a6074458ex10_6.htm


    Exhibit
10.6

     

    
      US Patent
application, Jan. 10, 2005, Appln. S.N. 11/031,534.

       

      


       

      


       

      


       

      


       

      


       

      


       

      METHOD
FOR TREATING EATING DISORDERS

       

      


       

      BY
SELECTIVE EXTINCTION WITH TRANSDERMAL NALOXONE

       

      


       

      


       

      


       

      


       

      


       

      Inventor:
John David Sinclair,
Vilniementie 4K42, FIN 02940 Espoo, Finland

       

       

       

       

       

      
        
          
          

        

        
          1

          
            

          

        

        
          
          

        

      

       

      References
cited

       

      UNITED
STATES PATENTS

       

      
        
          	
                  4,217,353

                	
                  August
      12, 1980

                	
                  Dewey
      H. Smith, Jr.

                	 
      
	
                  4,477,457

                	
                  October
      16, 1984

                	
                  Dewey
      H. Smith, Jr.

                	 
      
	
                  4,546,103

                	
                  October
      8, 1985

                	
                  Hans
      F. Huebner

                	 
      
	
                  4,882,335

                	
                  November
      21, 1989

                	
                  J.
      D. Sinclair

                	 
      
	
                  5,096,715

                	
                  March
      17, 1992

                	
                  J.
      D. Sinclair

                	 
      
	
                  5,587,381

                	
                  December
      24, 1996

                	
                  J.
      D. Sinclair

                	 
      
	
                  5,780,479

                	
                  July
      14, 1998

                	
                  Suck
      Won Kim

                	 
      


        



       

      OTHER
PUBLICATIONS

      


       

      "Naloxone in the Treatment of Anorexia
Nervosa: Effect on Weight Gain and Lipolysis” R. Moore, I.H Mills, A.
Forster, Journal of the Royal Society of
Medicine 1981, 74, 129-31.

       

      “Targeted
Use of Naltrexone Without Prior Detoxification in the Treatment of Alcohol
Dependence: A Factorial Double-Blind Placebo-Controlled Trial.” P Heinälä, H.
Alho, K. Kiianmaa, J. Lönnqvist, K. Kuoppasalmi, and J.D. Sinclair, Journal of
Clinical Psychopharmacology, 2001. 21, 287-292.

       

      “Evidence
about the Use of Naltrexone and for Different Ways of Using It in the Treatment
of Alcoholism” J. D. Sinclair, Alcohol and Alcoholism 2001,36,
2-10.

       

      "The Rest
Principle: A Neurophysiological Theory of Behavior" J. D. Sinclair, Lawrence
Erlbaum Associates, Hillsdale, NJ, 1981.

       

      “Rats
Learning to Work for Alcohol” J. D. Sinclair, Nature 1974, 249,
590-592.

       

      "Drugs to
Decrease Alcohol Drinking", J.D.Sinclair, Annals of Medicine, 1990, 22,
357-362.

       

      “Alcohol
and Opioid Peptides: Neuropharmacological Rational for Physical Craving of
Alcohol”  M.C. Tractenberg, and K. Blum. American Journal of Drug and
Alcohol Abuse 1987,13, 365-372.

       

      “Naltrexone
and the Treatment of Alcohol Dependence” J.R. Volpicelli, C.P.O'Brien,
A.I.Alterman, and M. Hayashida, In Opioids, Bulimia, and Alcohol Abuse &
Alcoholism, L.D.Reid, ed. Springer-Verlag, New York, 1990, pp
195-214.

       

      “Opioids
Modulate Rats’ Propensities to Take Alcoholic Beverages” L. D. Reid, and C. L.
Hubbell, in Novel Pharmacological Interventions for Alcoholism. C.A. Naranjo and
E.M. Sellers (eds) New York: Springer-Verlag, pp.121-134,1992

       

      “Uso Efficace del Naltrexone: Ciò Che Non è Stato Detto a Medici e Pazienti” (Effective use of naltrexone: What
doctors and patients have not been told)  D. Sinclair, F. Fantozzi,
and J. Yanai,  The Italian Journal of the Addictions, 2003,
41,15-21.

       

      “La
Ricaduta Nell'Alcol: un Concetto Vincente, Ma in Via di Estinzione?" F.
Fantozzi, and D. Sinclair, Personalit Dipendenze 2004,10, 219-243.

       

      “Naltrexone
and Brief Counselling to Reduce Heavy Drinking” M. J. Bohn, H.R. Kranzler, D.
Beazoglou, and B.A. Staehler, The American Journal on Addictions 1994, 3,
91-99.

       

      
        
          
          

        

        
          2

          
            

          

        

        
          
          

        

      

      


       

      “A
Randomized 6 Month Double-Blind Placebo-Controlled Study of Naltrexone and
Coping Skills Education Programme” J. Balldin, M. Berglund, S. Borg, M. Månsson,
P. Berndtsen, J. Franck, L. Gustafsson, J. Halldin, C. Hollstedt, L-H. Nilsson,
and G. Stolt, Alcohol and Alcoholism 1997, 32,
325.

       

      “The
Effect of Naltrexone on Taste Detection and Recognition Threshold” P.A. Arbisi,
C.J. Billington, A.S. Levine, Appetite 1999, 32, 241-249.

       

      “Long-Term
Follow Up of Continued Naltrexone Treatment” J. D. Sinclair, K. Sinclair, and H.
Alho, Alcoholism: Clinical and Experimental Research 2000, 24, suppl.
182A.

       

      “Double-Blind
Naltrexone and Placebo Comparison Study in The Treatment of Pathological
Gambling” S. W. Kim, J. E. Grant, D. E. Adson, and Y. C. Shin, Biological
Psychiatry 2001, 49:914-921.

       

      "Basic
Mechanisms of Opioids' Effects on Eating and Drinking", S.J. Cooper and T.C.
Kirkham, in Opioids, Bulimia, and Alcohol Abuse & Alcoholism, L.D. Reid, ed.
Springer-Verlag, New York, 1990, 91-110.

