METHOD FOR TREATING EATING DISORDERS

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

References cited

UNITED STATES PATENTS

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.

“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.

"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.

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.

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.

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).

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.

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 i