Issues Regarding the Use of Sedatives in Fisheries and the Need for Immediate-Release Options

The lack of an immediate-release sedative (i.e., one for which no postsedation holding or withdrawal period is required) jeopardizes fish and fisheries research and poses considerable risk to those involved in aquatic resource *Corresponding author: saluski@siu.edu Received March 29, 2012; accepted September 14, 2012 156 D ow nl oa de d by [ So ut he rn I lli no is U ni ve rs ity ] at 0 6: 46 1 2 D ec em be r 20 12 SEDATIVE OPTIONS IN FISHERIES 157 management and the operation of public hatcheries and commercial fish farms. Carbon dioxide may be used as an immediate-release sedative, but it is slow-acting and difficult to apply uniformly and effectively. Tricaine methanesulfonate (MS-222) is easier to apply but requires a 21-d withdrawal period. The lack of an immediate-release sedative approved by the U.S. Food and Drug Administration (FDA) is a consequence of numerous factors, including the complexities of the approval process, the substantial human and monetary resources involved, and the specialized nature of the work. Efforts are currently underway to demonstrate the safety and effectiveness of benzocaineand eugenol-based products as immediate-release sedatives. However, pursuing approvals within the current framework will consume an exorbitant amount of public and private resources and will take years to complete, even though both compounds are “generally recognized as safe” for certain applications by the FDA. We recommend using risk management–based approaches to increase the efficiency of the drug approval process and the availability of safe and effective drugs, including immediate-release sedatives, for use in the fisheries and aquaculture disciplines. Access to safe and effective fish sedatives is a critical need of fisheries researchers, managers, and culturists. Federal, state, private, tribal, and academic fisheries professionals routinely sedate1 fish for transport (e.g., moving them to a captive holding facility, stocking site, or to market), the collection of tissue samples (e.g., scales, spines, gametes, and fin clips) or morphometric data (e.g., length and weight), and the surgical implantation of tags or tracking devices (e.g., for monitoring movement, spawning behavior, or survival). Ideally, a fish sedative will be easy to administer, safe to use, and effective at low doses; provide quick and predictable sedation; offer some analgesia; elicit a state of sedation that is easily managed; have a reasonable margin of safety with respect to oversedation; be usable over a broad range of water chemistries; allow for rapid recovery from sedation and the physiological responses to the sedative; and be inexpensive. Additionally, it is often desirable that the sedative have no withdrawal period, meaning that sedated fish can be immediately released into the wild or taken to market upon recovery (typically referred to as “zero withdrawal” or “immediate release”). Unfortunately, there are few fish sedatives that possess all of these qualities, and at this time there are none that can be legally used in North America without a lengthy withdrawal period. Our objectives were to review the need for immediate-release sedatives, describe the current regulatory process for making such compounds available to fisheries professionals in North America, assess the relative risks associated with the use of two candidate immediate-release sedatives (a benzocaine-based product and a eugenol-based product), and provide recommendations to increase “regulatory efficiency” in 1As discussed by Trushenski et al. (2012), the terms “anesthesia,” “sedation,” and “immobilization” are used somewhat interchangeably in fisheries science, but they actually have distinct definitions. Anesthesia is “a reversible, generalized loss of sensory perception accompanied by a sleep-like state induced by drugs or by physical means”; sedation is “a preliminary level of anesthesia, in which the response to stimulation is greatly reduced and some analgesia is achieved but sensory abilities are generally intact and loss of equilibrium does not occur”; and immobilization generally means the prevention of movement only (Ross and Ross 2008). Although these different definitions may be appropriate under different circumstances, most of the scenarios described herein are best described by the terms “sedate,” “sedation,” and “sedative”; for simplicity, we have used these terms throughout. the area of aquatic animal drug approvals as they pertain to fish sedatives. Specifically, we recommend a risk management– based approach to regulating the candidate immediate-release sedatives and outline a semiquantitative risk assessment which indicates that the proposed uses of these compounds have negligible risk. GENERAL NEED FOR SEDATION WHEN HANDLING FISH Unlike most terrestrial vertebrates, which can be handled without causing significant mechanical damage, fish are