Use of tapentadol for inhibiting and/or treating depression and anxiety   

Abstract: The use of tapentadol (i) in the treatment of pain in a subject suffering from depression and/or from anxiety, and/or (ii) in the treatment or the inhibition of depression or anxiety.

This application claims priority from co-pending U.S. provisional patent application No. 61/480,621, filed Apr. 29, 2011, the entire disclosure of which is incorporated herein by reference. Priority is also claimed based on European patent application no. EP 11 003 508.6, filed Apr. 29, 2011, the entire disclosure of which is likewise incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to the use of tapentadol in the (i) treatment of pain, preferably of neuropathic pain, more preferably of neuropathic pain due to lumbar radiculopathy, in a subject suffering from depression and/or from anxiety, and/or in the (ii) treatment or the inhibition of depression and/or of anxiety.

Tapentadol (CG5503), the chemical name for which is (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, is a synthetic, centrally-acting analgesic that is effective for the treatment of moderate to moderately-severe acute or chronic pain. The compound can be employed as the free base or its physiologically acceptable salts and solvates. Preparation of the free base is known e.g. from U.S. Pat. No. 6,248,737 (=EP 693,475).

Tapentadol is a centrally acting analgesic with a dual mode of action consisting of μ-opioid receptor (MOR) agonism and norepinephrine (NE) reuptake inhibition. The efficacy, safety, and pharmacokinetic profile of tapentadol indicate that the drug is useful in treating acute as well as chronic pain.

Subjects suffering from pain often fall into depression and anxiety, especially if the pain is chronic or neuropathic. In patients with chronic or neuropathic pain 8 to 50% have been reported to have current major depression (Smith G R, The epidemiology and treatment of depression when it co-exists with somatoform disorders, somatization or pain. Gen Hosp Psychiatry 1992, 14: 265-276). In another analysis of 1,016 patients, the prevalence of depression was 12% in individuals with 3 or more pain complaints (Dworkin S F et al., Multiple pains and psychiatric disturbance: an epidemiological investigation. Arch Gen Psychiatry 1990, 47: 239-244).

The most serious consequences of major depression are suicide and increased rates of suicidal ideation and suicide completion have been reported by patients suffering from chronic pain conditions (Magni et al., Suicidality in chronic abdominal pain; an analysis of the Hispanic Health and Nutrition Examination Survey (HHANES). Pain 1998, 76: 137-144). Oncology patients with concomitant pain and depression were significantly more likely to request assistance in committing suicide as well as actively taking steps to commit suicide. In contrast those with pain in the absence of depression were unlikely to request the intervention of euthanasia and physician-assisted suicide (Emmanuel et al., Euthanasia and physician assisted suicide; attitudes and experiences of oncology patients, oncologists and the public. Lancet 1996, 347: 1810).

On the other hand, subjects suffering from depression and/or anxiety often have pain symptoms, which can be attributed to a somatoform disorder (psychogenic pain). The pain symptoms are physical symptoms, which typically do not have an identifiable physical origin. Instead, they are the result of internal psychological conflicts that are unconsciously expressed as physical signs.

It is evident that subjects suffering from depression and/or anxiety induced by pain or inducing pain symptoms are in need of medicaments for the treatment of both, the depression and/or anxiety as well as the pain.

US 2009/0215809 discloses pharmaceutical compositions comprising a crystalline prodrug of an antiepileptic drug, namely pregabalin ((S)-3-(Aminomethyl)-5-methylhexanoic acid) for the treatment of certain diseases and disorders, including, for example, neuropathic pain, generalized anxiety disorder, fibromyalgia, migraine, hot flashes, restless legs syndrome, and sleep disorders. The pharmaceutical composition may additionally comprise an opioid agonist selected from tramadol, tapentadol, and oxycodone as a second therapeutic agent.

Similarly, U.S. Pat. No. 7,868,043 discloses pharmaceutical compositions comprising a mesophasic pregabalin prodrug and methods of use thereof.

US 2010/0297181 discloses methods for treating epilepsy, mental disorders and/or deficits in sensory organ by administering to patients therapeutically effective amounts of AMPA receptor antagonists, i.e. antiepileptic drugs, in combination with one or more other active ingredients useful for treating epilepsy, mental disorders and/or deficits in the sensory organ. Tapentadol is mentioned in a list of suitable active ingredients to be administered in combination with AMPA receptor antagonists. As mental disorders, mood disorders, such as depressions, are listed.

