(21)   Application number: 06396001.7

(22)   Date of filing: 10.01.2006

Verwendung von Naloxon zur Behandlung von Essstörungen

Utilisation de Naloxone pour traiter les troubles alimentaires

(84) Designated Contracting States:

(30) Priority: 10.01.2005 US 31534

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).

[0001] The present invention relates to the treatment of eating disorders. In particular, the invention relates to the use of naloxone in methods of eating disorder ther­apy.

[0002] 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 can-not, however, be treated effectively by continual daily ad-ministration of opiate antagonists because normal healthy eating behavior is also reinforced by the opioi­dergic system. Instead, a selective extinction method is needed 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 must be 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, preparations with 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. In-stead it is administered transdermally or by nasal inha­lation. This provides additional advantages with eating disorders: the purging with bulimia does not affect the dosage; the gastrointestinal tract is not further disturbed by the antagonist administration; and altering eating re­sponses does not affect taking the medication.

[0003] 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 hyper-caloric diet (Moore et al., 1981).

[0004] 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 or equivalent European approval

[0008] The present invention relates to a new and al­ternative way of treating eating disorders based on the use of naloxone.

[0009] The above explained quest, utilizing antago­nists having a prolonged action and activity in the body, 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.

[0010] 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).

[0011] The present invention is, therefore based on the use of naloxone for the preparation of pharmaceutical compositions for methods of treating eating disorders in mammals, including human beings.

[0012] The method of treatment preferred comprises "selective extinction". 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.)

[0013] 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 opioidergically­reinforced behaviors that we wish to strengthen. This is not a problem with alcoholism or drug addiction.

[0014] 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.

[0015] 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.

[0016] The present invention contemplates the use of the opiate antagonist naloxone for the preparation of a pharmaceutical composition for the treatment of eating disorders. In particular the present invention provides for the use of naloxone (or a similar opiate antagonist having a half-life of less than about 2 hours, preferably less than 90 minutes).

[0017] In particular, the present invention contem­plates the use of naloxone in the formulation of a phar­maceutical composition used in a method based on se­lective extinction.

[0018] Particularly preferred compositions are those which are suitable for transdermal or nasal administration appropriate in a therapeutic method, utilizing the ability of opiate antagonist to block positive reinforcement from

30  [0022] 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. Further-

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Brief Description of the Drawings

50

Figure 1a shows selective extinction (interspersing periods when alcohol was drunk daily following naloxone injection with periods when saccharin was drunk with no injection) strongly reduced alcohol

55           drinking, while

Figure 1b depicts increasing saccharin drinking 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.

Description of Preferred Embodiments

[0025] The present invention involves taking the se­lective extinction method for separating the actions of opioid antagonists on different behaviors and contem­plates applying it to the treatment of eating disorders. Because the opioid antagonists conventionally used in treating alcoholism are not suitable for treating eating disorders, the present invention employs naloxone (or salts thereof) for use in preparations that can be taken either transdermally or by nasal inhalation in a manner suitable for selectively extinguishing eating disorders while reinforcing healthy eating behaviors. 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.

[0026] 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.

[0027] 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 some-thing 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.

[0028] 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.

[0029] 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 Hub-bell, 1922). According to these theories, the antagonists would be effective if given during abstinence; they would block craving and the onset of drinking.

[0030] Our preclinical experiments had shown that giv­ing opioid antagonists during abstinence not only failed to reduce subsequent drinking, but actually tended to in-crease 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 (Sin-

[0033] After the treatment has reduced craving for al-

[0034] The patients can return to naltrexone and drink-