       

      "Naltrexone
and Bulimia: Initial Observations", J.M. Jonas, in Opioids, Bulimia, and Alcohol
Abuse & Alcoholism, L.D. Reid,  ed., Springer-Verlag, New
York,  1990, 123-130.

       

      "Obesity,
Anorexia Nervosa, and Bulimia: A General Overview", K.D. Wild and L.D. Reid, in
Opioids, Bulimia, and Alcohol Abuse & Alcoholism, L.D. Reid, ed.,
Springer-Verlag, New York, 1990, 3-21.

       

      "Opioids
Modulate Rats' Intake of Alcoholic Beverages", C.L. Hubbell and L.D. Reid,
in  Opioids, Bulimia, and Alcohol Abuse & Alcoholism, L.D. Reid,
ed., Springer-Verlag, New York, 1990, 145-174.

       

      "Using
Drugs to Manage Binge-Eating among Obese and Normal Weight Patients", S.A.Alger,
M.J.Schwalberg, J.M. Bigaoutte, L.J. Howard, and L.D. Reid,
in:  Opioids, Bulimia, and Alcohol Abuse & Alcoholism, L.D.Reid,
ed., Springer-Verlag, New York, 1990, 131-142.

       

      “Pharmacologic
Treatment Of Binge Eating Disorder” W.P. Carter, J.I. Hudson, J.K. Lalonde, L.
Pindyck, S.L. McElroy, and H.G. Pope Jr., International Journal of Eating
Disorders 2003, 34, Suppl:S74-88.

       

      "Naloxone
Decreases Food Intake in Obese Humans", R. L. Atkinson, Journal of Clinical
Endocrinology and Metabolism, 1982, 55, 196-198.

       

      "The
Endogenous Opioidergic Systems" E.M.Unterwald and
R.S.Zukin,  in,  Opioids, Bulimia, and Alcohol Abuse &
Alcoholism, L.D. Reid, ed., Springer-Verlag, New York, 1990, 49-72.

       

      “Reduction
of Alcohol Drinking and Upregulation of Opioid Receptors by Oral Naltrexone in
AA Rats” J. H. Parkes and J.D.Sinclair. Alcohol, 2000, 21, 215-221.

       

      "Potential
Toxicities of High Doses of Naltrexone in Patients with Appetitive Disorders",
C.J. Morgan and T.R. Kosten, in Opioids, Bulimia, and Alcohol Abuse &
Alcoholism, L.D. Reid, ed. Springer-Verlag, New York,
1990,  261-273.

       

      "Flavor
Enhances the Antidipsogenic Effect of Naloxone", A. S. Levine, S. S. Murray, J.
Kneip, M. Grace and J. E. Morley, Physiology and Behavior, 1982, 28,
23-25.

       

      
        
          
          

        

        
          3

          
            

          

        

        
          
          

        

      

      "The
Effect of Naltrexone on Alcohol Consumption after Alcohol Deprivation in Rhesus
Monkeys", M. Kornet, C. Goosen, and J.M. Van Ree, Abstracts of the XXth Nordic
Meeting on Biological Alcohol Research, Espoo, Finland, May 13-15, 1990,
abstract 20

       

      "Pattern
of Onset of Bulimic Symptoms in Anorexia Nervosa", J.A. Kassett, H.E. Gwirtsman,
W.H. Kaye, H.A. Brandt, and D.C. Jimerson, American Journal of Psychiatry, 1988,
145, 1287-1288.

       

      "Case
Reports: Treatment of Chronic Anorexia Nervosa with Opiate Blockade", E.D. Luby,
M.A. Marrazzi, and J. Kinzie, Journal of Clinical Psychopharmacolgy, 1987, 7,
52-53.

       

      "An
Auto-Addiction Opioid Model of Chronic Anorexia Nervosa", M.A. Marrazzi and E.D.
Luby, International Journal of Eating Disorders, 1986, 5, 191-208.

       

      “Transdermal
Delivery of Naloxone: Effect of Water, Propylene Glycol, Ethanol and Their
Binary Combinations on Permeation Through Rat Skin” R. Panchagnula, P.S. Salve,
N.S. Thomas, A.K. Jain, and P. Ramarao,  International Journal of
Pharmacology 2001, 219, 95-105.

       

      “Nasal
Administration of Naloxone is as Effective as the Intravenous Route in Opiate
Addicts” N. Loimer, P. Hofmann, and H.R. Chaudhry,  International
Journal of Addictions, 1994, 29, 819-827.

       

      “The
Genetic Epidemiology of Bulimia Nervosa” K.S. Kendler, C. MacLean, M. Neale, R.
Kessler, A. Heath, and L. Eaves, American Journal of
Psychiatry, 1991,148,
1627-1637.

       

      “Selective
Extinction of Alcohol Drinking in Rats with Decreasing Doses of Opioid
Antagonists” J.D. Sinclair, L. Vilamo, and B. Jakobson.  Alcoholism:
Clinical and Experimental Research 1994, 18,
489.

       

      
        
          
          

        

        
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      ABSTRACT

      


       

      Various
eating disorders, including binge eating, bulimia, and stimulus-induced
over-eating, develop because the behaviors are reinforced by the opioidergic
system so often and so well that the person no longer can control the behavior.
Thus eating disorders resemble opiate addiction and
alcoholism.  Eating disorders cannot, however, be treated effectively
by continual daily administration of opiate antagonists because normal healthy
eating behavior is also reinforced by the opioidergic system. Instead, a
selective extinction method is provided that that weakens the eating disorder
while strengthening healthy eating. Extinction sessions in which the eating
disorder responses are emitted while an opiate antagonist blocks reinforcement
are interspersed with learning sessions in which healthy eating responses are
made while free of antagonist. In between extinction and learning sessions there
must be a wash-out period in which the antagonist is allowed to be eliminated
from the body, and during which neither problem eating nor healthy eating should
occur.  Consequently, long-lasting antagonists such as naltrexone and
nalmefene with wash-out periods of a day or more are not suitable, but naloxone
with a half life of only about an hour is excellent.  Naloxone cannot
be taken orally.  Instead it is administered
transdermally.  This provides the additional advantages with bulimia
that purging does not affect the dosage, that the gastrointestinal tract is not
further disturbed by the antagonist administration, and that altering eating
responses does not affect taking the medication.

