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Title:
PRODUCTS FOR TREATING PSYCHOGENIC PAIN DISORDERS
Document Type and Number:
WIPO Patent Application WO/2017/064098
Kind Code:
A1
Abstract:
The present invention relates to the use of naltrexone for the manufacture of a medicament for the treatment of somatoform pain disorder or persistent pain disorder. The medication is characterized by significant reduction of the symptoms.

Inventors:
HERMANN, Lars Holger (Lindenbachstraße 50, 8006 Zürich, 8006, CH)
Application Number:
EP2016/074417
Publication Date:
April 20, 2017
Filing Date:
October 12, 2016
Export Citation:
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Assignee:
HERMANN, Lars Holger (Lindenbachstraße 50, 8006 Zürich, 8006, CH)
International Classes:
A61K31/485; A61P25/00
Domestic Patent References:
2014-10-23
1992-09-03
1999-09-16
Foreign References:
US20130197015A12013-08-01
Other References:
CHERRY D A ET AL: "Diagnostic epidural opioid blockade and chronic pain: Preliminary report", PAIN, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 21, no. 2, 1 February 1985 (1985-02-01), pages 143 - 152, XP024381750, ISSN: 0304-3959, [retrieved on 19850201], DOI: 10.1016/0304-3959(85)90284-2
Attorney, Agent or Firm:
LADENDORF, Oliver (Thomas-Wimmer-Ring 15, München, 80539, DE)
Download PDF:
Claims:
C L A I M S

1 . An opioid antagonist for use in the treatment of a somatoform disorder according to ICD-10 code F 45.

2. The opioid antagonist for use according to claim 1 , wherein said somatoform disorder is persistent somatoform pain disorder according to ICD-10 code F 45.40 or chronic pain disorder with somatic and psychological factors according to ICD-10 code F 45.41 .

3. The opioid antagonist for use according to claim 1 or 2, wherein the subject to be treated has previously been treated with one or more opiates.

4. The opioid antagonist for use according to claim 1 to 3, which is selected from the group consisting of naltrexone, naloxone, 6-alpha-naltrexol, 6- beta-naltrexol, naloxol, naltrexamine and connective tissue activating peptide (CTAP).

5. The opioid antagonist for use according to any of claims 1 to 4, wherein said opioid antagonist is naltrexone.

6. The opioid antagonist for use according to any of claims 1 to 5, wherein said opioid antagonist is administered in the form of a pharmaceutically acceptable salt, preferably hydrochloride.

7. The opioid antagonist for use according to any of claims 1 to 6, wherein said opioid antagonist is administered in the form of a tablet, plaster, or a sustained release formulation, preferably a tablet.

8. The opioid antagonist for use according to any of claims 1 to 7, wherein said opioid antagonist is administered by oral, intravenous, intramuscular, sublingual, nasal, rectal or transdermal administration; preferably by oral administration.

9. The opioid antagonist for use according to any of claims 1 to 8, wherein said opioid antagonist is administered in an amount of 25-100 mg per day, preferably 50 mg per day.

10. The opioid antagonist for use according to any of claims 1 to 9, wherein said opioid antagonist is administered either (i) daily or (ii) less frequently than once per day, preferably every 48 hours.

1 1 . The opioid antagonist for use according to any of claims 1 to 10, wherein the duration of treatment session is less than six months, preferably less than two months.

12. A pharmaceutical composition, comprising the opioid antagonist for use according to any of claims 1 to 1 1 , and a pharmaceutically acceptable carrier.

13. An opioid antagonist for diagnosing a somatoform disorder according to ICD-10 code F 45.

14. A method of treating or preventing a somatoform disorder according to ICD-10 code F 45, comprising administering an effective dose of the opioid antagonist of any of claims 1 to 1 1 , or the pharmaceutical composition of claim 12, to a subject in need thereof.

Description:
Products for treating psychogenic pain disorders

FIELD OF THE INVENTION

[0001 ] The present invention relates to the use of naltrexone for the manufacture of a medicament for the treatment of somatoform pain disorder or persistent pain disorder. The medication is characterized by significant reduction of the symptoms.

BACKGROUND OF THE INVENTION

[0002] Somatoform pain disorder (psychalgia) is a type of psychogenic condition. It is characterized by a subjectively sensed, intense and torturing pain in a part of the body, which lasts for at least six months and cannot be sufficiently explained by a body condition or physiological incidence. General common symptoms of this disease comprise pain (headache, backache), which are associated with fatigue and exhaustion. The disease described herein is the chronic form of the disease, i.e. lasting longer than six months. Frequently, the symptoms change over the progress of the disease, and various, distinct organ systems are affected. It is very characteristic that the symptoms are described inconsistently. Importantly, it should be noted that neither the pain, nor other symptoms are described in the sense of conceitedness or exaggeration, but instead there is a real pathology which is authentically felt by the patient. The psychogenic pains can be considered as being caused primarily perceptively.

