Department of Energy an I National Nuclear Security Administration Service Center JUN 12 2803 CERTIFIED MAIL RETURN RECEIPT REQUESTED Mr. Edward Hammond The Sunshine Project 101 West Suite 607 Austin, TX 78701 Subject: Freedom of Information Act Request #2003?0Ks18 Dear Mr. Hammond: This office is in receipt of your May 20, 2003, Electronic Freedom of Information Act request. You requested Brian Andresen and Patrick Grant?s ?Dose Safety Margin Enhancement for Chemical Incapacitation and Less?Than?Lethal Targeting", Forensic Science Center at LLNL, January 1997 and the contract under which the report was produced. The document is released in its entirety. Also, I am providing you the home page for the National Institute of Justice where you may request under the FOIA a copy of their contract which produced this report. There is no charge for this service. If you have any questions, please contact RoseAnn Pelzner, the FOIA Officer at {510} 63??3l95. Sincerely, Douglas A. Ash Chief of Staff FOIA Authorizing Official Enclosures Albuquerque of?ce Gennantown Clt?ce Nevada Of?ce Oakland Of?ce Po Ba: 5400 Building Mecca PG. Ba: 93513 13th Clair Shem. Suite N-TDD Albuquerque. NM 3? 135-5400 1000 Independence Avenue. at Las Vegas. rw 39:93?85 13 Oakland Cit 9?61? Washington. DC 20585-1290 Dose Safety Margin Enhancement for Chemical Incapacitation and Less~Than?Letha1 Targeting Final Report and Recommendations January 1997 Brian D. Andresen and Patrick M. Grant Forensic Science Center R?Division Nonproliferation, Arms Control, and International Security Directorate Lawrence Livermore National Laboratory Dose Safety Margin Enhancement for Chemical Incapacitation and Less?Than-Lethal Targeting Final Report Executive Summary Over the past three years we have been investigating the feasibility of implementing a new approach to support less-than-lethal technologies. The uses of extremely potent pharmacological agents have been investigated, as well as their delivery to the target under prison disruption crises, hostage situations, law enforcement needs, special military operations, and low intensity con?ict. A review of the most potent and commercially available pharmaceutical compounds was undertaken. Various classes of chemical anesthetic agents were studied, and existing data concerning their potency were compared. Experiments also centered on modes of delivery of the pharmaceutical agent to the target and the stability of these compounds in a weapon system. From this data review, a new combination of pharmaceutical agents and materials was selected for a new pharmaceutical-based less-than-lethal technology. The design of a novel, non- lethal system integrated highly potent fentanyl?based anesthetic compounds, skin penetrating solvents, and timed-release antidotes, all delivered with a small felt pad projectile. It was determined that very small solvent-soaked projectiles could be accurately delivered to a human target using either an air gun or a blank 38- caliber cartridge, ?red only with a primer for projectile delivery. A solvent, containing the anesthetic drug and timed release antidote, facilitated absorption of the drugs through the skin and into the central nervous system. With these tactics, little sound is generated during the firing of the drug-soaked felt pad. Tests were performed to acquire initial data on non?lethal projectile range, type of weapon system required under different operational scenarios, accuracy, solventlanesthetic skin coverage, and clothes penetrating ability. Antidotes to the anesthetic compounds and timed recoveries were also investigated. Recommendations concerning ?nal design of the weapon system are presented. Page 1 Dose Safety Margin Enhancement for Chemical Incapacitation and Less-Than-Lethal Targeting Introduction The initial goals of this study were to investigate the possibility of utilizing anesthetic compounds in combination with antidotes to enhance the dose safety of chemical incapacitants incorporated into future less?than-lethai technologies. We were to investigate the feasibility of implementing a new approach to support less- than-lethal technologies. The uses of extremely potent pharmacological agents delivered to human targets during prison disruption crises, hostage situations, law enforcement needs, special military operations, and low intensity con?ict were to be considered. We were requested to investigate and compare the ef?cacy of the most potent pharmaceutical agents currently available that could incapacitate an individual. We were to perform a literature review and compare all of the potential less?than?lethal pharmaceutical agents. Finally, we were asked to recommend future research concerning less-than?lethal delivery systems. Background The use of chemical incapacitating agents in humans must be carefully considered because of the potential danger of overdose. Most notably, anesthetic agents can cause respiratory depression, leading to death or permanent brain damage. Thus, such chemical agents must be safe, yet extremely fast acting, progressing to full strength followed by a rapid decrease in anesthetic effects with no long?term effects. Clinical applications of anesthetic and neuromuscular blocking agents have a long and scienti?cally-based history. Following intentional exposure to either an intravenous (IV) or inhaled anesthetic, a patient is irnmmobilized and incapacitated, yet allowed to maintain reasonably stable metabolic pathways, with no long-term residual adverse effects following removal of the anesthetic. For law enforcement and other applications, in contrast to a clinical setting, the controls over the subject are minimal; therefore, safety margins, with respect to the dose of the drug, must be greater. Page 2 Previously, the National Institute of Justice (NIJ) sponsored research (inhalation and IV animal dose studies) on fentanyl-related anesthetic agents (namely alfentanil) as potential incapacitating agents. In both cases, the dose safety margin was not suf?cient for deployment in law enforcement situations. There has been a small amount of research on the potential for mixing