       

      
        
          
          

        

        
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      METHOD
FOR TREATING EATING DISORDERS

      BY
SELECTIVE EXTINCTION WITH TRANSDERMAL NALOXONE

       

      Background
from treating addictions

       

      Opioid antagonists have been patented
for inducing anorexia (Smith, US Patent 4,217,353, 1980; US Patent 4,477,457,
1984), and they also have been patented for treating anorexia (Huebner, US
Patent 4,546,103, 1985).  Both results are valid. The antagonists can
also reduce binge eating and also the purging associated with bulimia, but
normal eating, too. Narrowly limited experiments have found evidence for each of
these effects. When put into long term practice, however, the different effects
counteract each other and cause complications. For example, as Smith pointed
out, the only clinical trial using naloxone for anorexia was inconclusive
because they coupled the treatment with giving a hypercaloric diet (Moore et
al., 1981).

       

      Unfortunately, the methods used and
previously proposed for the treatment of eating disorders are unable to separate
these various actions.  Consequently, the antagonists have produced
mixed clinical results, have not received FDA approval for use with eating
disorders, and currently are not being used clinically for such
purposes.

       

      In contrast, in the field of alcoholism
and drug addiction treatment, I proposed a method in which the antagonists
specifically remove the addictive behavior (Sinclair, U.S. Patent 4,882,335,
Nov. 21, 1989; US Patent 5,587,381, Dec. 24, 1996). Our double-blind
placebo-controlled clinical trial has shown naltrexone is effective when used in
accord with this method but not when use otherwise (Heinälä et al., 2001).
Similar results have been obtained in nearly all trials (Sinclair, 2001).
Naltrexone has been approved by the FDA for use in alcoholism treatment. Going
one step further, I improved the method into a procedure of “selective
extinction” that not only removes alcoholism and drug addiction but also
enhances other competing behaviors (Sinclair, US Patent 5,587,381, 1996;
Sinclair et al., 1994; Sinclair, 2001).  Especially here in Finland
where naltrexone is used in this selective manner, it has become a major factor
in the treatment of alcoholism.

       

      The present invention takes this
selective extinction method for separating the actions of opioid antagonists on
different behaviors and contemplates applying it to the treatment of eating
disorders.  In addition, several innovations are proposed to optimize
the method to the eating disorder field and which then differentiate the method
from all previously proposed treatments.

       

      The key for how to separate the actions
of the antagonists comes from an understanding of how the antagonists act in the
nervous system to produce benefits.

       

      There are two basic processes through
which long-term change is made in the organization of the nervous system as a
result of experience: one causes learning by strengthening synapses; the other
causes habituation and extinction by weakening synapses (see Sinclair, 1981).
Experimental results also show that the two occur under different circumstances
and follow different rules. Thus, extinction is not simply learning to do
something else but rather a separate phenomenon. It also is distinct from
forgetting; it is an active process for removing unsuccessful responses and
requires the emission of the response in the absence reinforcement.

       

      
        
          
          

        

        
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      Our preclinical experimental results
had shown that alcohol drinking is a learned behavior (Sinclair, 1974), and that
opioid antagonists suppress alcohol drinking by mechanism of extinction
(Sinclair, U.S. Patent 4,882,335, Nov. 21, 1989; Sinclair, 1990). Extinction
weakens only those responses that are made while reinforcement is
blocked.  There the method I proposed for treating alcoholism had the
antagonist being administered just before the alcoholic drank
alcohol.

       

      Others in the field, however, believed
that opioid antagonists block the craving for alcohol caused by an imbalance,
either a deficiency in opioid receptor activity (Tractenberg and Blum, 1987;
Volpicelli et al., 1990) or having too much opioid receptor activity (Reid and
Hubbell, 1922).  According to these theories, the antagonists would be
effective if given during abstinence; they would block craving and the onset of
drinking.

       

      Our preclinical experiments had shown
that giving opioid antagonists during abstinence not only failed to reduce
subsequent drinking, but actually tended to increase subsequent drinking above
control levels (Sinclair et al., 2003). The same result was found in our dual
clinical trial (Heinola et al., 2001). Naltrexone was effective when paired with
alcohol drinking, but naltrexone tended to be worse than placebo when given
during abstinence.  Similar results can be seen in the other clinical
trials (Sinclair, 2001).  The latest published count had 41 clinical
trials that obtained significant results from using opioid antagonists in a
manner allowing extinction; 37 trials using the antagonists in ways precluding
extinction, however, got negative results; only 4 trials had results contrary to
this conclusion (Fantozzi and Sinclair, 2004).

       

      The mechanism causing the increase in
alcohol drinking when antagonists are administered only during abstinence can be
used to improve the efficacy of treatment. It can increase the strength of
behaviors other than alcohol drinking, of behaviors that can compete with
drinking and help fill the vacuum as drinking is extinguished. At the same time
other behaviors that are reinforced by endorphins are protected from extinction.
One problem noted in some of the clinical alcohol trials is a reduction in the
patients’ interest in sweets or carbohydrates, or in sex (Bohn et al. 1994;
Balldin et al., 1997)  This is probably caused by these behaviors
being made while on naltrexone and thus, along with alcohol drinking, being
partially extinguished.  Naltrexone given to humans reduces their
preference for saccharin (Arbisi et al., 1999)

       

      The first step in our clinical use of
selective extinction in alcoholism treatment is to have patients make a list of
behaviors they find pleasurable.  The clinician identifies the
behaviors on the list that are probably reinforced by the opioidergic system and
advises the patient to avoid engaging in these activities on the days when
taking naltrexone and drinking.  In the beginning of treatment, this
is essentially every day.

