an analgesia that does not last as long as morphine, but that is associated with a lower incidence of nausea and pruritus.

So What’s the Issue?

Everything in medicine has an associated risk-benefit issue. The higher the risk, the greater the benefit must be. The population in question (young healthy parturients) lies to the extreme in terms of the criteria for safety and lack of morbidity. Thus, let us consider the potential benefits and risks.

Risk-Benefit Ratio of Intrathecal Nalbuphine

The benefits of a new spinal drug may be summarized in terms of improved efficacy, reduced side effects, and improved duration of action. With regard to efficacy, the Culebras et al. (1) study indicates that, at the doses used, there is the ability to achieve a comparable effect, though not greater, to using several hundred micrograms of intrathecal morphine. Reduction of opioid side effects with improved patient satisfaction and recovery times is desirable with any anesthetic technique. In this regard, intrathecal nalbuphine at an appropriate dose may be better than morphine. However, consistent with nalbuphine’s physical chemistry (its lipid solubility lies between alfentanil and sufentanil), a limited duration of action is expected for intrathecal nalbuphine as has been evident in this and previous studies. In addition, all of the advantages of intrathecal nalbuphine may be achieved by the use of appropriate doses of spinal morphine and the adjuvant use of systemic nalbuphine, when required.

So much for advantages, what about the risks? After the spinal delivery of a drug, there are two concerns. First, does the drug have systemic effects that may lead to significant side effects? Intrathecal morphine produces respiratory depression and urinary retention, whereas clonidine causes hypotension. These effects have to do with mechanisms related to the role played by the opiate and ₂ adrenergic receptor in the brainstem and spinal cord. Nalbuphine, however, because of its pharmacodynamics, may have fewer side effects. The second and more important question is what are the local effects of the administered drug? Drugs administered into the spinal space have direct access to local tissue and may exert a variety of effects leading to meningeal inflammation, demyelination, and neuronal loss (12).

For a given class of molecules there is no a priori way to determine individual safety without an appropriate, targeted safety study. Moderate changes in molecular structure may alter the safety of a given class of drug. When we assess the "safety" of a given drug for clinical use, a variety of test models are used to define the effects of the drug in the respective organ systems when given by the respective route. After all of the initial in vitro work (cell carcinogenicity, for example), the final consideration of a drug for spinal delivery is to administer the drug into the respective space. As reviewed elsewhere, the definition of the safety of a drug in such models depends on the properties of the model and the degree to which the drug testing has challenged the mechanism that may lead to local spinal toxicity (13). Thus, for any given drug, local toxicity is governed by biophase concentration and duration of exposure. Concentration is reflected by the amount of drug delivered in a given volume. The duration of exposure is defined by the mode of delivery (infusion versus bolus) and by the rate at which the test article is cleared. To the extent that the preclinical model produces high and extended exposure concentrations, we can begin to accept the hypothesis that the drug is without toxicity under those test conditions. It is often said that there are no inherently unsafe drugs, there are only toxic doses.

What are the data reflecting on the safety of intrathecal nalbuphine? From a preclinical perspective, there have been several studies in which the pharmacological effects of nalbuphine have been reported. Such studies however, no matter how well intended, do not constitute safety data. There is a single systematic animal study by Rawal et al. (14) that examined the effects of intrathecal nalbuphine in a dose of 0.75 mg/kg and reported no behavioral or systematic histopathologic abnormalities. Although clearly encouraging, this is not a study of toxicity that can translate to the safety of the intrathecal administration of nalbuphine in parturients. The Culebras et al. (1) study used a single dose of nalbuphine, although the sheep study used repeated dosing. Thus, the exposure factor may have been more severe in the latter. Co-administration of local anesthetic, as was used by Culebras et al. (1) may result in possible toxic interactions and alterations in pH and drug clearance, which have not been previously investigated. Similarly, the use of hyperbaric bupivacaine reduces the rate of drug clearance and, thus, may increase the exposure factor. In this regard, the human exposure in the Culebras et al. (1) study was likely enhanced as compared with Rawal et al.’s (14) animal study.

What about previous clinical experiences? Some will argue that many currently used spinal drugs were never appropriately tested. The use of the newer spinal drugs began approximately 25 years ago, and in the early period, appropriate toxicology studies were not performed for drugs such as morphine. Nevertheless, thankfully, morphine is largely without local tissue toxicity, even at relatively high concentrations. Such historical clinical experience with a particular formulation may thus provide some support for safety. However, it appears that the Culebras et al. (1) study actually used nalbuphine concentrations exceeding those previously reported in humans, hyperbaric solutions, and a bupivacaine mixture (10,11).

What does this mean? In our opinion, the Culebras et al. (1) study should not have been done at this time, on these patients. Although it may be argued that the risks were negligible, we believe that the administration of intrathecal nalbuphine posed an unacceptable risk for a minimal benefit for this population of patients. Even well established drugs such as lidocaine are not without associated risk (15,16). Yet, even in the limited populations studied, the present study appears to use the highest nalbuphine dose/concentrations thus far reported. We believe that our comments are not a knee-jerk judgment, but rather an objective assessment of the facts.

What is Acceptable Risk for a Parturient and How Should the Issue of Informed Consent be Approached?

The Nuremberg Code (17) is a 10-point statement delineating permissible medical experimentation on human subjects that declares that the voluntary consent of the human subject is absolutely essential. According to the code, the person involved "should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in this experiment." In the United States, the Food and Drug Administration requires that an institutional review board ensure that these are appropriate safeguards to protect the rights and welfare of research subjects. In fulfilling these responsibilities, the institutional review board is expected to review all research documents and activities that bear directly on the welfare of the subjects of the proposed research. Is it possible that parturients enrolled in the Culebras et al. (1) study were informed that a drug with unknown potential for neurotoxicity and insufficient testing would be administered, and that even if it provided adequate pain relief, there was little hope of it lasting as long as other currently used drugs? Unlikely. Although the authors of this study state that it was approved by their institution’s ethics committee, were the committee members made aware of the trade-offs involved? Presumably not. Given the potential for risk, the difficulty in obtaining an informed consent, and the perception that consent in the obstetric patient may be invalid because of the presence of pain and stress, some believe that clinical studies should not be performed on obstetric patients (18,19). We do not agree with that sentiment and strongly support the continued use of parturients in clinical studies, but only when the previous knowledge from animal and human data indicates safety and benefit and thus allows the investigator to fully inform the patient of the potential risks.

Where Do We Go from Here?

If one truly wishes to pursue the use of spinal nalbuphine, an appropriate series of preclinical studies should be done to assess the range of safe doses in the corresponding formulations in validated animal models. Unfortunately, there is no simple algorithm for defining how safe a drug must be in animals before using it in humans. We would note that the preclinical studies for a number of spinally delivered drugs have clearly demonstrated safety factors in excess of 10–60 (13). Where nalbuphine falls in this range, no one knows.

In conclusion, we feel that, under the present circumstances, the burden of proof of safety of any intrathecal drug administered to a pregnant patient must be overwhelming. In the case of nalbuphine, the evidence to support its safe use is currently insufficient.

References

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