selective antidotes with alfentanil so as to retain the incapacitating effect while restraining the respiratory depressing in?uence. Combining a narcotic antagonist with a powerful, narcotic-based anesthetic was the major theme of the research. The potential bene?t to law enforcement operations and the personnel safety issues associated with the use of chemical incapacitants are extremely large. The operational considerations surrounding the use of highly potent, controlled substances are numerous and will require considerable policy assessment and mandated requirements. In addition to developing new less-than-lethal technology concepts, the Forensic Science Center at the Lawrence Livermore National Laboratory has provided technical support to local law enforcement agencies. These activities have typically taken the form of analyses of evidentiary materials. Since these analyses have been more complete than those readily available to local law enforcement, they have been of signi?cant value in pursuing a number of trial cases. Utilizing this experience base, expert scienti?c and technical support to plenary sessions were provided to address the critical concerns associated with application of less-than?lethal systems. In addition, the accomplished support interactions were to be documented to illustrate the capabilities of the FSC. Issues and requirements that arose were identi?ed in order to recommend speci?c methods whereby new forensic and scienti?c research technologies could be transferred to enhance law enforcement operations. Anesthetics Overview The history of the discoveries surrounding anesthetics is as colorful as any in medical science. Controlled surgical procedures were uncommon before 1846. Drugs such as alcohol, hashish, and opium derivatives taken by mouth were historically used for a variety of painful conditions. Other techniques, such a blow to the head or strangulation, did provide temporary relief from pain. However, the most common method to achieve a controlled surgical ?eld was to simply restrain the patient by force. Understandably, surgery was the last resort until anesthetics were readily available. Page 3 The history of modern day anesthesia begins with the discovery and use of "the first anesthetic", diethyl ether, in 1842 by Crowford Long and the application of nitrous oxide by Horace Wells in dentistry in 1845. In 1847, James Simpson discovered the use of chloroform, which experienced sustained use for nearly 100 years. In 1929, the ?rst respiratory gases -- cyclopropane, ethylene, and other hydrocarbon gases -- were introduced into surgery. In 1935, sodium pentothal and other barbiturates were ?rst used. In 1942, curare was used for complete skeletal paralysis, and in 1956, halothane and other ?uorinated and chlorinated gases were adopted into surgery. Modern surgery now utilizes a combination of solid dosage forms and mixed gases for well-controlled anesthesia in patients. From the beginning, it was appreciated that anesthetics were the most dangerous drugs approved for general use because the margin of safety was so small. Typically, in a clinical setting, the lethal dose of an anesthetic is only 2-4 times the therapeutic dose. In contrast, the safety margins of other therapeutic modalities are typically times greater. Stages of Anesthesia Before a new, less-than-slethal technology based on pharmaceutical agents can be selected, it is important to understand the effects that anesthetics have on the human body. The introduction of increasing amounts of an anesthetic causes a series of well-categorized levels of anesthesia to be observed. These are summarized below: S_tage 1 (minor sugary) a. There is analgesia without loss of consciousness b. There is only minor muscle relaxation c. There is retention of the swallowing re?exes d. There is some dizziness c. The patient can reply when spoken to f. The patient is conscious and progresses to unconsciousness Stage 2 {not desired in surgery} a. Stage between conscious and unconsciousness b. Purposeless muscular activity c. Excited state, laughing, shouting, thrashing about d. Pupils are dilated e. Hypertension and tachycardia are marked f. Irregular deep respiration Page 4 Stage 3 (desired for most surgeries) a. Complete anesthesia and full muscle relaxation b. Surgical state for most parts of the body Plane One a. Deep regular respiration b. Roving or eccentrically placed eyeballs c. Extrernities are moderately relaxed d. Abdominal muscles are not relaxed Plane Two a. Machine-er respiration b. Depth and length of inspiration and expiration are equal c. Eyes are centrally fixed Plane Three a. Irregular respiration Plane Four a. Shallow respiration b. Jaw fully moveable during inspiration Stage 4 a. No respiratory effort because all respiratory muscles are paralyzed b. Pupils excessively dilated and edges are irregular c. obvious, progressing rapidly without external support (1. Circulatory failure Graphically, these stages of anesthesia can be seen in Figure 1. With any type of anesthetic, it is observed that muscular tone is elevated in Stage 2 anesthesia, yet decreases signi?cantly in a Stage 3 state. In Stage 3, respiration is still maintained. However, Stage 4 should be avoided without mechanical respiratory support and consequently should be avoided in the ?eld where cardi0pulmonary equipment is not immediately available. Page 5 I Stage . . 