       

      After the treatment has reduced craving
for alcohol, usually during the first month, the patient is advised to have a
weekend, starting with Friday evening, with no naltrexone and drinking. Friday
night and Saturday constitute a wash-out period for naltrexone to be removed
from the body.  On Sunday afternoon, the patient chooses some of the
opioidergically-reinforced behaviors: eating a highly palatable meal, jogging,
having sex, cuddling, cards, etc.  As expected, patients usually
report that the activities at this time are unusually enjoyable.

       

      The patients can return to naltrexone
and drinking on Monday.  They are advised, however, to try the next
week to have a longer period without naltrexone and drinking but with the
alternative behaviors. A three-year follow-up showed that complying patients
reported a maximum of 1.5 ± 0.4 (SEM) days per week (Sinclair et al.,
2000).

       

      
        
          
          

        

        
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      The example included here is a prior
preclinical experiment in which the alternative opioidergically-reinforced
behavior was saccharin drinking.  Alcohol experienced rats had
continual access to food and water.  Alcohol solution was available
for only an hour a day for 2 to 4 days.  On the next day or two,
saccharin solution instead was available.  Naloxone (or saline for the
control group) was injected prior to the alcohol session.  During the
first three weeks when the naloxone doses were in the range previously found to
be effective, the alcohol drinking was practically
abolished.  Saccharin drinking in the same animals was significantly
increased.

       

      Background
for eating disorders

       

      The opioidergic system reinforces
responses, not only when activated by an opiate or alcohol, but also when
certain types of stimuli are experienced. The stimuli cause a release of opioids
in the brain, reinforcing the responses that produced these stimuli.
Consequently, opioid antagonists have been shown in clinical trials to be
effective in treating compulsive gambling (Kim, US Patent 5,780,479, 1998; Kim
et al., 2001).

       

      Opioidergic reinforcement is well
documented for food-related stimuli. On the basis of a large body of data,
Cooper and Kirkham (1990, p. 91) concluded that "ingested items provide stimuli
which lead to the release of endogenous opioidergic peptides in the central
nervous system". The system does not appear to be involved in the reinforcement
from eventually obtaining calories, but rather with that from the pleasant
stimulation. For example, opiate antagonists reduce sham feeding of sucrose, and
they suppress the eating of chocolate-coated cookies by rats, but not the intake
of normal rat chow. Similarly in humans, the antagonist nalmefene suppresses
intake of highly palatable foods but not that of less pleasant tasting
ones.  Another general finding is that antagonists suppress food
consumption (and alcohol drinking) only in the later parts of the first session
or eating binge but not at the beginning.

       

      Other workers in the field interpret
these results differently than I do. They suggest that "endogenous opioids play
a central role in the modulation of appetite" (Jonas, 1990). The opioids
released by food-related stimuli block satiety effects and make food stimuli
continue to be pleasant even after caloric needs have been satisfied; thus the
opioid release "contributes to the maintenance of ingestional behavior" (Cooper
and Kirkham, 1990) and is "involved with processes associated with continuance
of eating rather than starting to eat" (Wild and Reid, 1990). In some people the
opioid release is too large or too long, and thus they do not stop eating (or
alcohol drinking) normally but rather have "out of control" binges. An opiate
antagonist blocks this opioid action; therefore, so long as the antagonist is
present the duration of a binge is shortened. Similarly with alcohol drinking,
"antagonists at opioceptors [sic] would reduce the propensity to continue to
drink once drinking has begun" (Hubbell and Reid, 1990).  Another
interpretation was made by Huebner (US Patent 4,546,103, 1985).  He
saw endorphins providing satisfaction and pleasure from purging for bulimic
patients and from anorexic behavior.  Blocking the opioid system with
endorphins would remove the reason for patients making the behaviors, and thus
help them to stop.

       

      
        
          
          

        

        
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      Both of these interpretations are best
served by continual opioid blockade. If endorphins cause normal eating to expand
to a binge, then continual blockade would continually prevent binges. Or if
endorphins provide the pleasure from purging, continual naltrexone would
suppress purging at all times. No one previously has proposed using only short
periods of blockade interspersed with periods when the opioid system was
functional, as is done in the present invention.

       

      I see the results not as immediate
effects of the opioids and the antagonists on appetite or satiety, but rather as
aftereffects produced by learning and extinction. When a highly palatable food
is consumed, opioids are released and as a result, after consolidation, the
response is stronger. In some people the responses are reinforced so often and
so well that they become extremely strong and cannot be controlled properly.
When the response is emitted while an opiate antagonist blocks the
reinforcement, the response is weakened. The effect can be seen even during the
first session, not at the very beginning but reducing intake in the latter
portions and thus terminating a binge earlier. The antagonists can reduce
purging if the behavior is emitted while reinforcement is blocked because of
extinction.

       

      Opiate antagonists have been tested for
eating disorders but the methods used were ones that would be appropriate if the
antagonists worked by directly increasing satiety or reducing appetite. In
particular, the subjects were kept continually on the antagonists in order to
prevent all eating from getting out of control and turning into a binge. For
example, Alger et al. (1990) gave patients suffering from binge
eating  initially 50 mg of the longer lasting antagonist, naltrexone,
once daily, then twice daily, and if that did not work, 3 times daily,
apparently for the purpose of making sure the patient was never free of
naltrexone. Although some patients seemed to benefit, over all the naltrexone
treatment was not significantly better than placebo. Similarly, although some
uncontrolled studies found benefits from naltrexone in the treatment of bulimia,
the one placebo-controlled study did not (Jonas, 1990). A recent review of
pharmacological treatments for binge eating does not include opioid antagonists
among the medicines for which there is clinical support (Carter et al.,
2003).

