(19
`United States Patent
`4,882,335
`{11] Patent Number:
`Sinclair
`[45] Date of Patent: Noy. 21, 1989
`
`
`
`[54] METHOD FOR TREATING
`ALCOHOL-DRINKING RESPONSE
`
`ments for Alcoholism”, J. D. Sinclair, Ph.D, British
`Journal of Addition, 1987, 82, 1213-1223.
`
`John D.Sinclair, Espoo, Finland
`Inventor:
`[75]
`[73] Assignee: Alko Limited, Helsinki, Finland
`[21] Appl. No.: 205,758
`[22] Filed:
`Jun. 13, 1988
`[SEY
`STG CUS, eececnspsesespsnrevpneniacavennsecniervise AOE OAAe
`[$2] WS Cae sasssocssesas
`soseeee 514/282; 514/811
`
`[58] Field of Search ....
`ewe 514/810, 811, 812, 282
`References Cited
`[56]
`PUBLICATIONS
`
`Chem. Abst., 106-12821P, (1987).
`“Naloxone Persistently Modifies Water-Intake”, Phar-
`macology Biochemistry & Behavior, Mar. 25, 1986, vol.
`29, pp. 331-334.
`“Feasibility of Effective Psychopharmacological Treat-
`
`Primary Examiner—Stanley J. Friedman
`Attorney, Agent, or Firm—Armstrong, Nikaido,
`Marmelstein, Kubovcik & Murray
`
`[57]
`
`ABSTRACT
`
`A therapeutic method is provided for use as an adjunct
`in the treatment of alcoholism. The method consists of
`extinguishing the alcohol-drinking response of alcohol-
`ics during a relatively short period of time by having
`them drink alcoholic beverage repeatedly while an
`opiate antagonist blocks the positive reinforcement
`effects of ethanol in the brain.
`
`'8 Claims, 3 Drawing Sheets
`
`(cid:36)(cid:51)(cid:50)(cid:55)(cid:40)(cid:59)(cid:3)(cid:40)(cid:59)(cid:43)(cid:44)(cid:37)(cid:44)(cid:55)(cid:3)(cid:20)(cid:19)(cid:20)(cid:27)(cid:3)
`APOTEX EXHIBIT 1018
`(cid:36)(cid:83)(cid:82)(cid:87)(cid:72)(cid:91)(cid:3)(cid:89)(cid:17)(cid:3)(cid:36)(cid:79)(cid:78)(cid:72)(cid:85)(cid:80)(cid:72)(cid:86)(cid:3)
`Apotex v. Alkermes
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:21)(cid:24)(cid:16)(cid:19)(cid:19)(cid:24)(cid:20)(cid:23)
`IPR2025-00514
`
`

`

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`US. Patent—Nov.21, 1989 Sheet 1 of 3 4,882,335
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`US. Patent—Nov. 21, 1989 Sheet2 of 3 4,882,335
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`US. Patent
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`Nov.21, 1989
`
`Sheet 3 of 3
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`4,882,335
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`1
`
`4,882,335
`
`METHODFOR TREATING ALCOHOL-DRINKING
`RESPONSE
`
`FIELD OF THE INVENTION
`
`The invention is a treatment for alcohol abuse in
`which the alcohol-drinking response is extinguished
`over a limited number of sessions by being emitted
`while the reinforcement from alcoholis blocked with an
`opiate antagonist such as naloxone or naltrexone.
`BACKGROUND OF THE INVENTION
`
`Alcoholism is the most costly health problem in many
`countries. The cost, e.g., in America is estimated to be
`about $117,000,000,000 per year. The treatment meth-
`ods currently used are not very effective. Most alcohol-
`ics drop out of treatment within a month or two. Few
`alcoholics, regardless of the type of treatment, are able
`to avoid relapses and renewed alcohol abuse.
`Nooneis born an alcoholic. The drinking of alcohol
`(ethanol or ethyl alcohol) is a learned response, rein-
`forced largely by the rewarding effects of alcoholin the
`central nervous system—the euphoria from lower, stim-
`ulatory doses of ethanol. An alcoholic is a person who,
`through an interplay of genetic and environmental fac-
`tors, has had the alcohol-drinking response reinforced
`so often and so well that it becomes too strong for the
`individual to continue functioning properly in society.