5p" in? . E3413 EYE Pha?mm- Muscular Ins?lr?fl?? Ex?lfatl?? Movement Re?exes Lalyngeal Tone One Vocal Lid Highly Two Responds Excited Th ree Swallowing, Plane Retehing 1 Emesis 2: re Corneal 3m Responds Th ree Light Plane 3 Only Three 5 Plant! collapsible :1 Fixed and on Dilated Pupils I Figure 1. Stages of Anesthesia Selection of the Anesthetic Agent There are typically only three possible routes for the administration of anesthetic agents to a subject. One can apply inhalation gases, inject a solid dosage form, or be subjected to either IV or intramuscular (1M) injections. All modalities must allow the anesthetic agent to enter the blood stream in a timely manner, upon which it is carried to the central nervous system to render the subject either manageable or unconscious. For the present study, inhalation anesthetics were not addressed because of the lack of focus and control that would be associated with the administration of inhaled compounds in the field. Similarly, swallowing a solid dosage form is not realistic for law enforcement scenarios. Therefore, we primarily considered injectable anesthetic compounds that are currently utilized in surgery. All of the following anesthetics have been utilized, or are currently being utilized, for a variety of conditions in surgery or to render a patient semiconscious during heightened pain episodes burn victims). The injectable dosage forms currently utilized in surgery are grouped into the six categories. A brief description of each class of compounds is presented, Page 6 and various attributes of the most promising candidate from each group are discussed in more detail. Barbiturates Barbiturates have a long history in anesthesia. Pentobarbital, amobarbital, and secobarbital are the barbituric acid derivatives used most frequently to provide sedation and to relieve apprehension before an operation. Tolerance to barbiturates is observed in individuals who have been taking various types of drugs, including barbiturates, alcohol, and even aspirin. Sulfur?containing barbiturate analogs are noted for their ability to rapidly cross the blood-brain barrier. In particular, sodium pentothal (thiopental), an ultrafast?acting arbiturate, is highly ef?cient and has a high af?nity for speci?c brain receptors. It is typically utilized to rapidly induce Stage 3 anesthesia so that an inhalation gas can be subsequently used to maintain a controlled level of anesthesia. The typical anesthetic dose of pentothal is 100?500 mg (depending upon body size). It will produce an anesthetic effect in 10-20 seconds after a single injection. Although very potent, sodium thiopental can produce a dose-related depression of respiration as well as hypotension, both of which can be profound. This compound, under controlled conditions, could be utilized in less-than-lethal technologies at dose levels of 200- 500 mg. However, it would have to be delivered IV for maximum effect at these quantities. scpentyl 1Meihy1butyl Barbllurlc acld Mammal ?mm! HacHs . mimml Seeoberhltal Page 7 Tranquilizers Beuzodiazepines, such as Librium, Valium, and Serex, serve as anesthetics when sedation is needed to reduce anxiety prior to minor surgical procedures. Hunltrazapam (MW. These compounds are potent when taken orally or injected IV. Following a single injection of 0.2-1.5 rug/kg (typically 20 mg), full sedation can be realized in 1-2 minutes. The drug of choice in this class is diazepam (Valium), which is often substituted for sodium pentothal in selected patients at risk for cardiopulmonary depression. It is also noted that ?unitrazeparn (Rohypnol), is presently being abused and associated with date-rape. The victim's memory is signi?cantly impaired following moderate alcohol/drug exposure. In well?controlled settings, a benzodiazepine dose of 25 mg could be utilized in a less-than-lethal technology. However, if the concentration administered is not high enough for some target subjects, an increase in hostility Page 8 can result. However, the drug would have to be delivered IV for maximum effect, and the onset of action is slow because bloodfbrain passage is limited. Opioids A single IV injection of morphine (1-2 mg), meperidine (10-25 mg), fentanyl (ODS-0.1 mg), and other similar narcotic analogs is frequently employed to alleviate pain and are used in conjunction with inhalation anesthetics. At higher doses morphine, 3 rug/kg over 15 minutes), narcotics can induce complete anesthesia. However, respiratory depression is severe, and an antidote (such as naloxone) with mechanical ventilation is critically necessary in all cases. Page 9 If the individual is also taking other narcotics such as codeine, heroin, meperidine (Demerol), methadone, or other opioids, the effects of an additional narcotic can overwhelm any supportive treatments. Although the amount of drug is small, the added risk associated with utilizing morphine alone in a less-than- lethal technology appears problematic. Other narcotics appear to be similarly dangerous if used in pure forms. Neuroleptic-Opioid Combinations In humans, neuroleptic compounds, such as butyrophenone (Droperidol), produce a state of quiescence with reduced motor activity, reduced anxiety, and indifference to the surroundings. At moderately low doses of 1?3 mg, the compound does not elicit narcotic-like and the subject is responsive to commands. The only side effects is reported to be muscle twitching. However, research has shown that Droperidol enhances the effects of other central nervous system (CNS) depressants. In fact, when Droperidol and fentanyl are mixed, a new formulation (Innovar) is produced that appears to be especially effective as an injectable anesthetic. 0 Droporidel Page 10 A useful drug regime for humans is to administer a mixture of 0.1 of Innovar (0.05 mg fentanyl and 2.5 mg of droperidol) in 250 m1 of dextrose, infused over a period of 5?10 minutes. After 34 minutes the patient falls asleep and can stop breathing unless startled into taking a breath. Naloxone quickly reverses the effects of fentanyl. All other circulatory and biochemical pathways are less affected, and few side effects are observed with a combination of fentanyl and droperidol. Recovery is rapid, while nausea and vomiting are observed in only 540% of surgical patients. Fentanyl Analogues From the above review of injectable anesthetics, it became apparent that fentanyl (Janssen Pharmaceuticals) is an uncommon and very powerful drug. Whereas other compounds, such as sodium pentothal, benzodiazepines, and morphine, elicit an anesthetic response at dosage levels of 3?200 mg, fentanyl is highly effective in humans at microgram levels. Therefore, a literature review was undertaken to investigate the possibility of utilizing fentanyl or one of its analogues as less?than?lethal technology. The piperidinyl family of opioids include Fentanyl, Alfentanil, Sufentanil, Lofentanil