[0003] The invention recited herein is defined for both ICD-10 codes, F 45.40 persistent somatoform pain disorder, and F 45.41 , chronic pain disorder with somatic and psychological factors. The distinction between these symptomatically identical disease forms is that for F 45.41 , a causative organic correlate may be considered as the cause. However, it becomes independent in a way that it leads to a persistent pain disorder. Therefore, the present invention defines disease patterns, wherein the prevalent symptoms of persistent, strong pains cannot be sufficiently explained by a physiological process or a physical disorder. An emotional conflict or social burdens can be defined, but also an organic correlate, such as in F 45.41 , can be found, which however does not (or not any more) suffice as an explanation, and cause clinically relevant suffering and compromise social, working and other major functional sectors.

[0004] The pain disorders are diagnosed when organic causes of pain are substantially excluded, or do not suffice to explain the severe duration or type of pains. According to the guideline of ICD-10, there are pains occurring on the majority of days for more than six months, which are severely distressing and without sufficient organic explanation. The attention of the patient must be focused on the disease patterns. Disorders comprising disorders of the schizophrenic type, or the occurrence during an affected or hypochondriac disorder, are considered an exclusive diagnosis.

[0005] The disease definitions presented herein are based both on the classification according to DSM 4 and 5, as well as on the definitions according to ICD 10. According to ICD 10, these are diseases of the type of soma- toform pain disorder, ICD 10 F 45.4; according to DSM 4, these are pain disorders associated with psychological factors, 307.80.

OBJECTS AND SUMMARY OF THE INVENTION

[0006] The present invention is directed to an opioid antagonist for use in the treatment of a somatoform disorder. In particular, this may be a disorder according to ICD-10 code F 45 as described in the background section, e.g. F 45.40 persistent somatoform pain disorder, or F 45.41 , chronic pain disorder with somatic and psychological factors.

[0007] It has been surprisingly found that naltrexone can be used for the treatment of somatoform disorders. Likewise, other opioid antagonists may be used for this treatment, for example naloxone, 6-alpha-naltrexol, 6-beta- naltrexol, naloxol, naltrexamine or connective tissue activating peptide (CTAP).

[0008] The present invention also provides a pharmaceutical composition, comprising the opioid antagonist for use as described above, and a pharmaceutically acceptable carrier.

[0009] In another aspect, the present invention provides an opioid antagonist for diagnosing a somatoform disorder according to ICD-10 code F 45, e.g. F 45.40 persistent somatoform pain disorder, or F 45.41 , chronic pain disorder with somatic and psychological factors.

[0010] Finally, still another aspect of the invention relates to a method of treating or preventing a somatoform disorder according to ICD-10 code F 45, e.g. F 45.40 or F 45.41 , comprising administering an effective dose of the opioid antagonist as described above, or the pharmaceutical composition as described above, to a subject in need thereof. DETAILED DESCRIPTION OF THE EMBODIMENTS

[001 1 ] Naltrexone is a drug of the opioid antagonist group. Naltrexon abolishes the effects of opioids. Naltrexone (C2oH23NO 4 , Mr = 341 .40 g/mol) is a synthetically produced opioid.

Naltrexone (Formula I)

[0012] lUPAC: (5R,9R,13S,14S)-17-cyclopropylmethyl-3,14-dihydroxy-4,5- epoxy-mor-phinan-6-one, latin: naltrexonum, molecular formula: C2oH23NO 4 (naltrexone), C2oH23NO 4 -HCI (naltrexone hydrochloride)

[0013] Naltrexone mainly occurs in the form of naltrexone hydrochloride salt.

The invention comprises the molecule and all physiologically acceptable salts. Naltrexone hydrochloride is preferred based on existing experience.

[0014] The molecule is a complete antagonist for all opiate receptors, but does not have any opioid properties itself, neither does it produce addiction by itself. For oral administration, naltrexone is resorbed virtually completely. It is subject to the first pass effect. Its half life is about 9 hours. A degradation product is beta-naltrexole, which is also antagonistically active.

[0015] The presently known indications are the treatment of opiate addiction, treatment of alcohol addiction and emergency use for opiate overdose.

[0016] In the present invention, oral administration is the preferred form of oral administration. However, it is also possible to use intravenous, intramuscular, sublingual, nasal, rectal or transdermal administration. [0017] It was surprisingly found that the substance naltrexone can be used for consecutive every day care.

[0018] The present invention is directed to an opioid antagonist for use in the treatment of a somatoform disorder according to ICD-10 code F 45.

[0019] According to one embodiment, said somatoform disorder is persistent somatoform pain disorder according to ICD-10 code F 45.40 or chronic pain disorder with somatic and psychological factors according to ICD-10 code F 45.41 .

[0020] In another embodiment, the opioid antagonist is for use as above, wherein the subject to be treated has previously been treated with one or more opiates.

[0021 ] In yet another embodiment, the opioid antagonist for use as above is selected from the group consisting of naltrexone, naloxone, 6-alpha- naltrexol, 6-beta-naltrexol, naloxol, naltrexamine and connective tissue activating peptide (CTAP).