`The strong alcohol-drinking response—i.e., the drive
`for alcohol—then dominates the person’s behavior and
`life.
`The current methods for treating alcoholism are not
`very successful probably because they do not effec-
`tively weaken the alcoholic’s alcohol-drinking re-
`sponse. Some methods (e.g., counselling, Alcoholics
`Anonymous) are aimed at
`increasing the alcoholic’s
`ability or will power to withstand the drive for alcohol.
`The drive, however, is not weakened andthepatientis
`told that he will remain an alcoholic, that is, a person
`with an overly strong alcohol-drinking response, for the
`rést ofhis life. These methods succeed in somealcohol-
`ics, but in most the time eventually comes when a mo-
`mentary decrease in will power causes a resumption of
`alcohol drinking and alcohol abuse.
`Other treatments use punishment of various sorts
`(e.g., electric shock, disulfiram reactions, loss of a job)
`to try to stop alcohol drinking. Punishmentis, however,
`a poor method for changing behavior and has many
`limitations. In particular,it is ineffective when positive
`reinforcementis still being received for the same re-
`sponse that is punished. Since the treatments that punish
`alcohol drinking do not block the positive reinforce-
`ment of the same response coming from alcoholin the
`brain, they should not be expected to be very effective.
`A third type of treatment has been proposed. Alcohol
`and opiates appear to cause positive reinforcement
`largely through the same neuronal system in the brain.
`Consequently, opiates such as morphine or methadone
`might be able to satisfy the drive for alcohol and thus
`abolish alcohol drinking. This does indeed occurin rats
`and other animals, and there is evidence suggesting
`opiates could also succeed in making alcoholics stop
`drinking alcohol. The treatment probably would, how-
`ever, turn alcoholics into opiate addicts, which is, of
`course, not a good solution.
`Instead of counteracting the drive for alcohol or
`temporarily satisfying it, a successful treatmentfor alco-
`holics should permanently weaken the alcohol-drinking
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`there is a well-established
`response. Fortunately,
`method for weakening a learned response: “extinction”.
`Extinction consists of having the response emitted re-
`peatedly in the absence of positive reinforcement.
`It is relatively simple to remove external sources of
`positive reinforcement, such as the food a rat gets for
`pressing a lever or even the social reinforcementa per-
`son sometimes gets for drinking alcohol. But much of
`the positive reinforcement for alcohol drinkingis inter-
`nal, from the rewarding effects of alcohol in the brain.
`The results showing that alcohol and opiates share a
`common mechanism of reinforcement show how the
`internal positive reinforcement from alcohol might be
`blocked. Various substances, called opiate antagonists,
`are able to block the receptors for opiates and thus
`prevent the effects of, e.g. morphine. Furthermore,
`there is already evidence that the two most commonly
`used opiate antagonists, naloxone and naltrexone, do
`block positive reinforcement from alcohol. First, they
`block the stimulatory effect of alcohol which is gener-
`ally thought to be related to the euphoria and positive
`reinforcement. Second, it has been shown that while
`they are in the body they reduce voluntary alcohol
`drinking and intragastric self-administration of alcohol
`by animals.
`Naloxone and naltrexone were originally intended
`for use in treating overdoses of opiates. They have since
`been suggested for use against a wide variety of prob-
`lems including respiratory failure, anorexia nervosa,
`bulimia, obesity, emesis and nausea, shock, severe itch-
`ing, constipation, growth of neoplasms, and sexual im-
`potence and frigidity. There have been many studies
`attempting to use naloxone to reverse alcohol intoxica-
`tion and especially the coma produced by very large
`amounts of alcohol; although the results have been
`mixed and thereis still controversy as to whether nalox-
`one can antagonize severe alcohol
`intoxication,
`it is
`important to note that none of these studies reported
`any bad effects from giving naloxone in conjunction
`with alcohol. The doses of naloxone have ranged be-
`tween about 0.2 and 30 mg daily, and naltrexone from
`about 20 to 300 mg daily. Other suggested uses are for
`the opiate antagonists in conjunction with other drugs,
`particularly, opiate agonists. For instance, U.S. Pat. No.