and Carfentanil. Because this class of drugs is very lipophilic, they cross the blood?brain barrier quickly and induce an extremely rapid onset of anesthetic action. Alfentanil may be classi?ed as an ultrashort-acting drug, fentanyl and Sufentanil as short-acting, and Lofentanil as long?duration anesthetic. The analgesic doses of piperidinyl opioid drugs are not large (typically 0.3-44 plkg), and the typical analgesic plasma concentrations are very low (1-30 ng/ml). Anesthetic effects are observed at 30?100 ng/Inl. Because so little quantity of the drug needs to be introduced into the patient, it is cleared quickly following a single IV injection. Anesthetic effects can be further maintained by continuing a dilute IV drip of the anesthetic agent. Adverse effects following a single dose of 100 pg IV include bardycardia or tachycardia, hypotention, chest wall rigidity, seizures, and respiratory depression and collapse (in proportion to the overdose). 1. Fenta_nvl (Subliminal - Fentanyl is the oldest of the class of piperidinyl opioids. In contrast to other injectable anesthetics, it is an extremely powerful anesthetic and analgesic. Fentanyl was first in 1960 and is 100 times more potent than morphine. Page 11 2. Sufentanil gSufenta! Sufentanil was first in 1974 and is approximately 1,000 times more potent than morphine. It is often utilized for certain types of surgeries because it has lesser of an impact on cardiac stability. 3. Alfentanil (Alfenta) - Alfentanil was ?rst in 1978 and is approximately 5-3 times less potent than fentanyl, yet it reaches bloodfbrain equilibrium in only 1.1 minutes. Consequently, Alfentanil induces its anesthetic effect very rapidly. 0 below3 mew/?Nomen? 0 CH MI 203 CHEOCHS 0 ?3?3 Boom 0 CH mm LIOCHS CH QC 2 2 Page 12 4. Lofcntanil Lofentanil was ?rst prepared in 1976. Because this compound possesses 2060 times the potency of fentanyl (2,000~3,000 times more potent than morphineclinical role. 5. Carfentanjl - Carfentanil was also ?rst in the 19705. It, too, is 20- 30 times more potent than fentanyl and has yet to find a clinical role. Pharmacological Comparisons of Fentanyl Analogs Comparison of pharmacological data between fentanyl, its analogues, and other narcotic agents is most interesting. Mather (1983) presented data on the effects of opioids in dogs and rats for both analgesia and anesthetic potency. The data (Fable 1) clearly reveal the potency of fentanyl and its analogues compared to morphine and pethidine (Demerol). Table 1. Pharmacological data for fentanyl and its analogs compared to standard opiates* Acute Therapeutic Amthe?c Analge?c Potency? To?cityb Index Potency? LIE-1350 TMEDSO Potency MLDSO Potency Safety (mania) Ratios (mm) mesa (mm) Rance Margin? Opiate Fenlanyl 0.01 1 0.093 292 3.5 323 0.0012 125 60 Alfentanil 0.044 0.03 73 47.5 i080 0.005 30 50 Snfentanil 0.00071 0.14 4521 17.9 2521 1 0.00025 625 am Lofentanil 0.00070 0.55 4536 0.20 286 0.003025 6250 10000 Carfentanil 0.00032 0.29 3.39 10594 na na na Pethidine (I-lCl) 6.04 0.1 0.53 29 4.8 0.45 0.3 0 Morphine 3.21 0.31 223 69 0.15 1 33 Abbreviations: LD50 lethal dose; E1350 effective docs; MEDSO minimum EDSO by intravenous administration; TMEDSO time of maximum effect after single intravenous (5 sec) bolus dose; MLD mean value of na not available. a. an: tail withdrawal from water. Rat: intravenous bolus. c. Dog: begins to go unconscious, intubated with no increase in blood pressure, Dog: ratio of single intravenous dose for surgical anesthesia (20 MED) to dose producing severe cardiovascular side effects (alternating hyperactivity and depression} together with acidosis and hypermetabolism, convulsions and EG exhaustion. e. Normalized to morphine. E. Mather, Clinical Phamacokinerics ofFenranyl and its Newer Derivatives, ?nial Wham. 8: 422-446 (1983). Page 13 From Table 1, it can be seen that minimum effective anesthetic doses (MEDSO) for the fentanyi class of drugs are considerably less than that for morphine. Whereas morphine elicits its effects at 150 jig/kg, Fentanyl, Alfentanil, Stifentanil, and Lofentanil produce anesthesia at 1.2ug, 5.0ttg, 0.25ttg, and 0.025 1.1g per kg, respectively. In this study, anesthetic levels for Carfentanil were not determined. However, from studies of the analgesic potency of this drug, we surmise that this compound also possesses extraordinary anesthetic potency. From this initial study it was apparent that these newer anesthetic agents were not only potent, but that their anesthetic safety margin also appeared to be quite high. Fentanyl and Alfentanil have signi?cant safety margins compared to Demerol. However, Lofentanil and Sufentanil appear to have exceptional safety margins when compared to both morphine and Demerol. This observation is due mainly to (1) the very high speci?c activity of these drugs for speci?c opioid brain-receptors, (2) ultralow bloodfbrain concentrations, (3) rapid redistribution following the initial anesthetic effect, (4) metabolic inactivation, and (5) efficient clearance from the plasma following an initial bolus dose. All pharmacologic and pharmacokinetic parameters point to this class of drugs as an ideal candidate for less?than?lethal technology. Getting the Drug to the Target An initial requirement of from the beginning of this study was that injectable anesthetic dosage forms, including darts or syringes, not be considered. A visit to the San Francisco Zoo revealed that current primate immobilizing systems are only available with injecting darts, syringes on poles, or exploding projectiles with anesthetizing delivery injectors. Upon viewing and evaluating these devices, it became clear that present veterinary control systems would be unacceptable for less-than?lethal technologies for a variety of social and logistical reasons. Therefore, an alternative drug-delivery system was investigated that could humanely deliver a less-than-lethal drug system to an individual without requiring a needle, dart, or cartridgeafired injector. Transdermal Solvent Delivery Systems Transdermal patches have been well studied, and preparations for motion sickness (Transdermal