United States Patent (19) 11 Patent Number: 4,692,451 Dodman Et Al

United States Patent (19) 11 Patent Number: 4,692,451 Dodman et al. 45 Date of Patent: Sep. 8, 1987

54 METHOD FOR PREVENTING Hypothermia in Mice, Weiss, et al., Neopharmacology, STEREOTYPC BEHAVIOR IN ANIMALS vol. 23, No. 5, pp. 483-489, 1984. 75) Inventors: Nicholas H. Dodman, Grafton; Louis In Vivo and In Vitro Studies with Agents That Cause Shuster, Brookline, both of Mass. Quasi-Morphine Withdrawal Syndromes, Sheldon, et al., Life Sciences, vol. 31, pp. 1699-1702. 73 Assignee: Trustees of Tufts College, Medford, The Twitch in Horses: A Variant of Acupuncture, Sci Mass. ence, vol. 225, pp. 1172-1174. 21 Appl. No.: 807,814 Nature's "fix" article, Leith. 22 Filed: Dec. 11, 1985 Primary Examiner-Stanley J. Friedman 51) Int. Cl:"...... A61K 31/44 Attorney, Agent, or Firm-David G. Conlin; Ronald I. 52 U.S.C...... 514/282 Eisenstein 58) Field of Search ...... 514/282 56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS A method of treating animals exhibiting stereotypic

3,308,791 3/1967 D'Elia ...... 119/129 behavior by administering a therapeutically effective 3,687, 12 8/1972 Hendersen ...... 119/129 amount of a narcotic antagonist is disclosed. The stereo typic behaviors include cribbing, wind-sucking, head OTHER PUBLICATIONS bobbing, head skaking, head nodding, pacing, pawing Equine Medicine and Surgery, pp. 758–759. and stall-walking. A kit for treating this stereotypic Reverse Tolerance to the Stimulant Effects of Mor behavior is also disclosed. phine in Horses, Shuster, et al., Pharmacology, vol. 4, No. 5, pp. 233-236. Effects of Naloxone and Naltrexone on Drug-Induced 9 Claims, 3 Drawing Figures U.S. Patent Sep. 8, 1987 4,692.451

235O

88O

4 O CUM. SCORE 94O

47 O FG. O 77 355 532 TIME (min)

687

55O

42 CUM, SCORE 275

F. G.2 37

O 55 O 165 22O TME (min)