       

      According to the extinction hypothesis,
keeping a person continually on the antagonist is not optimal for treating
eating disorders. In the case of binge eating, it weakens not only the
binge-eating response but also all other emitted responses reinforced through
the opioidergic system. This makes the procedure less effective because the
probability of binge-eating is determined not by its absolute strength but
rather by its strength relative to all competing responses. Of particular
importance, eating in a healthy manner is also extinguished.

       

      The present invention instead employs
the "selective extinction" procedure (Sinclair, US Patent 5,587,381, 1996) which
has the person take an antagonist only before making the problem response but
free of the antagonist at times when the problem response is not made. Thus
extinction sessions, when mainly the problem response is weakened, are
interspersed with "learning periods" when other competing response including
healthy eating responses can regain their strength. In the treatment of bulimia,
only binge-eating of specific highly palatable food is weakened, but other
competing responses are not.

       

      Experimental support comes from my
studies with alcohol drinking: keeping rats continually on an antagonist (large
doses of naltrexone or nalmefene in the food) significantly lowered alcohol
drinking but did not reduce it as completely as selective extinction produced by
1 hour sessions daily when alcohol and the short-acting antagonist, naloxone,
were present, as shown in the example here.

       

      
        
          
          

        

        
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      Support may also be seen in the fact
that the only blind, placebo-controlled experiment with humans to obtain
significant results involving binge eating and antagonists was an acute study in
which naloxone significantly reduced the size of an eating binge (Atkinson,
1982).

       

      There are two other advantages of
selective extinction. First, the continual presence of an antagonist produces
up-regulation of opioid receptors (Unterwald and Zukin, 1990; Parkes and
Sinclair, 2000). Consequently, a problem response would produce more
reinforcement after the end of antagonist treatment, than it did before.
Up-regulation should be attenuated with the selective extinction procedure
because the antagonist is present only for relative short sessions interspersed
with antagonist-free periods.

       

      Second, although opiate antagonists are
considered safe, there are side-effects, such as liver toxicity with naltrexone,
elevated cortisol levels, and possible immunosuppressive effects (Morgan and
Kosten, 1990). These side-effects should be greatly reduced or eliminated with
only periodic administration of the antagonist. The dysphoria sometimes reported
with continual administration might also be caused by the general blocking of
pleasure from a wide range of activities, and should be less of a problem with
selective extinction where the person is free to enjoy opioidergic reinforcement
from other responses during the learning periods.

       

      Selective extinction can be used for
treating a variety of eating disorders. In addition to bulimia and binge-eating,
it could be used as a dieting aid. A contributing factor to obesity for many
people is overly-strong eating responses and cravings for a few highly palatable
and high-energy foods: chocolate, cookies, peanut butter, etc.  Losing
weight and then maintaining a normal weight would be possible after these
specific responses were removed by selective extinction. Similarly, selective
extinction could be used by people who are not necessarily over-weight but have
to restrict their intake of a particular substance (e.g., sugar or sodium
chloride) that can be identified with a specific stimulus that activates the
opioidergic system. (There is evidence that both sweet and salty tastes are
reinforcing through this system (Levine et al., 1982).)

       

      The present invention takes advantage
of a relationship between opiate antagonists and a phenomenon I discovered
called the "alcohol-deprivation effects". Taking alcohol away after prolonged
prior experience gradually over several days increases the desire for it. When
it is first returned, intense drinking begins immediately, probably accompanied
by intensified pleasure and reinforcement. Deprivation effects also develop for
saccharin and specific highly-palatable foods, as well as for many habitual
behaviors. Opiate antagonists have been found to be more effective in
suppressing alcohol drinking after deprivation (Kornet et al., 1990). The
probable reason is that extinction (unlike learning) is most effective with
“massed trials”, i.e., when the response is made over and over again,
vigorously, without pausing (see Sinclair, 1981). Therefore, the extinction of
specific eating responses will generally be done after several days of
deprivation of the specific food item.  For example, if chocolate ice
cream is listed by patients as a triggering food for bulimia, these patients
will be told to abstain from eating chocolate ice cream, plus ice cream in
general and chocolate in general, for a week before taking an opioid antagonists
and getting unlimited chocolate ice cream to eat and purge.

       

      
        
          
          

        

        
          10

          
            

          

        

        
          
          

        

      

      There is evidence linking anorexia
nervosa to the opioidergic system. First, it may develop from bulimia (Kassett
and Gwirtsman, 1988). Second, there is some preliminary evidence from a small
study showing for improvement of anorexia nervosa from treatment with an opiate
antagonist (Luby et al., 1987). Marrazzi and Luby (1986) suggested that
starvation causes the release of endorphins; anorexic patients starve themselves
supposedly to get elation from their own opioids. I suspect the situation is
somewhat more complicated. The specific anorexic behaviors may be reinforced by
the opioid system, but a major factor contributing to the condition is the
extinction of normal eating response.  During the developmental phase,
the patients make all of the normal eating responses: going to the table, taking
the food, pushing it around with a fork, but then willfully withholding the
responses of tasting and swallowing the food. Thus the preliminary responses are
made but do not get reinforcement from taste or from removal of hunger, and as a
result are extinguished. In any case, it is clear that the solution is a
strengthening of normal eating behaviors, and extinction of the responses
maintaining anorexia. This should be accomplished by administering opioid
antagonists while the patient is not eating, interspersed with antagonist-free
periods when the patient does in fact eat a small amount of highly palatable
food

       

      Extinguished responses can be
relearned; indeed they are relearned more readily than they were learned the
first time. Subjects can be advised after a given period of treatment to refrain
henceforth from making the extinguished response ever again in order to avoid
relearning, but they cannot avoid all responses reinforced through the
opioidergic system. One solution, used in alcoholism treatment, is to continue
taking antagonist indefinitely whenever there is a risk of drinking, or in this
case of making the eating disorder response again. Alternatively, selective
extinction can be used to "trim" offending responses that are beginning to arise
again before they become harmfully strong. Like finger-nails, the growth of
responses is a useful natural process but can become harmful when left
uncontrolled. Thus individuals with a predilection for developing overly-strong
responses might periodically review their current activities and then trim those
responses that were beginning to get too strong -- as casually and almost as
easily as we trim our nails.