Scop?), nicotine withdrawal (Nicoderm?), and severely burned patients (Fentanyl patch) are commercially available. The patches contain Page 14 a polymeric reservoir of the drug dissolved in a solvent that carries the drug through the skin in a well?controlled, time?release manner. Unique solvents that penetrate the skin easily are utilized to carry the drug directly through the epidermal layer (Figure 2). Once through the upper skin, the drug is absorbed into the capillary bed from which it is rapidly transported to the target tissues. The main advantages of transdermal patches are that (1) a sustained blood?level concentration can be maintained over extended periods of time, and (2) only a single patch is needed to maintain the therapeutic dose. The solvents utilized for transdermal patch systems include ethanol, glycerol, and (DMSO). Ethanol and glycerol deliver the pharmaceutic preparation slowly, whereas the latter solvent facilitates a transfer of drugs very rapidly through the skin. is approved for use in veterinary medicine and also has some limited medical uses in human disease interstitial cystitis). The solvent is often used in sports medicine in an "unof?cial" manner as a topical liniment for arthritic conditions, joint pain, and soft-tissue injuries. This solvent has not exhibited signi?cant toxicology when used correctly. Therefore, it would appear that DMSO could be utilized as an inert carrier to rapidly transfer a fentanyl?based anesthetic into a target, without need of a dart?based injection system. lEpidermi g, - -.-- . . .., .e . 1.- . .. . '1+5 ., 'c I :IEfl . gsti?lil?. -- rue Sebaceuus Gland Sweat Gland Jamar??r IInl'ein He Figure 2. Blood supply to the different layers of the skin. Page 15 Delivery System for Icss-than-Lethal Technology To effectively deliver an anesthetic dose of a mixture for less-than-lethal technology, a mechanism to transport the drug to the target must be developed. The most direct application would be simply a solvent/drug? soaked sponge pressed against the subject. However, if the individual is brandishing a weapon, close contact with the target could be problematic. We therefore investigated a novel possibility for the delivery of the anesthetic compound to the target. We designed and tested a small felt pad soaked with solvent as a method for remotely delivering the drug/DMSO mixture to the skin of an individual. The main advantage of a delivery system is that the anesthetic drug formulation need only pass through the epidermis laver of the sign to reach the MM vessels. If the drug is so absorbed, it will elicit identical rapid anesthetic effects identical to any drug injection approach. Proof of Concept - An Airgun Delivered Systems Modern pellet pistols and pellet ri?es are highly sophisticated and accurate weapons. They are capable of ?ring a variety of caliber pellet-projectiles at considerable velocities 400-1300 feetlsecond). They also have the capability of shooting felt cleaning pads. This possibility allowed us to test the concept of delivering a solvent-soaked felt pad to a target. We performed experiments to determine whether solvent would indeed be deposited on a target, how dangerous felt impact might be, and whether felt pads could be accurately carried to a target. To demonstrate proof of concept, we initially considered the Beeman Sports Air Ri?e or pellet pistol (Figure 3). Because samples could be more easily loaded into the breach of a pistol, experiments were performed with the Beeman Hurricane? pellet pistol. This 22-caliber weapon is capable of delivering a pellet at 400 feetl?second and was found to easily launch a 22-caliber felt cleaning pad (see Figure 4). The pads were soaked with 0.5 ml DMSO and ?red at various targets (Figure 5). These results were encouraging. At a distance of 15 feet, a tight pattern (approximale 2 inches) was generated by the experimenter. Although a sheet of standard notebook-paper could be penetrated at this distance, the solvent-soaked pads could not penetrate thick cardboard. The titling of the pistol barrel allowed the solvent-soaked felt cleaning pads to accurately hit the target. The solvent was also evenly distributed upon impact, indicating a Page 16 controlled and uniform delivery of the solvent to the test surface. This fact is important in order to obtain consistent results with any drug delivery projectile. Figure 3. Beeman air ri?e and pistol. SPORTING All? RIFLES LIFETIME, factory authorized backing! Military Speci?cation comm" 3m 5 - Year Serwce Contract Available. sacrum ml!- .22 {5.5mm} 3'35-815 3:3" Fae-2t .25 {as m] nan-am mete LIFETIME, factory authorized backing! 5- Year Service Contract Available. in ?Limbs [Ii-Tum unwar- am :nr. 5a! AEL ?no: . . . mammarth Spa: Surnrnaly Tempe-st Hurricane . . . .., Caliber: as: 1 22? opt-fig; .t'angar I sent-"I. 3' 113? yary' mam]; fag. 1330133 403115 l'cc: Pounds? 3 as 3.6 an FF Accuracyc-tvcf 35-1.? 0.1-1.0' 3 that Cacao; EHon; 25 lbs. 255 he. '93 lbs. Ins: Hum Lia: Nurrmers: 2261 we: Pitt-:5 mm; ,1 9mg; Airgun Comparison Fable mm. myab?. mea at Humane snow.? war. standard gains. Myron-ammo, ama- scopa ease (incense). scope, :3 . . - . Jammy shaped Hurricane-Mount a: scope Ema-e 1.11 a 1 auupe i . I . 55 "all? :1 Great me In the he'd. Sec sen-co soc-hm to- Model . Fri-"0 WM ?if-?mil 0: spani?razicra. Gar. Numb-Era: EEG-1C I31 and 925513 - I Teamst- 5'95 Beeman /Webley Hurrin At a distance of 23 feet, the felt pads would not penetrate the paper target, yet still deposited a uniform solvent residue. At this distance or greater, the impact of the solvent soaked felt pad would probably not be harmful, even if it impacted a sensitive area of the skin eyes, ear, lips, etc.). If clothing were hit (instead of bare skin), the solvent could still penetrate a single layer of thin fabric cotton shirt). However, any type of thick cloth material would not be ef?ciently permeated by the DMSO solvent system. The ease with which a DMSO soaked felt pad delivery system could be carried efficiently to a target was encouraging. However, loading such a projectile Page 17 would require that a felt pad with DMSOfdrug formulation be inserted in an open environment, potentially exposing the law enforcement of?ce to the effects of the drug. A fully encapsulated solvent/drug delivery package would be needed. Future system developments should include small (22?ca1iber), paintball?type, fully encapsulated delivery projectiles, containing a sealed solvent and drug formulation. Figure 4. 