The Advantages and Limitations of Calmatives for Use as a Non-Lethal Technique

by Dr. Joan M. Lakoski, Dr. W. Bosseau Murray, Dr. John M. Kenny

Pennstate College of Medicine Applied Research Lab Laboratory Pennsylvania State University 3oct00

Dr. Joan M. Lakoski, Dr. W. Bosseau Murray, Dr. John M. Kenny

Executive Summary

The purpose of this study was to assess the potential use of calmatives as nonlethal techniques. This research included 1) defining the advantages and limitations of pharmaceutical agents as calmatives with potential use as non-lethal techniques, 2) providing a comprehensive survey of the medical literature identifying pharmaceutical agents that produce a calm sate and developing this information into a database of me relevant literature on calmatives, 3) providing an in-depth review of selected calmatives identified by the literature search with high potential for further consideration as a non-lethal technique, and L) to identify and provide recommendations on new areas in pharmaceutical drug development that may 2 uniquely meet the requirements of calmatives as non-lethal techniques.

There may be a need for development of non-lethal techniques with a high degree of specificity, se selectivity safety and reversibility ty that world avoid production of a lasting impairment to the subjects) or in individual (s) activating the technique. Pharmaceutical agents, or calmatives. with a profile of producing a cairn-like behavioral state vie re considered highly appropriate for consideration n the design, enhancement, and implementation of non-lethal techniques. While ethical issues are involved with the use of calmatives in this context, consideration of these issues was beyond the scope of this project. The Researchers concentrated on the task of defining the ideal characteristics of a non-lethal calmative technique, conducting extensive literature searches and providing an in-depth analysis of this material. In addition, the Researchers have provided recommendations for The development and use of calmatives and other pharmaceutical agents, including convulsants, as non-lethal techniques.

Pharmaceutical agents considered under the topic of "calmatives" include compounds known to depress or inhibit the function of the central nervous system. Several major classes of pharmacological compounds under this category include sedative-hypnotic agents, anesthetic agents, skeletal muscle relaxants, oploid analgesics, anxiolyrics, antipsychotics, antidepressants and selected drugs of abuse. Drugs which depress the nervous system have a range of effects that are dependent on the dose and duration of drug administered; these physiological and behavioral effects range from amelioration of anxiety; mild sedation, hypnotic effects to coma and death. Pharmaceutical compounds recommended for use as non-lethal cal calmatives will typically not be administered to produce deep sedation or hypnosis; rather, calmatives will be used to relieve anxiety and produce mi d sedation, Moreover, the compounds featured for in-depth discussion in this report, have unique characteristics that offer specific advantages in a non-lethal warfare setting.

The pharmacological effects include consideration of a calmative's route(s) of administration, rate of absorption and distribution, biotransformation and excretion profiles, mechanism of actions. as well as consideration of known side effects, The Importance of data on calm calmatives obtained from both preclinical and clinical research was considered to be vitally needed information in the assessment of a calmative agent. Additional consideration was also given to research with calmatives conducted in patient populations with a range of disruptive behaviors, ranging from treatment of withdrawal from alcohol, alleviation of debilitating anxiety concomitant with social phobia. therapeutic treatment of violent parolees, as wet as others to provide information relevant to the application on of a calmative in an agitated population, riot and/or hostage situation requiring deployment of a non-lethal technique.

The Researchers identified the characteristics of an "ideal' calmative as a nonlethal technique to include:

easy administration adaptable for administration via topical, subcutaneous, intramuscular, or oral routes rapid in onset most likely of short or limited duration production of a approximately the sane magnitude of calm (ranging from a less agitated, groggy, sleepy-like slate to a stunned state of consciousness) in all individuals of similar body mass index and age range the effects should be reversible by a profile of rapid turnover and/or the availability of a selective antagonist to serve as an antidote the compound should be safely administered by an individual and free of prolonged toxicity to the individual(s) receiving the agent only be administered on a temporary basis produce side effects, If any, of short duration. on.

The Researchers noted that in identifying an optimum calmative for use as a non-lethal technique, the choice of agent for application in a field setting would depend upon the situation of the crisis requiring intervention. In this regard, wide ranges of potential agents were considered and it was noted that a series of calmatives with different mechanisms of action, duration of effects and depths of "calm" might be appropriate far development. It was noted that drugs can be tailored to be highly selective and specific for known receptor (protein) targets in the nervous system with unique profiles of bid biological effects on consciousness, motor activity and psychiatric impact.