       

      Technical
innovations

       

      Perhaps the greatest technological
quest in this field since the discovery of the opioid antagonists has been for
preparations that would cause the antagonists to remain in the body for longer
periods of time. Naltrexone and nalmefene have been preferred over naloxone not
only because they can be taken orally but also because of their much longer
half-lives. Various slow-release methods for naltrexone and nalmefene have been
developed over the passed two decades to provide weeks or months of constant
blockade.

       

      This quest
is consistent with the previously proposed methods for treating bulimia and
binge eating with opioid antagonists. Their imagined mechanisms of action would
work best if the antagonists were always present, thus eliminating supposed
problems of patient compliance.

       

      The present invention, however,
contemplates alternating periods when an opioid antagonist blocks the opioid
system (during which the eating disorder behaviors are emitted) with periods
when the patient’s body is free of antagonist (during which normal healthy
eating behaviors are made).

       

      We have used a similar “selective
extinction” procedure extensively in treating alcoholism (Sinclair,
2001).  (Incidentally, there has been little problem here with
compliance. Alcoholics have difficulty complying if you tell them to refrain
from drinking.  They do not have a problem, however, with obeying the
instruction to take a pill always before drinking.)

       

      
        
          
          

        

        
          11

          
            

          

        

        
          
          

        

      

      With alcoholics, we include a wash-out
period of about 48 hours for removal of the naltrexone.  During this
time the patients should not drink alcohol and they also should not engage in
the alternative opioidergically-reinforced behaviors that we wish to strengthen.
This is not a problem with alcoholism or drug addiction.

       

      In the case of eating disorders, such
long wash-out periods are not possible.  For example, when treating
bulimia, the behavior we wish to extinguish is eating foods that trigger
bulimia.  The alternative behavior we wish to strengthen is eating
foods that do not trigger bulimia.  Obviously patients cannot be
expected to avoid both activities, that is, to refrain from all eating, for a 48
hour wash-out period. Nalmefene is removed even more slowly.

       

      Naloxone, however, has a half-life of
only 30 to 80 minutes in humans.  A patient given naloxone on one day
would be free of it the following day.

       

      Naloxone is metabolized so rapidly in
the liver that all of it is removed during the first pass after oral
administration. Consequently. it usually is injected, as was the case in a
previous test for treating anorexia (Huebner, US Patent 4,546,103,
1985).

       

      Transdermal administration of naloxone,
however, is much better suited for repeated self-administration.  I
previously proposed a transdermal devise for administering a fixed dose of an
opioid antagonist, including naloxone, for use in alcoholism treatment
(Sinclair, US Patent 5,096,715, 1992). Recent experiments
(Panchagnula  et al., 2001) have shown this devise with 33% propylene
glycol as the vehicle and ethanol as the permeation enhancer is even more
effective for transdermal delivery of naloxone than I had anticipated:
“theoretically blood levels well above the therapeutic concentration of naloxone
can be achieved” with a transdermal patch of a convenient size.  An
intranasal spray has also been shown suitable for rapid administration of
naloxone for the majority of subjects and could also be used, probably in
combination with transdermal administration (Loimer et al., 1992).

       

      Avoiding the oral route also has
distinct advantages for selective extinction of eating disorders. First, there
is the problem that some of an orally administered medication would be lost by
purging, or not taken by anorexic patients.  Second, troubles with the
gastrointestinal tract are common complications with eating
disorders.  Oral administration itself irritates the throat and it
directs the highest concentration of the medication to intestines where it
interacts with opioidergically controlled motility. Third, the response of
taking an oral medication is similar to the eating responses we are trying to
alter with the treatment, thus adding a possible complication to the
procedure.

       

       

      SUMMARY OF
THE INVENTION


       

      The lifetime prevalence of bulimia is
2.8 % for women, and 5.7 % of women will show bulimia-like syndromes (Kendler et
al., 1992).  The disorder was strongly influence by genetics, with a
heritability coefficient of 55%. Comorbidity was reported between bulimia and
anorexia nervosa, alcoholism, panic disorder, generalized anxiety disorder,
phobia, and major depression.

       

      
        
          
          

        

        
          12

          
            

          

        

        
          
          

        

      

      The present invention contemplates a
therapeutic method, utilizing the ability of opiate antagonist to block positive
reinforcement from stimuli produced by highly-palatable foods, from purging, and
from anorexic behavior in order to extinguish bulimia and other eating disorders
while simultaneously strengthening normal healthy eating behaviors and the
consumption of foods conducive to health.

       

      The subject suffering from one of these
overly-strong eating disorder responses makes the response repeatedly, in the
presence of stimuli similar to those to which the response had been learned,
while active quantities of naloxone are in his or her brain, thus eventually
extinguishing the response and removing the desire to make the response. These
extinction sessions are separated by "learning periods" when the subject is free
of antagonist and can make other responses but not the problem response, in
order to restore the strength of competing responses. Thus the problem response
is selectively extinguished.

       

      In most cases the subject will suffer
from several related problem responses: e.g., overly-strong eating responses for
a dozen specific highly palatable food items. Each will be extinguished
separately.  Furthermore, prior to extinguishing a particular
response, the subject will not be allowed to make that response for at least a
week.  The resulting "deprivation effect" will assure that the subject
is highly motivated to make that response at the beginning of extinction and
will increase the effectiveness of extinction.

       

      Depending upon the severity and nature
of the problem responses, provisions are made for using the method within a
treatment center, as an out-patient treatment, and as a combination of the
two.

       

       

      DESCRIPTION
OF PREFERRED EMBODIMENTS


       

      The selective extinction method here
can be used with subjects diagnosed as suffering from maladaptive overly-strong
responses reinforced by stimulation-induced release of opioids and resulting in
eating disorders. It cannot be used for patients for whom the opiate antagonist
is contraindicated. In particularly, patients who are physiologically dependent
upon opiates must be excluded.