22?caliber felt pads to deliver DMSO soaked formulation '22.c.IFe.rt.Pa.as~ 38-Caliber Cartridge Deliverv Package In order to test a fully encapsulated system, a blank 38?caliber cartridge was utilized to deliver a DMSO/drug-soaked felt projectile to the target. This system was investigated because many law enforcement of?cials possess 38?caliber weapons, the weapon need not be modified, and the sealed cartridge could allow for a long shelf-life of a DMSO/drug formulation. We initially investigated the powder charge of a normal BEE?caliber handgun. A fully loaded blank cartridge proved to be totally unacceptable. However, projectiles launched with only the 38?caliber primer caps performed well and did not destroy the felt ball. Of several systems considered, acceptable launch velocities were generated with Speer's 38-caliber plastic cartridge cases and Page 18 Omark Industries "Magnum" primers (Figure 6). Projectile configurations were prepared and tested in the laboratory using these components. Figure 5. Target results for 22?caliber felt pad experiments show reasonably uniform distribution of solvent on the target. 5 Figure 6. 38-Ca1iber plastic shell casing, felt-ball, and "Magnum" primers assembl to launch DMSO soaked formulation. At ten feet, the hand-made felt cylinders impacted the target and delivered the DMSO solvent in a manner identical to the airgun experiments. This ?nding was very important because this 38?caliber system (1) allowed the delivery system to be totally encapsulated, (2) did not expose law enforcement to Page 19 any open DMSOldrug formulation, (3) should allow for an extended formulation shelf-life, and (4) delivered the less-than-lethal projectile at a consistent and well controlled velocity to the target. All of these are signi?cant attributes that would allow development of a pharmacology?based less-than?lethal technology. Antidote Considerations From this pharmacologic review, the most dangerous side effect from any of the narcotic-based anesthetics considered is respiratory depression. The use of less-than-lethal technology based on an anesthetic is made more problematic if the subject has recently injected other stimulants or narcotics. Therefore, an antidote should be added as an essential component of the drug-delivery formulation. The antidote of choice for respiratory depression associated with narcotic toxicity is naloxone. Naloxone and related opioid antagonists typically have no side effects when administered intermittently. A small, Mug-Swag dose of naloxone prevents or reverses the effects of most opioid narcotics. Respiratory depression, low blood pressure, and sedative effects are returned to normal within 1-2 minutes. The antidote remains active for 1 to 4 hours, which affords ample time for all effects of the anesthetic drug-formulation to be eliminated. Although opioid~antagonists might appear promising for a less?than-lethal technology, simply mixing naloxone with a fentanyl?based formulation would defeat the intent of the anesthetic. Therefore, it appears desirable to utilize ?med?relegse combingtion of naloxone with an ultrafast-acting fentanvl-based anesthetic formulation. After contacting the skin, the formulation . would be quickly absorbed to induce anesthesia. If the naloxone were delivered within a caged structure, such as a cyclodextrin, then a slower acting, timed- release antidote could be provided for the technology. Cyclodextrin compounds are currently used in a variety of pharmaceutical and cosmetics industries for their ability to capture and slowly release selected compounds. The internal receptive structure of the cyclodextrin can be with different dimensions to control the timed-release aspects of the formulation. Private discussions with Fuisz Technologies (Chartilly, Virginia), a manufacturer of cyclodextrin, indicated that such a timed-release molecular structure could be easily prepared. Page 20 A major research issue will be to design a slowly released antidote that reaches its maximum effects only after the anesthetic has had suf?cient time to render the subject amenable to capture or restraint. Future research should include studies of the size and solubility relationships of the cyclodextrinlnaloxone complex necessary for optimum timed delivery of the antidote. Meetings with Fuisz Technologies also produced another idea for placing a fentanyl-basedfantidote system within a cyclodextrin 10-micron powder. The dry powder could be dispersed as a smoke during a hostage situation. Terrorists would be incapacitated by breathing anesthetic smoke injected into an air duct or of?ce building air conditioning system. Marlene (R: Naltrexune (R: -CH2-cyclopropane) Mrcotic antidotes in a timed-release eyelodextrin molecule Page 21 Proposed Testing of the New Less-Than-Lethal Technology Because a phannacologically-based, less-than?lethal technology possesses both projectile delivery and drug absorption requirements, an in vitro assay is necessary prior to animal and human tests to insure proper timed delivery of the anesthetic and antidote. A survey of the literature revealed that both the cosmetics and pharmaceutical industries employ many types of skin tosts on a variety of products prior to general use. These biological assays are typically performed using animal and cadaver skin stretched over a small receptor chamber bathed in saline (Figure 7). Cosmetics, drugs, pesticides. and industrial compounds are applied to prepared samples, and measurements are made to determine the passage of target compounds through skin. The temperature of the apparatus is controlled in order to more realistically obtain transdermal information. Pharmacokinetic data on cosmetics/drug formulations are obtained as a function of variations in skin