4 CUM, SCORE 76 F. G. 3 38

O 8O 59 239 39 TIME (min) 4,692,451 1. 2 according to this invention (solid line) and in the same METHOD FOR PREVENTING STEREOTYPC animal when untreated (broken line). BEHAVIOR IN ANIMALS FIG. 2 is a graph showing the effect of cribbing over time in a horse injected with naloxone in accord with BACKGROUND the present invention. This invention relates to a process for a treating ste FIG. 3 is a graph showing the effect of cribbing over reotypic behavior in animals. This process is particu time in a horse injected with naltrexone in accord with larly useful in treating a specific stereotypic behavior, the present invention. cribbing, in horses. The term stereotypic behavior is used herein to de O DETAILED DESCRIPTION OF THE scribe the repetitive and pointless behavior frequently INVENTION shown by domesticated animals and animals in captiv We have discovered that by administering a thera ity. This behavior has been observed, for example, in peutic amount of a narcotic antagonist to a domestic zoos where a caged bear or lion is seen pacing up and mammal such as a horse which exhibits a stereotypic down the cage repetitively for many hours. Horses 15 behavior, for example, cribbing, and wind-sucking, display a number of different stereotypic behaviors. head bobbing, head nodding, head shaking, pacing, stall These include cribbing, wind-sucking, weaving, head walking, pawing, etc., that the stereotypic behavior is in bobbing, head shaking, head nodding, pawing, stall most instances greatly reduced. It is believed that envi walking, etc. Of these behaviors, cribbing and wind ronmental modification should be combined with the sucking have long been recognized as a serious problem 20 drug administration in order to prevent recurrence of in this species. the stereotypic behavior. The environmental modifica Cribbing is often associated with aerophagia. A horse tion includes, but is not limited to, moving the animal to that exhibits this behavior typically grabs an object with a more interesting environment, such as outdoor stall its incisor teeth, then arches its neck, and by depressing ing, providing regular exercise, and providing the com the tongue and elevating the larynx, pulls backward and 25 upwards and swallows air. As a result of this behavior, pany of other animals. which is an acquired habit, the horse suffers many prob We have found that a variety of different drugs classi lems, including erosion of the incisor teeth, digestive fied as pure narcotic antagonists or partial antagonists disturbances, colic, flatulence, and weight loss. Conse are useful in the present invention. Pure antagonists, quently, owners of such horses will go to great lengths 30 such as naloxone are preferable, but other drugs which to prevent this behavior. possess varying degrees of antagonist activity may be The typical treatment for this behavior includes me used. The invention includes, but is not restricted to the chanical prevention by use of throat straps and fluted following narcotic antogonists: bits as described for example in U.S. Pat. Nos. 3,687,112 naloxone, and 3,308,791. Electric shock has been tried as another 35 naltrexone, method of restraint. More radical treatment involves nalmefene, surgical excision of the throat muscles-Forssell's opera nalorphine, tion (Equine Medicine and Surgery, pages 758-759), or diprenorphine, the creation of permanent buccal fistulas. levallorphan, None of the above methods is entirely satisfactory. 40 pentazocine, The mechanical methods do not prevent cribbing or metazocine, wind sucking, but merely reduce the frequency by cyclazocine, physical restraint. Furthermore, it is not always possible etazocine, and or desirable to maintain use of the mechanical restraint. peptide drugs with opiate receptor antagonist activity. The surgical measures result in disfigurement, and in 45 Also any drug with demonstrable agonist activity can any case, a successful outcome is not always guaranteed be imparted with antagonist activity by the addition of (The success rate is only about 25%). an aliphatic group to its nitrogen moiety (e.g., nalor It would be desirable to have a simple means of pre phine is N-allylnormorphine) and the use of such drugs venting stereotypic behavior that does not result in is included within the scope of this invention. either mechanical constraint or surgical changes. The 50 Preferably the narcotic antagonist is selected from treatment is simple to administer and will have long the group consisting of naloxone, naltrexone, di lasting effects. prenorophine and nalmefene. Further, the use of pharmaceutically acceptable acid SUMMARY OF INVENTION addition salt of narcotic antagonists is also within the We have now discovered a method for treating ani 55 scope of this invention. In general, any suitable inor mals exhibiting stereotypic behavior, using narcotic ganic or organic acid may be used to prepare such salt. antagonists. Anarcotic antagonist is administered in a Examples of suitable inorganic acids are hydrochloric, therapeutically effective amount to an animal exhibiting hydrobromic, sulfuric, nitric, phosphoric, phosphorous, stereotypic behavior, such as cribbing, wind-sucking, and perchloric acids. Examples of suitable organic acids pawing and pacing. The abnormal behavior stops soon 60 include tartaric, citric, acetic, succinic, maleic, malic, are administration of the drug. Animals that could be fumaric, oxalic, ascorbic, benzoic, lactic, palmitic, pa treated by the use of this method include horses, other moic, lauric, stearic, oleic, myriatic, lauryl, linoleic and domestic mammals, and, caged mammals, such as bears linolenic, acids. However, other organic and inorganic and lions. acids which are well known to the person of ordinary 65 skill in the art can be used. BRIEF DESCRIPTION OF THE DRAWINGS In order for most effective treatment, one would use FIG. 1 is a graph contrasting the cumulative amount a drug that can be administered in a form which will of cribbing observed over time in an animal treated have long lasting effect. Thus, although one can use 4,692,451 3 4. simple intraveneous and oral methods of administration, the line on the following day prior to injection with the it would be preferable to use a dosage form that could narcotic antagonist is similar, 5.2, whereas shortly after be administered over a long period of time. This type of injection cribbing has essentially stopped and the slope administration is well known to the person of ordinary is 0.045. skill in the art. For example, one of ordinary skill can 5 FIG. 2 and FIG. 3 show representative results ob select from intraveneous, intra-muscular, subcutaneous, tained by use of naloxone and naltrexone injected intra transdermal, oral, and rectal routes of administration. venously into two other horses. In FIG. 2, a horse was The dose of the drug to be used is the therapeutically injected with 20 mg of naltrexone and this injection was effective amount which will be determined depending repeated one hour later. Cribbing decreased