An extensive review of the medical research literature and several commercial sources of current pharmaceutical Information were searched on topics ca carefully selected far their relevance to calmatives. The CALMATIVE database generated Includes over 7,000 references obtained in conducting this research. These results demonstrated that a large body of highly relevant information is available on calmative agents.

Several classes of compounds were identified from the CA CALMATIVE database as having high potential for use as a non-lethal cal calmative agent and include:

benzodiazepines<br> alpha2-adrenorecptor agonists <br> dopamine D3 receptor agonists <br> serotonin selective reuptake inhibitors <br> serotonin 5-HT1A receptor agonists <br> opioid receptors and mu agonists <br> neurolept an anesthetics <br> corticotrophin-releasing factor receptor antagonists <br> cholecystokinin B receptor antagonists.

The discussion for each category of agent includes identification of specific compounds (typically receptor agonists and antagonists) as well as review of the clinical effects and the mechanism of action. In addition, each class of compounds and specific drugs were discussed In light of their proposed contribution as a nonlethal technique. The Researchers identified several drug classes (e.g. benzodiazepines, alpha2-adrenoreceplor agonists) and individual drugs (diazepam, dexmedetomidine) found appropriate for immediate consideration as a non-lethal technique. Equally important, the Researchers identified many promising new developments that deserve further consideration with high potential as prototypical calmatives with availability in the near future.

It should be noted that the Researchers did no: consider that a particular drug does not currently have a method of administration appropriate for immediate use as a non-lethal technique sufficient to disqualify a compound from further consideration as a non-lethal calmative agent, as the area of drug delivery continues to be a rapidly developing field. The Researchers has directed attention to several promising breakthroughs in improving drug delivery of macromolecular compounds and recommends this issue for further discussion.

Introduction

The Research Objective

The research objective for this project includes the accomplishment of the following:

Define [the advantages and limitations of pharmaceutical compounds as calmatives with potential use in non-lethal techniques.

Provide a comprehensive survey of the medical literature utilizing pharmaceutical scents to produce a calm state with potential for use as a non-lethal technique. This information will provide a current database of the relevant literature on calmatives.

Provide an in-depth review of selected cal calmatives identified by the literature search with high potential for further consideration as a non-lethal technique. • Identify and recommend promising new areas in pharmaceutical drug development that are poised to uniquely meet the requirements of calmatives as non-lethal techniques.

The Subject of Review

Calmatives have potential for use in non-lethal techniques. Currently, the majority of non-lethal techniques involve the use of physical restraint, induction of acute physical pain, or other immobilization strategy. Chemical irritants, which include pepper spray or tear gas, serve to illustrate another series of approaches currently used in situations of crowd control. However, to date, the vast array of pharmaceutical compounds that produce a calm. non-agitated behavioral state, may have potential utility as non-lethal techniques, either alone or in combination will r established approaches described above.

Since the mid-1960s, the availability of these pharmaceutical agents, herein termed "calmatives," have undergone a remarkably rapid phase of growth. Indeed, the premier status of the US pharmaceutical Industry the world markets, combined with the exponential developments in the fields of pharmacology, neuroscience, anesthesia, and biotechnology fields, among others, has brought forth a diverse array of compounds that produce sedation and/or a calm state as either a primary or secondary effect. The challenge of assessing the potential use of calmatives as non-lethal techniques requires an initial screening of a broad array of potential candidates, followed by an In-depth assessment of compounds with features uniquely suited towards use as a non-lethal technique. The approach taken for This report on calmatives as non-lethal techniques was to a) define the characteristics of an "ideal" non-lethal calmative, b) provide a broad-based yet targeted review of medical based literature and commercial databases containing calmative properties with pharmaceutical agents to create a database resource, and c) conduct in-depth literature reviews of drug classes an and prototype compounds which may best meet the profile of a non-lethal calmative technique. In addition, this report highlights several new areas in pharmaceutical drug development with high potential for impact on development of non-lethal techniques.