       

      Specific details for the use of
selective extinction with each of the different varieties of problem responses
are presented below. The initial steps, however, in each case are similar.
First, detailed information is obtained about the patient's responses: the
particular responses that cause the patient problems, the situations in which
they have typically been emitted, and particularly the foods that trigger the
behavior. Second, the patient is checked for alcoholism, drug addiction, or
other contraindications. Third, if there is any possibility of an active opiate
addiction despite denials by the patient, a small dose of opiate antagonist is
administered under close medical supervision.

       

      Binge-eating
and bulimia

       

      Severe cases should be handled
initially in a treatment center to assure compliance, to increase motivation, to
monitor health, and to provide counseling and training concerning correct eating
habits. The information obtained includes a list of the patient's "trigger
foods", i.e., those highly palatable foods that precipitate binges, are
frequently included in binges, are greatly craved, or give the patient intense
pleasure when the first bite is eaten. A list is also prepared for the patient
of "healthy foods", i.e., nutritious foods that do meet any of the above
characteristics for trigger foods.

       

      
        
          
          

        

        
          13

          
            

          

        

        
          
          

        

      

      The patient is kept initially on diet
specifically excluding a particular trigger food and foods with similar
characteristics for a week prior to treatment. (In the aforementioned example,
if the trigger is chocolate ice cream, the patient avoids not only chocolate ice
cream but all ice cream and all chocolate.) Naloxone is then administered,
perhaps first by nasal spray and then transdermally, and then while active
quantities are present in the system, the patient is presented with the trigger
food and encouraged to have an eating binge of it.  If possible, the
situation in which the food is eaten should be similar to that in which the
patient usually has had eating binges. The response set should also be similar;
e.g., if the patient typically has purged after an eating binge previously,
purging should occur also in the extinction session. No healthy foods should be
available.

       

      The
duration of an extinction session should match the patient’s previous binging
behavior.  If binging normally continued for several days, the same
should occur in treatment, with additional transdermal administrations of
naloxone being given as needed.

       

      At the end
of the extinction session, the transdermal administration is stopped and the
skin area involved is washed thoroughly.

       

      The extinction session is followed the
next day by a "learning period" of one day or more when no antagonist is given
and only healthy foods are available. Not only are trigger foods not available,
but also all stimuli related to them; the patient should not see them or smell
them, nor should they be discussed in counseling. The safe foods can be
restricted to meal times, but the patient can eat as much as desired then: no
attempt at dieting should occur during the learning periods. Learning of
alternative behaviors can be encouraged, but care should be used with regard to
responses reinforced through the opioid system. For example, greater than normal
intake of alcohol should not be allowed.)

       

      In subsequent extinction sessions, the
patient binges on other trigger foods that have not been included in the
previous sessions. In severe case being handled at a clinical center, treatment
continues until binge eating with most of the patient's trigger foods has been
extinguished and the person has gained greater control over his or her eating
habits. Thereafter, an out-patient mode of selective extinction treatment can be
used. The subject is given take-home doses of the opiate antagonist and told to
take one whenever there is a high probability that unsafe foods will be eaten in
the next few hours. The instructions state that the patients should go ahead and
have an eating binge if they feel like it, but only after taking naloxone. Under
no circumstance should they binge without taking the antagonist. The antagonist
should not be taken otherwise, i.e., when the patient thinks there is little
chance of eating trigger foods.

       

      Dietary
aid for stimulus-bound overeating

       

      An out-patient mode of selective
extinction is used for patients with less severe eating problems and high
motivation and ability for compliance. It can be used with subjects who are
obese or only moderately overweight whose weight problem is not due to glandular
anomalies but rather is caused by eating more than more than caloric needs in
response to specific stimuli. The stimuli can be specific highly-palatable
("trigger") food items, situations, or moods.  Examples of trigger
food items would be chocolate, mayonnaise, peanut butter, potato chips, cream,
butter, and cheese.  Examples of trigger situations are watching
television, fast food and other restaurants, parties, holidays, and “midnight
snack” excursions.  Examples of moods are premenstrual syndrome (PMS),
post-traumatic stress (PTS), anxiety in anticipation of a stress situation, and
celebration euphoria.

       

      
        
          
          

        

        
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      The procedure is the same as that with
binge-eating and bulimia except the subject is not kept in a treatment center
but rather conducts his or her own extinction sessions in the outside world. The
subject is given clear, precise instructions (similar to those specified above
for binge eating and bulimia) on how to extinguish the problem eating responses
(e.g., 1. create a list of trigger stimuli, 2. choose one, 3 refrain from it for
one week,  4. arrange for the trigger stimulus to be present, 5.
self-administer naloxone, 6. what to do during intervening "learning periods"
when the antagonist is not taken and the trigger stimuli are avoided as much as
possible.

       

      Dietary
aid for limiting intake of specific substances (sugar, salt, etc.)

       

      Selective extinction can be used for
people who are not necessarily overweight but must reduce their intake of a
particular substance that is closely associated with a distinct stimulus that
causes opioid release.

       

      One example is with people who need to
reduce their intake of sodium chloride. Sodium chloride is closely associated
with salty tastes, and there is evidence showing that a salty taste produces
reinforcement through the opioidergic system (Levine et al., 1982). The person
is given a series of extinction sessions on naloxone and learning periods off of
the antagonist. During the extinction sessions a variety of salty-tasting foods
are eaten. If necessary, the salty taste could be produced by a salt substitute,
but sodium chloride should be used if there is no medical danger from short-term
intake of the substance. During the learning sessions, salty-tasting foods are
omitted from the diet completely. The responses of eating salty foods are thus
selectively extinguished, while the responses of eating non-salty foods are not
weakened and may be enhanced. This will reduce the desire for salty foods and
make it easier for the person to stay on a low salt diet.