from a rate upon the particular animal used by techniques well O of 12.4 cribs per minute to a rate of 2.86 cribs per minute known to the person of ordinary skill in the art. Typi after the first injection and 2.04 cribs per minute follow cally, this would range from about 0.01 mg per kilo ing the second injection before the effect of the narcotic gram to about 10 mg per kilogram body weight of the antagonist began wearing off. Analogous results are animal. shown in FIG. 3 where 20 mg of maltrexone was in Kits containing therapeutically effective amounts of 15 jected intra-venously. Cribbing decreased from a rate of the narcotic antagonist can be used in the present pro 1.08 cribs per minute to 0.005 cribs per minute before cess for controlling stereotypic behavior. These kits the horse was fed sweet feed approximately two and would include sterile and pyrogen-free solutions of the one-half hours later. Sweet feed has a tendency to stim narcotic antagonist sealed in sterile and non-pyrogenic ulate cribbing. storage vials. The narcotic antagonists include but are 20 Control injections of saline did not alter the cribbing not restricted to the following: naloxone; naltrexone; rate of the animals. nalmefene, nalorphine; diprenorphine; levallorphan; pentazocine; metazocine; cyclazocine, etazocine and EXAMPLE 2 pharmaceutically acceptable acid addition salts thereof. Long term treatment is provided by use of ambula The solutions can be administered by intravenous injec- 25 tory infusion pumps (Autosyringe manufactured by tions or other techniques well known to the person of Baxter Travenol) set to inject nalmefene at a rate of 10 ordinary skill in the art. mg per hour. The pumps are attached to the animal and Preferably, the narcotic antagonist should be injected set up according to directions of the manufacturer. subcutaneously in the form of a pellet in order to obtain Table 1 describes a series of treatments in one animal sustained relief for long periods of time. However, 30 using the methods of the present invention. other methods of sustained long-term release can be TABLE 1 used. These would include plastic patches for trans dermal absorption, ambulatory infusion and other tech Cribs per niques. Treatment Duration Minute Control 2 hours 19 The following examples are given solely for the pur-35 Control 7 hours 5.4 pose of illustration and are not to be considered limita Control 1 hour 5.2 tions on the method of the present invention. Naimefene, 2 inj. 10 hours O of 40 mg., i.m., at EXAMPLE 1 0 and 3 hours Control 5 hours 8.6 A horse exhibiting cribbing behavior was observed 40 Diprenorphine, 10 mg i.m. 5 hours 0.06 for a control period to establish a base-line for the Control 2 hours 6.3 Nalmefine, osmotic 2 days 0 amount of cribbing. The cribbing rate was expressed in pump S.C., 2 mg/hr, five minute intervals and cumulatively followed for the Same osmotic pump 1 hour (AM) 1.8 entire control period. Thereafter, the horse was injected not working 1 hour (PM) 2.1 with a narcotic antagonist, such as naloxone, nalmefene, 45 anymore Control hour 6.7 naltrexone and diprenorphine, or a saline solution and Nalmefene, 40 mg i.m. 4.3 hours O observed during a follow up time period. The observer Control 1 hour 1. had no knowledge of the material with which the horse 1 g, nalmefene in 22 hours 0. is injected, thus resulting in a blind trial. If a horse was oil, S.C. 50 No longer working 10 minutes 4.0 injected with saline, it was subsequently injected with No longer working hour 1.8 the narcotic antagonist and vice-versa. Namefene in 4 hour Horses were injected with either a narcotic antago osmotic pumps, S.C. nist or saline solution intravenously by use of an intrave Same as above 1 hour 0.25 nous catheter or intramuscularly by use of techniques Control 5 minutes 1.8 55 Naimefene, 50 mg S.C. 1.5 hours (at up O well known to person skilled in the art. to FIG. 1 is a graph plotting the cumulative amount of Nalmefene, 50 mg S.C. between 3 and 4 2.8 cribbing observed over time. The dotted line is a fitted hours Nalmefene, 10 mg 1 hr 5 days O regression line based on actual data points for a cribbing Continuous infusion S.C. horse without treatment (control). Nalmefene 10 mg per hr 8 days O The solid line is a fitted regression line based on ac- 60 continuous infusion, i.v. tual data points for the same horse on the following day, Off pump (day 9) 1 hour obs, 1.2 where the animal received two intramuscular injections Off pump (day 10) 1.5 hours 8.0 of 40 mgnalmefene spaced three hours apart. The use of Off pump (day 11) 1 hour 2.6 the narcotic antagonist resulted in the horse being essen tially crib free whereas the animal cribbed almost 2000 65 It can be seen from Table 1 the use of the narcotic times on the same period on the previous day. antagonist according to the present invention signifi The slope of the lines represent cribs/minute. The cantly lowers the rate of a stereotypic behavior, crib slope of the line for the control day is 5.4. The slope of bing. 4,692,451 5 6 The use of behavioral therapy may be required in bing, wind-sucking, head-bobbing, head shaking, head some animals in order to result in an effective treatment nodding, pacing, pawing and stall-walking. mechanism. Such therapy techniques are well known to 3. The method of claim 1 wherein the narcotic antag the skilled practioner. onist is selected from the group consisting of naloxone, It is expected that the combination of the present naltrexone, nalmefene, nalorphine, diprenorphine, lev treatment with behavioral therapy may allow one to allorphan, pentazocine, matazocine, cyclazocine, etazo discontinue the use of the narcotic antagonist and not cine and a pharmaceutically acceptable acid addition have a recurrence of the stereotypic behavior. salt thereof. The above-described process has also been used suc 4. The method of claim 3 wherein the narcotic antag cessfully in horses that were hyperactive and engaged 10 onist is selected from the group consisting of naloxone, in stall walking, pawing and digging. maltrexone, diprenorphine and nalmefene. It will be appreciated that those skilled in the art may 5. The method of claim 1 wherein the treatment fur make modifications and improvements upon the inven ther comprises the use of behavioral therapy. tion disclosed herein without departing from the spirit 6. The method of claim 2 wherein the animal is a and the scope of the invention as described in the 15 horse. claims. 7. The method of claim 1 wherein the narcotic antag We claim: onist is administered by transdermal absorption. 1. A method of treating an animal exhibiting stereo 8. The method of claim 1 wherein the narcotic antag typic behavior which comprises administering a thera onist is administered in the form of a subcutaneous in peutically effective amount of a narcotic antagonist to 20 plant. said animal. 9. The method of claim 1 wherein the narcotic antag 2. The method of claim 1 wherein the stereotypic onist is administered by injection. behavior is selected from the group consisting of crib s k sk ck sk