`3,966,940 is for a compound containing narcotics or
`analgesics plus naloxone to be given especially to nar-
`cotic addicts. In these cases the opiate or other drug is
`seen to be active pharmacological agent and the opiate
`antagonist is included to counteract someofits effects.
`Continual treatment with opiate antagonists should
`reduce the alcohol intake of alcoholics: so long as the
`antagonistis in the body, the alcoholic should havelittle
`incentive for drinking because alcoholis not rewarding.
`This maintenance treatment, however, has the same
`problem found with other long-term deterrent treat-
`ments, such as that with disulfiram: how to keep the
`alcoholic on the medication.Since thereis still a strong
`drive for alcohol, the alcoholic is likely to drop out of
`treatment and stop taking the antagonist so that he or
`she cansatisfy the drive by drinking again.
`However, combining the well-established procedure
`of extinction from psychology with the pharmacologi-
`cal findings that opiate antagonists block reinforcement
`from alcohol provides a new and much more promising
`way of treating alcoholism. Indeed,
`it provides what
`could be called the first true cure for alcoholism. After
`a relatively short period of treatment during which an
`
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`

`3
`opiate antagonist is employed in extinction therapy, the
`patient is no longer an alcoholic, because the overly-
`strong alcohol-drinking response that made the patient
`be an alcoholic is extinguished. The method for using
`this extinction procedure is the present invention.
`The idea of using extinction therapy with an opiate
`antagonists for alcoholics has not been suggested previ-
`ously. A similar idea with naltrexone has, however,
`been suggested for opiate addicts (see P. F. Renault,
`NIDA Research Monograph No.28, pp. 11-22, 1981),
`but extinction was not included in the design of the
`clinical tests. The patients were simply detoxified, given
`naltrexone or placebo, and released. There was no pro-
`gram for encouraging them to take opiates while under
`the influence of naltrexone, as required for extinction.
`Consequently, the general result was what would likely
`happen also with such a naltrexone maintenance pro-
`gram with alcoholics: a very large percentage of the
`addicts dropped out, stopped taking naltrexone, and
`started taking opiates again. Of the total of 1005 sub-
`jects, however, “17 of the naltrexone and 18 of the
`placebo subjects actually tested the blockade by using
`an opiate agonist” when naltrexone would have been
`active, and “in this subsample, the naltrexone patients
`had significantly fewer subsequent urines positive for
`methadone or morphine. .
`. The pattern in the naltrex-
`one group was to test once or twice with heroin or
`methadone and then to stop. The use of these drugs in
`the placebo group was sporadic duringthe entire course
`of treatment. .
`. [Also, on an analog craving scale] the
`naltrexone patients reported significantly less craving
`toward the endoftheir evaluation than did the placebo-
`treated patients.”
`These results suggest that naltrexone would be much
`more useful against opiate addiction if the addicts were
`given extinction sessions in which-they were encour-
`aged to use narcotics while the positive reinforcement
`was blocked. Furthermore, in relation to the present
`invention, by showing the extinction therapy with nal-
`trexone does work in humans, they support the hypoth-
`esis that it would reduce alcohol abuse and the craving
`for alcoholin alcoholics.
`The example included here showsthat the extinction
`procedure progressively decreases and eventually al-
`mostabolishes alcohol drinking byrats and that alcohol
`intake remains reduced longafter all naloxone should
`have been removed from the body. Thehigh predictive
`validity of this animal model for indicating treatments
`that affect human alcohol consumption is discussed in
`Sinclair, British Journal of Addiction 82, 1213-1223
`(1987).
`
`SUMMARYOF THE INVENTION
`The present
`invention contemplates a therapeutic
`method,utilizing the ability of opiate antagonists to
`block the positive reinforcement from alcohol, to extin-
`guish the alcohol-drinking response of alcoholics. The
`extinction program consists of numerous sessions in
`which the alcoholic has an opiate antagonist adminis-
`tered and then drinks alcohol.