temperature and blood perfusion. Temperature .Jamperature Controlled Water Jacket Temperature Bar Controlled Water out?ow Figure 7. Test apparatus for less-than-lethal projectile 22 One company (Reifenrath Consulting and Research, Richmond, California) was consulted upon learning that they have utilized this type of apparatus extensively in a variety of studies for the Anny. Our discussions elucidated the testing requirements needed to accurately determine the absorption fate of chemicals through human skin. In order to develop pharmaceutical-based less-than-lethal technologies, studies employing similar apparatus must be performed. Human skin samples would be impacted (shot) with a projectile laced with DMSO/fentanybrelated mixtures in order to measure (in nearly real time) the passage of the drugs through skin. These in vitro experiments would be essential for understanding the dermal transport and pharmacokinetics of the solvent/drug/antidote formulation following an impulse impact of iess-than-lethal projectiles on the skin. In contrast to simply painting an anesthetic formulation on the skin, our experimental design would have a projectile impact the skin with some concomitant erythema. Following irnpact, the dilated blood vessels beneath the site of projectile impact should cause an enhancement in the skin absorption of the anesthetic formulation. This, in turn, should accelerate the overall effect of the anesthetic. However, these types of in vitro studies should be performed in the laboratory ?rst in order to study the effect of projectile velocity on drug absorption. The dermal transport apparatus would be con?gured at the center of a target. An airgun or a 38-caliber DMSO/drug projectile would be ?red at the target from a variety of distances. The saline outflow from the apparatus would be attached to a variety of highly sensitive experimental instruments ultraviolet or mass spectrometer, or solid?phase microextraction (SPME), for tinted isolation of drugs, etc.). These experiments would be used to measure the transport speed of the anesthetic across the skin under different conditions and variable drug concentrations. The skin-penetrating solvents will also carry the fentanyl-based anesthetic and cyclodextrin/naloxone. Measurements would be made to determine which of the fentanyl-based anesthetics was transported through the skin most quickly, as well as the effects obtained when a timed-release antidote is simultaneously carried across the dermal layer. These initial in vitro studies would greatly facilitate the development of the pharmaceutical-based, less-than-iethal technology under conditions 23 that closely resemble human skin. These tests should clearly determine the feasibility of reaching speci?c concentrations of the anesthetic drug under a variety of conditions drug concentration, solvents utilized, projectile speed, etc.). These investigations would optimally produce data that would guide future animal studies. Conclusions and Future Recommendations Safety The purpose of this study was to identify a highly potent anesthetic that could be introduced into a subject and elicit its affects quickly, but for only a very short duration. Anesthesia was to be implemented to subsequently restrain target personnel in law enforcement or terrorist situations. In contrast to surgical anesthesia, unconsciousness may only be required for 15 seconds to 1 minute; as short a period as necessary to place restraints or remove a person from a regulated situation. The results of this study point to a possibility that pharmaceutical? based, less-than-lethal technologies could be developed. This new approach would implement anesthetic drugs to brie?y reach the blood-brain concentration necessary for unconsciousness. Fortunately, under these circumstances, short duration anesthetic excursions are induced by highly potent, low-concentration drugs. They quickly cross the blood-brain barrier, impact opioid brain receptors, induce unconsciousness, and subsequently redistribute harmlessly to other body compartments. The result is transient sleep and an opportune moment for law enforcement. Because the anesthetic concentration will be very low and applied for only for a very short period of time, toxic side effects should be Ideally, low concentrations of the anesthetic will function effectively and quickly, rendering the individual incapacitated, but not subject to respiratory depression. This scenario contrasts surgical anesthesia, in which an individual is "put under" for a considerable period of time. During surgery, redistribution of the anesthetic ultimately lowers the concentration of and anesthetic in the brain. The anesthesiologist must consequently maintain drug concentration by continually dosing the drug. The goal is to sustain brain-level concentrations well into Stage 3 anesthesia. The 24 potential for side effects and residual cardioepulmonary depression is signi?cant following surgery because of the quantity of anesthetic utilized during the procedure. In contrast, a pharmaceuticabbased, less-than?lethal technology is intended to elicit a low-level, short-duration anesthetic concentration, thereby furthering the safety margin. From our evaluation, it does not appear that respiratory depression will be a signi?cant side effect under these low-level anesthetic administrations. Our approach to also implement a timed?release antidote (naloxone or naltrexone) should afford an additional level of safety. This consideration will be important for narcotic-sensitive individuals, or for targets who have recently ingested or injected other narcotic agents. In Vitro Studies It appears that in vitro studies with animal and human cadaver skin can be utilized to develop this new less-thandethal technology. Techniques are well developed in the pharmaceutical and cosmetics industries for skin- penetration testing. The in vitro testing of projectiles soaked with penetrating solvents and anesthetic drugs is an essential and logical next step in the development of a reliable, pharmaceutical-based, short-duration anesthetic approach for law enforcement. Animal