Contribution of the Report on Calmatives

There is a need for non-lethal techniques with a high degree of specificity, selectivity, safety, and reversibility to avoid producing a lasting impairment to the subjects) or individuals) activating the technique, Consideration of the use of calmatives as non-lethal techniques is both timely and warranted.

There are numerous pharmaceutical agents with a profile of producing a calm-like behavioral state currently available in clinical practice. Moreover, wide arrays of new compounds with unique cellular and molecular mechanisms are under development by the pharmaceutical industry for their ability to produce calm and tranquil-like states of behavior. Therefore, this report serves as an essential first step in identification of calmative pharmaceutical agents with potential utility as non-lethal techniques. The extensive survey of the literature conducted on calmatives serves to emphasize that the "time is right" with respect to considering pharmaceutical agents as appropriate new approaches to be Incorporated in the design, enhancement, and implementation of non-lethal techniques,

In considering the application of calmatives as non-lethal techniques, The Researchers would also like to note that the use of these agents should be considered in an ethical context. While a review of the ethical principles and practices for use of non-lethal techniques is beyond the scope of this report, it is important to note that there are both national and international standards of conduct applicable to the practice of medicine and military conduct that may require consideration in the implementation of a calmative as a non-lethal technique,

Important Observations from Literature Search on Calmatives

Several key observations emerged during the course of conducting extensive literature research on calmatives. First, there is an explosion of new knowledge and developments in pharmaceuticals producing sedation and/or calm behavior as a direct an and/or side effect. This wealth of information Includes rapidly emerging developments it the fields of cellular and molecular biology, neuroscience, psychiatry and anesthesia, among others. Second, the goals of new drug development efforts, namely continued improvement in specificity, selectivity, safety, and reversibility are the goals for improvements in non-lethal techniques. The compounds discussed that are under development by the pharmaceutical industry were selected for these advantages. Thus, new compounds are in "the drug development pipeline" that will have an improved ease of delivery, specific control of duration of effect, specific sites of action and other properties I hat may prove advantageous to design of innovative non-lethal techniques. Third, new classes of pharmaceutical agents and now compounds, are poised to meet the unique requirements of the non-lethal warfare arena. Ultimately, new compounds can be designed to better meet the requirements of non-lethal techniques for use in specific military and civilian situations.

Calmatives - Advantages and Limitations

Define the advantages and limitations of pharmaceutical compounds as calmatives with potential use as non-lethal techniques.

What Is A Calmative?

A wide variety of pharmacological approaches modulate mammalian behavior, including human, non-human primates and rodent species. Pharmacological compounds (or agents) producing a calm or tranquil behavioral slate upon administration are termed "calmatives." n most cases, the state of calm produced will, it part, depend on the existing behavioral state of the individual before the pharmaceutical agent is administered (e.g. agitated, aggressively violent) and the dose and route of drug to be administered, and the pharmacokinetic and pharmacodynamic properties of a given compound,

Pharmaceutical agents to be considered under the topic of "calmatives" will include compounds known to depress or inhibit the function of the central nervous system termed (depressants). There are several major classes of pharmaceutical compounds that fall under the category of depressants including sedative-hypnotic agents, anesthetic agents, skeletal muscle relaxants, opioid analgesics, an anti-anxiety or anxiolytics, antipsychotics, antidepressants, and selected drugs of abuse. These pharmaceutical agents or "drugs" produce their effects by actions targeted to specific targets, typically receptor proteins that are located in the central nervous system, including the brain. While each of these drug classes have diverse mechanisms of effects on their target tissue (the nervous system), the range of drug-induced affects are dose-dependent. Depressant drugs can produce erects that range from anxiolytic, mild sedation, hypnotic and even coma and death as dependent upon the dose of drug administered and its spectrum of pharmacological effects.

Pharmaceutical compounds recommended for use as calmatives with high potential as non-lethal techniques will typically not be administered to produce deep sedation or hypnosis. Those recommended will relieve anxiety and mild sedation. Compounds selected for in-depth discussion will also have features that offer specific advantages in a non-lethal warfare setting (see following section on "An Ideal Non-Lethal Calmative').