       

      A similar procedure could be used with
people who need to restrict their intake of sugars. Sweet foods are eaten during
the extinction sessions and non-sweet ones during the learning periods. The
sweet taste could be produced with artificial sweeteners, but sugar should be
used if there is no medical danger from such limited intake.

       

      The method also can be used with people
who need to restrict their intake of cholesterols or specifically low-density
cholesterols. Although there probably is no specific taste stimuli associated
with cholesterols, they tend to be present in highest amounts in particular
highly-palatable foods. Consequently, during the extinction sessions the person
eats these particular foods and during the learning session the person eats
foods with low amounts of cholesterol or low-density cholesterols.

       

      This procedure could be used either in
a treatment center or on an out-patient basis depending upon the person's
ability to comply and the severity of the ailment requiring the dietary
limitations.

       

      
        
          
          

        

        
          15

          
            

          

        

        
          
          

        

      

      


      Anorexia
nervosa

       

      The patient is kept continually on a
transdermal opiate antagonist for a period (probably 2 days or more) while
intravenous nutrients are supplied. Naltrexone or nalmefene could be used
initially but naloxone should be used in the last day.

       

      Antagonist administration is then
abruptly terminated. During the next day (a learning period when the system is
free of active levels of antagonist), the patient is given small portions of a
variety of highly-palatable foods and strongly encouraged to eat at least a
small amount. The rebound supersensitivity of the opioid system should help to
reinforce the eating responses that are made.

       

      The next day the patient is placed
again on the antagonists and fed intravenously.  The pattern of
extinction sessions and learning periods continues. New highly-palatable foods
are introduced on each antagonist-free day, with at least a week between
duplication of the same food item in order to allow deprivation effects to
increase the reinforcement. After the first sessions, increasing attention is
paid to providing a well-rounded, nutritious variety of highly-palatable foods.
Pharmacological potentiation of the opioidergic response, e.g., with moderate
amounts of alcohol, can be employed.

       

      During extinction session days on the
antagonist, the patient is encouraged to make the most common responses from his
or her own list of previously-learned competing anorexic responses (e.g.,
vigorous exercise) that are probably reinforced through the opioid system. In
most cases, the aim should be weakening these responses only to a normal
level.

       

       

      EXAMPLE


       

      Male Wistar rats (n=26) were
individually housed with daily access to 10% ethanol, with food and water always
present.  After 2 months prior experience, the rats were switched to
having 2-4 alcohol-access days interspersed with 1 or 2 days when saccharin
solution (1 g/l) was available for 1 hr.  The rats were then divided
into 2 matched groups, one always receiving a subcutaneous dose of naloxone
prior to alcohol access and a control group receiving a similar injection of
saline prior to alcohol access.  No injections were made prior to
saccharin access. In addition, the naloxone dose was progressively reduced from
10.000 to 0.005 mg/kg.

       

      The naloxone injections significantly
reduced alcohol drinking in comparison with both the alcohol intake by the
controls and in comparison with their own prior levels (see Fig.
1a).  The alcohol drinking continued to be significantly reduced for 8
weeks; many of these weeks involved doses far lower than previously found to be
effective.  Alcohol drinking was reduced to nearly zero for most rats
for 6 weeks.  The suppression of drinking of alcohol drinking appears
greater than in previous experiments in which both alcohol drinking and
antagonist administration occurred every day and specifically greater than in
studies aimed at maintaining a continual presence of the antagonist by using
longer lasting naltrexone or nalmefene and mixing them with the
food.

       

      In contrast to the sharp reduction in
alcohol drinking, saccharin drinking was consistently higher in the naloxone
treated rats than in the controls and significantly so during the first three
weeks when doses of naloxone previously shown to be effective were used (see
Fig. 1b).

       

      
        
          
          

        

        
          16

          
            

          

        

        
          
          

        

      

      


      

       

      Figure. Selective extinction
(interspersing periods when alcohol was drunk daily following naloxone injection
with periods when saccharin was drunk with no injection) strongly reduced
alcohol drinking (Fig. 1a) while increasing saccharin drinking (Fig. 1b) in the
same animals relative to intakes by control animals injected with saline. Each
data point is the mean of 1 to 4 days. The extremely low doses used from week 4
on have not previously been found to be effective.  * p<0.05
relative to saline controls.

       

      
        
          
          

        

        
          17

          
            

          

        

        
          
          

        

      

      I
claim:


       

      1. A method for treating eating
disorders by selectively extinguishing the behaviors causing the disorder while
strengthening normal health eating behaviors, comprising the steps
of:

       

      repeatedly
administering naloxone in a dosage sufficient to block the effects of opiate
agonists to a subject suffering from an eating disorder caused by one or more
related problem responses;

       

      while the
amount of naloxone in the subject's body is sufficient to block opiate effects,
having the subject make one of the problem responses from which the subject
suffers in the presence of stimuli similar to those to which it had been
learned,

       

      after the
amount of naloxone is no longer sufficient to block opiate effects, having the
subject make healthy eating responses to food items that do not trigger the
problem responses; and

       

      continuing
the steps of administration of naloxone and having one after another of the
problem responses made, followed by having a naloxone-free period in which
healthy eating occurs, until the problem responses are
extinguished.

       

      2. The
method in accordance with claim 1 wherein the eating disorder is selected from
the group comprising, binge eating, bulimia, bulimia-like syndrome, anorexia
nervosa, and habitual over-eating stimulated by specific stimuli including
certain foods, situations, or moods.

       

      3. The
method in accordance with claim 1 wherein the subject must lower intake of a
particular class of dietary substances including sodium chloride, sugars,
cholesterols or low-density cholesterols, and the responses to be selectively
extinguished are the eating of particular foods with high amounts of these
substances.

       

      4. The
method in accordance with claims 1, 2, and 3 wherein naloxone is given
transdermally and the dose per day is 0.01 to 50 mg.

       

      5.  The
method in accordance with claim 4 in which the dose of naloxone is started at a
high level of 5 to 50 mg and then is progressively reduced over the days of
treatment.

       

       

      
        18