and In Vivo Testing We have demonstrated two similar approaches for the delivery of anesthetic?based, less?than-lethal drugs to targets. They both utilize solvent soaked projectiles, launched with either an air gun or a 38-caliber pistol. It is proposed that this approach be utilized for experiments that would deliver non-lethal, anesthe?chMSO?soaked felt pads for animal studies. Experiments should be conducted under well-controlled laboratory and ?eld conditions in order to gather reliable physiological and dosearesponse data for the five fentanyl-related anesthetics dissolved in DMSO. These experiments should investigate relationships between projectile speed, distance to target, drug delivery capabilities upon impact, drug concentration, and time to maximum anesthetic response of the animal. Additional studies and observations of the penetration of the solvent/drug system through different types and layers of clothing would contribute ?eld operational data for future deployment of the new 25 technology. Detailed delivery studies and pharmacokinetic data in animals such as hairless mice or pigs could generate essential data that would be necessary prior to human testing. Animal studies should also explore the effects of pre-treatment with narcotics and their result on targeting with variable concentrations of the anesthetic agents. These studies would generate informative data and an understanding of the pharmacokinetic parameters and anesthetic rendering capabilities associated with mixed drug impairment (morphine, amphetamines, cocaine, etc.) that could be encountered during street-crimes or in a prison environment. In these experiments, variable concentrations of the timed-release antidotes could be also be tested in order to insure maximum ef?cacy and safety. A favorable aspect of the antidote treatment in animal investigations is that these compounds generate few side effects. Human Volunteer Testing After extensive in vitro and in viva testing, human trials should be conducted with the new less-than-lethal technology. At face value, this recommendation may appear extreme. However, human volunteers have somewhat routinely been subjected to sticky foam, mechanically restrained and crushed in the rear seat of police cars, shot with pancake bullets, netted with exploding grenade launchers, and rendered unconscious with stun-guns and high voltage Tasers. Thus, human trials with anesthetic-based, less-than?lethal technology is not an outlandish extension of this new technology. To test an anesthetic projectile delivery system, a university medical center and associated hospital environment would provide an ideal facility to determine the merit of this less-than-lethal technology. Many university research hospitals in the US and worldwide conduct investigational drug studies every year with both animals and human volunteers. Many of these studies are conducted with paid subjects exposed to a variety of new pharmaceutical agents. Such experiments are typically performed on healthy adult males. All necessary emergency medical support would thus be available for any contingency. Such experiments with human subjects should be coordinated through a staff composed of both research anesthesiologists and attending emergency physicians. These would be the initial studies of very controlled environments to obtain baseline data on human responses. These results would guide further human studies and determine the feasibility of this new technology. 26 Future Design Concepts for Anesthetic-Based, less-Than-Lethal Technologies From this detailed summary of anesthesia pharmacology, the potency of fentanyl?related anesthetics, non?injected, projectile delivery systems, timed-release antidotes, and data obtained from potential animal and human studies, a projected, less?than?lethal ?eld design package can be envisioned. This could be an emergency briefcase containing a weapons delivery component, color?coded projectile cartridges, and additional auto- injector naloxone antidote syringes. The weapon system could be con?gured for the environment in which deployed prison riot, street crime, hostage rescue, etc.), where law enforcement may be either at a distance or near the subject. The sealed, less-than-lethal cartridge arrangement could also contain a dye to mark where a projectile had hit the target. Such a stain would also indicate the likely location of the anesthetic agent during prisoner clean-up and surveillance following apprehension. The shelf-life of the anesthetic cartridge projectile would reasonably be on the order of one or two years. Conclusions In many situations an anesthetic-based, less?than?lethal technology would be most desirable for law enforcement. However, this technology must be simple to use and safe for the law enforcement of?cer. The pharmacologic, physiologic, and phamacokinetic parameters associated with the new delivery system must be well established through extensive in vitro and in viva testing. An experimental outline to measure these essential data was presented in this report. Focused experimental work can begin through studies using human cadaver skin and live animal models. Such studies can be performed in a safe and humane manner to assess the viability of this future technology. Human trial experiments could then be performed in a research hospital environment. With positive results, we estimate that a ?nal anesthetic-based, less?than-lethal delivery weapon could be possible in 2-5 years, depending upon the available funding, number of research institutions involved, and extent of validation testing. The success of such a promising program would be a great bene?t to law enforcement and other agencies often confronted by situations that would be humaner resolved by less-than-lethal solutions. 27 Further information: Brian D. Andresen P.0. Box 808, Forensic Science Center Lawrence Evermore National Laboratory Livermore, California 94550 (510) 422-0903 (510) 422-3570 (FAX) Pat Grant P.O. Box 803, L-371 Forensic Science Center Lawrence Livermore National Laboratory Liverwore, California 94550 (510) 423-6772 (510) 423-9014 (FAX) 28