[0022] In a particularly preferred embodiment, said opioid antagonist is naltrexone.

[0023] The opioid antagonist for use as mentioned above may be administered in the form of a pharmaceutically acceptable salt, preferably hydrochloride. The opiate antagonist may also be provided as a derivative of the above mentioned compounds, such as an ester, as long as the opioid antagonistic effect is not substantially decreased in the body. Such a deri- vate may be converted to the active form within the human body, for example by enzymatic cleavage of the derivatizing moiety.

[0024] In a particular embodiment, said opioid antagonist is administered in the form of a tablet, plaster, or a sustained release formulation, preferably a tablet. [0025] The opioid antagonist may be administered by oral, intravenous, intramuscular, sublingual, nasal, rectal or transdermal administration. Oral administration is particularly preferred.

[0026] The opioid antagonist may be administered in an amount of 25-100 mg per day, preferably 50 mg per day. For example, it may be administered in an amount of 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 mg per day, but higher doses may also be possible, such as 1 10, 120, 130, 140, 150 or 200 mg per day. A physician can routinely determine a suitably adapted dose for a given patient according to established medical practice.

[0027] The opioid antagonist may be administered either (i) daily or (ii) less frequently than once per day, preferably every 48 hours. It is particularly preferred to administer the opioid antagonist once per day, e.g. every 24 hours or approximately every 24 hours, such as once every 20, 22, 26 or 30 hours.

[0028] According to one embodiment, the duration of the treatment session is less than six months, preferably less than two months, such as 4, 5, 6 or 7 weeks.

[0029] In another aspect, the present invention provides a pharmaceutical composition, comprising the opioid antagonist for use as described above, and a pharmaceutically acceptable carrier.

[0030] In yet another aspect, the present invention provides an opioid antagonist for diagnosing a somatoform disorder according to ICD-10 code F 45, e.g. F 45.40 persistent somatoform pain disorder, or F 45.41 , chronic pain disorder with somatic and psychological factors.

[0031 ] Finally, still another aspect relates to a method of treating or preventing a somatoform disorder according to ICD-10 code F 45, e.g. F 45.40 persistent somatoform pain disorder, or F 45.41 , chronic pain disorder with so- matic and psychological factors, comprising administering an effective dose of the opioid antagonist as described above, or the pharmaceutical composition as described above, to a subject in need thereof.

[0032] The present invention is to be interpreted in the light of the application as the whole, i.e. the definitions as stated in the background sections are also applicable. However, the scope of the invention is solely limited by the claims, and therefore the invention is not limited to said definitions.

EXAMPLES

Example 1

[0033] The present inventor was consulted in a medical emergency, wherein a patient suffered from an opiate overdose. According to his relatives, the patient had been prediagnosed with a somatoform pain disorder. Due to the current deterioration of the pain symptoms, the patient had increased the opiate dose without consulting the responsible physician. The consequence was an overdose with decreasing breathing rate, cognitive impairment and somnolescence. Since the patient refused to have an injection and was still able to swallow, the patient was given naltrexone orally. The opiate adverse effects ameliorated within 20 minutes.

[0034] Since the patient did not suffer any pain in the following 12 hours, the hypothesis that the sufficient opiate dose had sufficiently ameliorated the somatoform pain disorder was maintained for 48 hours. Surprisingly, the patient presented himself at the inventor's private practice 72 hours later and insisted to be attended to. The patient stated not to have any, or only minor, pain at the areas which were typical for his disorder, even after 72 hours. The patient asked to be given the same medicament on a regular basis, without knowledge of the identity of this medicament. It was agreed with the patient to perform a drug evaluation (Heilversuch), including the evaluation of any adverse effects, which implied continuing the prescription of 100 mg naltrexone in the evening and 100 mg in the morning. After four weeks, the amelioration of all pain areas progressed significantly. In conclusion, this completely surprising effect was achieved, although all existing theories predicted that naltrexone would not have an effect of its own.

Example 2

[0035] The examples are used as treatment options for somatoform pain disorders with naltrexone.

[0036] Giving a patient a 50 mg tablet naltrexone hydrochloride daily results in a significant amelioration of pain symptoms for a 22-year-old patient with diagnosed persistent somatoform disorder.

[0037] The patient described strong changing pain, localized throughout the whole body. There was no continuously localized pain, but the pain was distributed throughout the whole body, and focused variably. In summary, the patient reported that the whole body hurts. On the visual analogue scale (VAS) for pain, the patient indicated daily-dependent pain from 5 to 8, localisation-independent. After intake of a 50 mg naltrexone hydrochloride tablet for one week, the patient reported a significant amelioration, with daily-dependent VAS values from 3 to 5. This amelioration also stabilized after four weeks of therapy, and the values stabilized to 3-4. As a result, the patient could overcome the social retraction and was able to return to everyday life.