`The extinction procedure abolishes the alcoholic’s
`strong alcohol-drinking response. Optimally,
`the pa-
`tient’s drive for alcoholis returned to the level present
`before he or she evertasted alcohol. Thus, by definition,
`the patient is no longer an alcoholic.
`Admittedly, the patient can relearn the alcohol-drink-
`ing response and become an alcoholic again, and re-
`learning a response that has been extinguished occurs
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`4,882,335
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`4
`more rapidly than theinitial acquisition. But with the
`first-hand knowledge of the consequencesof the first
`acquisition of alcoholism, and with even a moderate
`level of will power and outside support, most alcoholics
`will avoid making the same mistake twice.
`This extinction procedureis a useful adjunct for vari-
`ous other methods of treating alcoholics,
`including
`punishmentof alcohol drinking, procedures to improve
`will power and social rehabilitation, and maintenance
`procedures for preventing renewed use of alcohol.
`These other methods have previously been very limited
`because of the continuing high drive for alcohol, but
`they should be much moreeffective once the alcohol-
`drinking response has been extinguished.
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 shows the apparent extinction of alcohol
`drinking in Long Evans and AA rats caused by 4 daily
`sessions of drinking alcoholafter administration ofnal-
`oxone (mean-standarderror).
`FIG. 2 shows the apparent extinction of alcohol
`drinking in Wistar rats caused by 4 daily sessions when
`naloxone was administered 5 minutes before the hourof
`drinking alcohol (“paired naloxone” group) and the
`lack of effect of naloxone injected each day 3 hours
`after alcohol drinking (“unpaired naloxone” group).
`FIG. 3 shows the continued reduction in alcohol
`drinking by the Long Evansrats that had previously
`undergoneextinction (see FIG. 1) relative to their con-
`trols. No naloxone was administered during this time,
`but the rats treated before with naloxone drank signifi-
`cantly less than the controls on eachofthe first 7 days.
`They eventually returned to the control level, appar-
`ently because they were not made to abstain com-
`pletely, did drink some alcohol, and thus relearned the
`alcohol-drinking response.
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`The extinction procedure can be used in all individu-
`als classified by any of various means as alcoholics or
`alcohol abusers, except those in which the administra-
`tion of an opiate antagonist is contraindicated and those
`suffering from Korsakoff’s syndrome. (The extinction
`procedure would probably work poorlyin patients with
`Korsakoff’s syndrome.)
`The patients can be interviewed to determine the
`alcoholic beverages they usually drink and the drinking
`situations in which they normally imbibe. They can
`then be informed that unlike most treatments, this one
`does not involve immediately becoming abstinent; in-
`stead, their alcohol drinking is to be slowly diminished
`over many days and only after that will they have to
`abstain. This procedure should also help to reduce the
`severity of withdrawal symptomsthat are often pro-
`duced by abrupt termination ofalcoholintake.
`The patient can then have an opiate antagonist ad-
`ministered shortly before beginning to drink an alco-
`holic beverage. Examples of opiate antagonists are nal-
`oxone, naltrexone, cyclazocine, diprenorphine, etazo-
`cine,
`levalorphan, metazocine, nalorphine, and their
`salts. The preferred opiate antagonists are naloxone and
`naltrexone, both of which have been approved for use
`in humans and have been shown to be free of severe
`side-effects, Neither is addicting or habit forming. The
`preferred dose range for naloxoneis 0.4 to 10 mg daily
`if taken by injection; the dose would have to be much
`largerif it were taken orally. The preferred dose range
`
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`

`4,882,335
`
`5
`for naltrexone is 50 to 200 mg daily. The dose adminis-
`tered in a specific case will depend upon the age and
`weight of the patient, the frequency of administration,
`and the route of administration, but mustbe sufficientto
`assure that the antagonist will be present in sufficient
`quantities in the body throughout the entire evening of
`alcohol drinking. The antagonist could be administered
`in such a waythat it is continually present in the body
`throughout the weeks of extinction therapy. Adminis-
`tration in a way that allows the patient to be free of
`pharmacologically-active quantities of the antagonist
`during the following day may be preferred, since it
`allows the alcoholic to eat food and drink non-alcoholic
`beverages during the daytime without
`interference
`from the antagonist. In the latter case, the patient will
`be under strict orders to confine all alcohol drinking to
`the evening hours after the antagonist has been adminis-
`tered.