particularly vulnerable to external and internal injury during physical restraint. Compared with the epithelium of terrestrial vertebrates, that of most fishes is delicate and prone to damage. The epithelium can be damaged by simply disrupting the protective mucus layer, potentially compromising osmoregulation and predisposing the fish to infection or infestation (Shephard 1994). Fish are innately difficult to handle, and when they actively resist restraint, epithelial damage or other physical injury to the fish or the handler is more likely. If fish are sedated prior to handling, the risk to both fish and handler is greatly minimized. In addition to suffering mechanical damage, fish handled without proper sedation may be physiologically compromised as a result of stress. Stress may be defined as a natural reaction to a negative stimulus culminating in the mobilization and redirection of energy to support the “fight or flight” response (Selye 1950). During the stress response, the maintenance of important but not immediately critical functions is often sacrificed as a consequence of stress hormone release (Barton and Iwama 1991; Barton 2002). In fish, noncritical functions can include osmoregulation, reproduction, feeding, and particularly the exclusion and/or clearance of pathogens (Tort et al. 2004). As a result, stressed individuals may become homeostatically compromised and suffer tertiary consequences of stress, such as increased vulnerability to disease, reduced reproductive performance, and reduced growth (Barton and Iwama 1991; Wendelaar Bonga 1997; Barton 2002; Tort et al. 2004). Beyond the readily quantified physiological consequences of handling unsedated fish, fisheries professionals must consider D ow nl oa de d by [ So ut he rn I lli no is U ni ve rs ity ] at 0 6: 46 1 2 D ec em be r 20 12 158 TRUSHENSKI ET AL. TABLE 1. Attributes of currently available sedatives. Sedative Approved? Limitations Benzocaine No, but can be used under INADa authorization 3-d withdrawal period CO2 No, but FDAb unlikely to use regulatory authority Cumbersome and not all fish respond well Eugenol No, but can be used under INAD authorization 3-d withdrawal period MS-222 Yes for temporary immobilization 21-d withdrawal period aInvestigational New Animal Drug. bU.S. Food and Drug Administration. animal welfare (Huntingford et al. 2006). There is considerable scientific debate as to whether fish are capable of feeling pain or only exhibit nociception2 (e.g., Rose 2002, 2003; Chandroo et al. 2004; Sneddon 2006); the specifics of this debate and its resolution are largely outside the scope of the present review. Regardless of whether fish perceive pain in the same manner as higher vertebrates, with respect to fisheries research, relevant guidelines advise that “investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals” (USPHS 1986; CCAC 2005), “prolonged stressful restraint [without appropriate sedation or anesthesia] should be avoided” (UFR 2004), and “procedures with animals that may cause more than momentary or slight pain or distress should be performed with appropriate sedation, analgesia, or anesthesia” (USPHS 1986). CURRENTLY AVAILABLE SEDATIVES AND THEIR LIMITATIONS Currently, there are few sedative options available to fisheries professionals that are safe, effective, and practical to use (Table 1). Perhaps more importantly, MS-222 (tricaine methanesulfonate [3-aminobenzoic acid ethyl ester methanesulfonate]) is the only compound approved by the U.S. Food and Drug Administration (FDA) and Health Canada for such use in these countries. Two MS-222 products (Tricaine-S and Finquel) are approved in the United States for the temporary immobilization of fish and other aquatic, cold-blooded animals, and one MS-222 product (Aqualife TMS) is approved in Canada for veterinary use only for anesthesia or the sedation of salmonids. Like other local anesthetics, MS-222 is rapidly absorbed through the gills and believed to exert its sedative effect by preventing the generation and conduction of nerve impulses (Frazier and Narahashi 1975), though there is some uncertainty regarding this (Popovic et al. 2012). MS-222 has direct actions on the central nervous system, cardiovascular system, neuro2As discussed by Sneddon (2009), the generally accepted definition of “pain” involves two elements: (1) the perception of stimuli associated with actual or potential tissue damage, referred to as nociception; and (2) awareness of an associated negative emotional experience, sometimes described as discomfort or suffering. It is relatively easy to demonstrate nociception in fish. However, it is impossible to demonstrate what a fish “feels” and therefore whether it can experience pain as it is defined. muscular junctions, and ganglion synapses. Lower doses induce tranquilization and sedation, and higher doses result in general/surgical anesthetic planes (Alpharma 2001). In fish, brief tachycardia (elevated heart rate) occurs within 30 s of exposure, follow