application, Jan. 10, 2005, Appln. S.N. 11/031,534.
METHOD FOR TREATING EATING
BY SELECTIVE EXTINCTION WITH
Inventor: John David Sinclair
, Vilniementie 4K42, FIN 02940 Espoo, Finland
"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.
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.
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.
Principle: A Neurophysiological Theory of Behavior" J. D. Sinclair,
Lawrence Erlbaum Associates, Hillsdale, NJ, 1981.
Learning to Work for Alcohol” J. D. Sinclair, Nature 1974,
Decrease Alcohol Drinking", J.D.Sinclair, Annals of Medicine, 1990,
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,
“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
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
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.
Ricaduta Nell'Alcol: un Concetto Vincente, Ma in Via di
Estinzione?" F. Fantozzi, and D. Sinclair, Personalit Dipendenze
“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,
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.
Effect of Naltrexone on Taste Detection and Recognition
Threshold” P.A. Arbisi, C.J. Billington, A.S. Levine,
Appetite 1999, 32, 241-249.
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.
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,
Bulimia: Initial Observations", J.M. Jonas, in Opioids, Bulimia,
and Alcohol Abuse & Alcoholism, L.D. Reid, ed.,
Springer-Verlag, New York, 1990, 123-130.
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.
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,
"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,
“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.
Decreases Food Intake in Obese Humans", R. L. Atkinson, Journal of
Clinical Endocrinology and Metabolism, 1982, 55,
Opioidergic Systems" E.M.Unterwald and
R.S.Zukin, in, Opioids, Bulimia, and Alcohol
Abuse & Alcoholism, L.D. Reid, ed., Springer-Verlag, New York,
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.
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.
the Antidipsogenic Effect of Naloxone", A. S. Levine, S. S. Murray,
J. Kneip, M. Grace and J. E. Morley, Physiology and Behavior, 1982,
"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
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.
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.
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.
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,
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.
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.
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.
METHOD FOR TREATING EATING
BY SELECTIVE EXTINCTION WITH
from treating addictions
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).
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
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.
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
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
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.
experimental results had shown that alcohol drinking is a learned
behavior (Sinclair, 1