`Examples of routes of administration for the antago-
`nist are injection, oral consumption in any form,trans-
`dermal administration, slow-release injection, nasal ad-
`ministration,
`sublingual administration,
`implantable
`drug delivery depots, and the like. A non-obtrusive,
`non-painful route would be preferred.
`Thefirst extinction session (i.e., drinking after admin-
`istration of the antagonist) can be conducted under
`close supervisionin the treatmentcenter.It is important
`that later extinction sessions be conducted in the same
`drinking situations and with the same alcoholic bever-
`ages that the patient usually has employed in the past.
`Thestimuli from these specific beverages and situations
`help to elicit somewhat separate alcohol-drinking re-
`sponses for the individual. For example, in a particular
`alcoholic, the alcohol-drinking response of having beers
`while watching a game on TV maybe atleast partly
`independentof his responses of imbibing cocktails at a
`party or drinking whiskey at a bar. Each should be
`extinguished in order to assure the generality of the
`treatment. Although the alcoholic should be encour-
`aged to drink alcohol in the extinction sessions, there
`should be no social reinforcement for doing so.
`The numberof extinction sessions required for each
`patient will depend uponthe severity ofhis or her alco-
`holism and the numberof specific drinkingsituationsin
`which the alcohol-drinking response must be extin-
`guished. The duration of the extinction program may
`therefore range from about | to 5 weeks.
`Once the alcohol-drinking response has been suffi-
`ciently weakened, the final extinction sessions could be
`conducted along with an element of punishment. Exam-
`ples of punishmentinclude mild electric shock when the
`alcohol is consumed, production of conditioned taste
`aversion from very large doses of alcohol with or with-
`out emetics, aversion therapy with an alcohol-sensitiz-
`ing compoundsuchas disulfiram or cyanamide, and the
`like.
`After the final extinction session,the patientis told to
`abstain from all alcohol in the future. Various proce-
`dures can then be used to help ensure that the patient
`does in fact refrain from drinking alcohol. Such proce-
`dures include counselling, psychotherapy, family ther-
`apy, job therapy, joining Alcoholics Anonymous and
`the like. Efforts should also be taken to help thepatient
`resume a normal productive life.
`Thepatient shouldalso be informed thatalthough his
`or her alcohol-drinking response has been extinguished
`in the most frequently used drinking situations,
`it
`is
`possible that some have been missed. Consequently,if
`
`6
`the patient anticipates or is experiencing a situation in
`whichthe response has not been extinguished, he or she
`should request additional extinction sessions involving
`this new situation. Alternatively, the patient could be
`kept on a maintenance program with continued admin-
`istration of the opiate antagonist.
`The present invention is further illustrated by the
`following example.
`
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`EXAMPLE
`
`Extinction of alcohol drinking in 3 strains of rats
`Methods
`
`The effects of drinking alcohol after being injected
`with naloxone was studied in male rats of the AA strain
`developed for very high levels of alcohol drinking by
`selective breeding, in male Long Evans rats, and in male
`Wistar rats. In each case the animals first had several
`weeks of continual access to 10% (v/v) ethanol, plus
`food and water, during which timetheir alcohol drink-
`ing increased rapidly at first and eventually,after 3 to 4
`weeks, approached a stable asymptotic level. They
`were then switched to having access to 10% alcohol for
`only | hour each day. After alcohol consumption had
`stabilized, the rats of each strain were divided into
`groups matchedfor alcohol consumption during the last
`week of 1 hour daily access. One group in each strain
`was then injected with 10 mg/kg naloxone hydrochlo-
`tide 5 minutes before their hour of alcohol access for
`the next 4 days and a control group was injected with a
`similar volume ofsaline. There was a third group (“‘un-
`paired naloxone’’) of Wistar rats that was injected with
`10 mg/kg of naloxone 3 hoursafter the end of their hour
`of alcohol access. The alcohol drinking during 1 hour
`on the day after the last injection was also recorded.