Pharmacological Effects of a Calmative

The pharmacological effects of a given compound are critically affected by its pharmacokinetic profile, which include its route of administration, rate of drug absorption and distribution, biotransformation, and excretion, as well as its pharmacodynamic profile, which determines its mechanism of action. For example, in order to understand the pharmacokinetic effects of a cal calmative agent, information is needed on how the drug has access to the brain (e.g. is it absorbed through the skin topics topically). Information on variables which may enhance or inhibit the compound's distribution and/or metabolism (e. g. was the subject ingesting large quantities of alcohol), as well as the ability of the drug to be removed or cleared from tie subject by excretion needs to be established. A critical factor with all drugs, including agents which act on the central nervous system, is their ability to enter the brain. The entry of drugs into cerebrospinal fluids and extracellular space of the central nervous system is restricted by the an arrangement of endothelial cells described as "the blood brain barrier." Not only is the rate of cerebral blood flow an important facto- in allowing a compound to reach the b-sin tissue, but the rate of diffusion of a drug into the central nervous system is affected by the size and the chemical charge or polarity of the agent.

In order to establish the pharmacodynamic profile of a compound, the chemical and physical interaction of a given drug with ifs target tissue must be del nested to understand the mechanism of action at a specific anatomical site in the central nervous system (CNS). Drug action in the CNS includes a critical role for receptors, which are proteins that serve as binding sites for endogenous regulatory ligands, Including hormones arc neurotransmitters. Receptors, and their associated effector and signal transduction systems, act as Ire integrators of extracellular information. Stimulation of a drug at its receptor try an agonist {termed receptor agonist) generally transmits a signal to an individual cell that, in turn; begins a cascade of cellular and molecular effects that alter the regulation of that cell. In turn, the specific effect of a drug on a given receptor may be chemically blocked by a targeted compound (termed receptor antagonist). As will be evident in the discussion of agents identified for use as potential calmatives in a non-lethal warfare setting, the specificity of the agent will be closely linked to actions as a receptor agonist or antagonist. The ability to stop or terminate the effective action of a given calmative may be linked to the administration of a specific receptor antagonist, which wit, in turn, block the actions of the pharmaceutical agent at the target region in the brain or other central nervous system site.

Preclinical and Clinical Information on Calmatives

In order to obtain as complete Information as possible on a given calmative agent with potential as a non-lethal technique, close attention to two distinctly different types of mad medical research literature was deemed essential -- both preclinical and clinical research literature. Each type of research data provides a valuable and unique contribution to our current knowledge of ca calmative agents. Both preclinical and clinical research provides important information vital toward identification of calmatives that may be best suited for use as non-lethal techniques.

In the preclinical arena, research investigations are typically conducted in a variety of models ranging from in vitro isolated cell cultures to recording in brain slices or in anesthetized small animals. Often data obtained In a preclinical research setting is obtained using bacteria or yeast cell models in addition, receptor pharmacology is often established in isolated membrane preparations. Each of these types of preparations allow for the precise quantification of dose-response effects for a drug and provide the opportunity to explore cellular and molecular mechanisms of drug action; such experiments are simply not feasible or ethical in the intact human brain.

Results obtained from research conducted in a clinical setting provide additional information that is vitally needed n assessment of calmative pharmaceutical agents. Firs€. such data is re required to demonstrate that a given drug will provide the desired behavioral effects. Moreover, while effective dose ranges can often he estimated In a preclinical research setting, the doses and routes of drug administration must Ire confirmed in a human population. Likewise, potential toxicities and side effects that may cause se harm to an individual can be identified in a clinical research setting.

An additional feature of clinical literature, with particular relevance to the identification of pharmaceutical agents that may be effective non-lethal calmatives, is the use of research results obtained from specific patient populations. For example, pharmacotherapeutic approaches for the treatment of alcoholism, where patients are often experiencing withdrawal syndromes that include anxiety, agitation, disorientation and hallucinations, have identified serotonergic drugs and benzodiazepines as useful candidates in reduction of these withdrawal symptoms (see Objective 3). The application of serotonin active drugs as psychotropic agents to the treatment of patients suffering from social phobia, anti- anxiety-related disorder characterized by excessive fear in performance or interactive situations involving intensive evaluation by others, identified the effectiveness of treatment -with buspirone and seretonin selective reuptake inhibitors (SSRIs) in these patient populations. Other selected patient populations, including individuals with obsessive-compulsive disorders, attention deficit hyperactivity disorders, or behavioral disturbances with dementia including ng disruptive be behaviors and aggression, provide information directly relevant to the application of a calmative in an agitated population, riot or hostage situation requiring use of a non non-lethal technique.

An Ideal Non-Lethal Calmative

In seeking to identify pharmaceutical agents useful as calmatives in a non-lethal technique, several characteristics may contribute to the profile of an "ideal" agent. The calmative should be easy to administer and adaptable for administration via topical, subcutaneous, intramuscular or oral route. The onset of action for this compound should be fast (seconds to minutes) and most likely of short or of a limited duration (minutes). A given dose of the agent should produce approximately the same magnitude of calm (ranging from a less agitated, groggy, sleepy-like state to a stunned state of consciousness, sleep state, deep steep or light anesthesia) in individuals of similar body mass index and age range. The effects of producing a calm state with this agent should be reversible either by a profile of rapid metabolism and elimination and/or the administration of a selective antagonist specifically designed to block the effects of the administered calmative. The compound should be able to be safely administered by the individual utilising the non-lethal technique and free of any prolonged toxicity to the individual receiving the agent; the calmative should only be administered on a temporary, typically ore lime basis, and therefore produce side effects (headache, nausea vomiting), if any, of short duration. Note that a series of calmatives may be appropriate for consideration with different rent mechanisms of act action, du radon of effects and different depths of "calm."

In identifying an optimum or ideal calm calmative for use as a non-lethal technique, it should be recognized that the choice of agent for application in a field settling would depend upon the situation of the crisis requiring intervention. For example, an individual running towards you with a gun may pose an immediate threat or perhaps be trying to protect you; in contrast w with this immediate threat are a group of hungry refugees that are excited over the distribution of food and unwilling to wait patiently in these two cases the degree of "calm" required is vastly different in magnitude and the target populations are also different, to many cases the choice of administration route, whether application to drinking water, topical ad administration to the skin, an aerosol spray Inhalation rove, or a drug-filled rubber bullet, among others, will depend on the environment. It [s also important to note that a pharmaceutical agent or drug cannot discriminate a target: whoever comes in contact with the agent will experience the intended dose-dependent pharmacological and physiological effects. However, drugs can be tailored to be highly selective and specific for known receptors and their biological effects on consciousness, motor activity and psychiatric profile.

As will be discussed under Objective 4, new and improved methods for administration of pharmacological agents are under continuing development, it should be noted that the fact that a particular drug does not currently have a method of administration appropriate for immediate use as a non- non-lethal technique should not disqualify this compound from present and/or future consideration ns a non-lethal calmative agent. The developments in this arena of drug application/administration will continue to emerge in a rapid fashion.

Required Use of Medical Attention with States of Unconsciousness

It should be recognized that all drugs, including calmatives the: may cause unconsciousness might necessitate medical attention for the following:

Ensure that the subjects did not "go to sleep" in positions that obstruct their airway,

Check for the occasional person who may stop breathing (many medical reasons in the unhealthy, the elderly and very young but very unlikely in fit, healthy soldiers or other individuals who may not be the target population), Avoid injuries due to the fall of "falling asleep" (bump to heat on object or fl floor), r),

Administer an antidote which may require medical attention; and Determine how long to monitor and provide medical alteration as dependent upon the route of Rd administration and dose of the active calmative an and/or anti antidote/selective antagonist.

Specific Advantages of Calmatives Over Other Nor-lethal Techniques

Are there advantages to the production on of a calm state in a non-lethal technique versus the use of blunt trauma and/or compliance through pain? One area of consideration is that blunt trauma has an incidence of organ damage, which may include the eyes, liver, kidney, spleen, heart and brain, that may be permanent or even death. Other methods of inflicting pain or control of an individual are sometimes socially unacceptable. In contrast, a pharmaceutical agent may the administered in a disc rate manner to a selected individual or a drug agent may be selected with a known duration of effect. Moreover, much like compliance produced with blunt trauma or other restraint method, virtually all individuals will respond n a dose-dependent manner. The limitation to the use at calmatives in a non-lethal technique may, therefore, be relatively few.