`The Long Evans rats were then switched back to con-
`tinual access to alcohol and their intake measured for
`the next 13 days.
`
`Results
`
`Administering naloxone before providing access to
`alcohol progressively decreased alcohol drinking in all
`.3 strains (FIGS. 1 and 2). By the fourth day it was
`almost abolished in each strain, and the alcohol intake
`was significantly (p<0.05) lower than both the “pre”
`level (during the preceding week) andthelevelafter the
`first naloxone injection. The saline controls tended to
`increase their alcoholintake across days, perhaps due to
`the stress of injection, and drank significantly more
`alcohol than the rats given naloxone before alcohol on
`at least the last 3 extinction days and on the “post” day,
`24 hours after the last injection.
`The subsequent alcohol drinking by the Long Evans
`rats is shown in FIG.3. The rats subjected to extinction
`with naloxone continued to drink significantly less alco-
`hol than their saline controls on each day ofthefirst
`week and then gradually returned to the controllevel.
`Thelatter is probably the result of relearning the al-
`cohol-drinking response. Consistent with the common
`finding that a response is reacquired after extinction
`more rapidly than it is initially acquired, they took less
`than 2 weeks to reacquire the response, whereas naive
`Long Evans rats (i.e., ones that have never had alcohol
`before) require 3 to 4 weeks to reach this level of alco-
`holintake.
`The Wistar rats given naloxone 3 hours after alcohol
`drinking (“unpaired naloxone”) did not differ signifi-
`cantly from the controls at any time (FIG. 2); their
`
`

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`5
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`7
`slightly lower intake can probably be attributed to the
`fact that, unlike the controls, they were not stressed by
`injection immediately before having access to alcohol.
`The “unpaired naloxone” group drank significantly
`morealcohol than the “paired naloxone” group on each
`of the 4 extinction days. This suggests that the reduction
`in alcohol drinking was caused specifically by the expe-
`rience acquired while naloxone was paired with alcohol
`drinking.
`These results are all consistent with the hypothesis
`that consuming alcohol while naloxoneis present causes
`the alcohol-drinking response to be extinguished. Water
`intake and body weight were not reduced and there
`were no indications of any effects detrimental to the 15
`health of the animals.
`.
`I claim:
`1. A method for treating alcoholism by extinguishing
`the alcohol-drinking response, comprising thesteps of:
`Tepeatedly administering to a subject suffering from
`alcoholism, an opiate antagonists selected from the
`group consisting of naloxone, naltrexone, cyclazo-
`cine,
`diprenorphine,
`etazocine,
`levalorphan,
`metazocine, nalorphine and salts thereof in a daily 35
`dosagesufficient to block the stimulatory effect of
`alcohol;
`
`4,882,335
`
`8
`while the amountof antagonist in the subject’s body
`is sufficient to block the stimulatory effect of alco-
`hol, having the subject drink an alcoholic bever-
`age; and
`continuing the steps of administration of the opiate
`antagonist and drinking of an alcoholic beverage
`until the alcohol-drinking response is extinguished.
`2. The method of claim 1 further comprising the step
`of punishing the patient after the alcoholic beverageis
`consumed, said step of punishment being selected from
`the group consisting of administrationof electric shock,
`administration of emetics, and administration of an alco-
`hol sensitizing compound.
`3. The method of claim 2 wherein the alcohol sensi-
`tizing compoundis disulfiram or cyanamide.
`4. The method ofclaim 1 further comprising continu-
`ing the administration of an opiate antagonist after the
`alcohol-drinking response is extinguished.
`5. The method in accordance with claim 1 wherein
`the opiate antagonist is naloxone.
`6. The method in accordance with claim 5 wherein
`the dose of naloxoneis from 0.2 to 30 mgdaily.
`7. The method in accordance with claim 1 wherein
`the opiate antagonist is naltrexone.
`8. The method in accordance with claim 7 wherein
`the dose of naltrexoneis from 20 to 300 mgdaily.
`+
`*
`*
`*#
`*
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`