The use of antiepileptic drugs, however, can be detrimental because it has been found that it can be associated with a significantly increased risk for suicide-related events in patients with depression (Arana et al., Suicide-related events in patients treated with antiepileptic drugs. N Engl J Med 2010, 363: 542-551). Furthermore, a pharmaceutical composition comprising a combination of an antiepileptic and tapentadol can be disadvantageous because of adverse events caused by each drug itself and due to interactions of the drugs with each other, respectively.

Accordingly, there is a need for pharmaceutical compositions comprising a single pharmacologically active ingredient for use in the treatment of pain in a subject suffering from depression and/or anxiety, and/or for use in the treatment or the inhibition of depression and/or anxiety, wherein the single pharmacologically active ingredient may simultaneously or sequentially act as an antidepressant and as an analgesic.

US 2009/0306050 discloses compounds, such as lofepramine, exhibiting an activity as a potent norepinephrine (NE) reuptake inhibitor, and an activity at the dopamine D2 receptor sites. It was found that these special compounds are effective in the treatment and inhibition of various diseases and disorders associated with norepinephrine reuptake, such as pain predominant-type depression and depression secondary to chronic or neuropathic pain. However, antidepressants such as lofepramine exhibit several nuisance side effects and several warnings have been reported.

M. Afilalo et al., Clin. Drug Investig. 2010, 30(8), 489-505 discloses information concerning the efficacy and safety of tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee.

B. Kupferwasser et al., Osteoarthritis and Cartilage 2009, Vol. 17, Supplement 1, 179 discloses an evaluation of long-term treatment with tapentadol extended release and oxycodone controlled release in patients with chronic low back or osteoarthritis pain.

R. Lange et al., Osteoarthritis and Cartilage 2010, Vol. 18, Supplement 2, 147-148 discloses results from randomized, double-blind phase 3 studies of tapentadol prolonged release in patients with moderate to severe chronic nociceptive and neuropathic pain.

B. Kupferwasser et al., Osteoarthritis and Cartilage 2010, Vol. 18, Supplement 2, 149 discloses information concerning the health status of patients who received tapentadol prolonged release during an open-label extension study.

S. Schwartz et al., Current Medical Research & Opinion, 27(1), 2011, 151-162 discloses results of a randomized-withdrawal, placebo-controlled trial concerning safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy.

Accordingly, there remains a need for improved pharmaceutical compositions comprising a single pharmacologically active ingredient useful for treating pain and simultaneously or sequentially treating depression and/or anxiety.

SUMMARY

It is an object of the invention to provide medicaments for the treatment and inhibition of depression and/or of anxiety that have advantages compared to the medicaments of the prior art. This object has been achieved by the invention as described and claimed hereinafter.

While the analgesic efficacy of tapentadol is generally known, it has surprisingly been found that tapentadol is also effective in the treatment or inhibition of depression and/or of anxiety, preferably of depression and/or of anxiety that is induced by pain in a subject suffering from pain, and of depression and/or of anxiety inducing psychogenic pain.

In particular, in clinical trials concerning the efficacy of tapentadol against low back pain, depression (measured with HADS) was observed as undesired side effect. While in general, the occurrence of this symptom was at the borderline with respect to its clinical relevance, in the patient sub-population suffering from neuropathic pain, i.e. suffering from low back pain with a neuropathic component, a significant occurrence of depression was observed and tapentadol unexpectedly provided significant improvement.

In a first aspect, the invention is directed to the use of tapentadol in (i) the treatment of pain, preferably of neuropathic pain, more preferably of neuropathic pain due to lumbar radiculopathy, in a subject suffering from depression and/or from anxiety, and/or (ii) the treatment or inhibition of depression and/or of anxiety, with the proviso tapentadol is not administered in combination with an antiepileptic.

Thus, the invention relates to, inter alia, the use of tapentadol in a) the treatment of pain, preferably of neuropathic pain, more preferably of neuropathic pain due to lumbar radiculopathy, in a subject suffering from depression and/or from anxiety; b) the treatment of depression and/or of anxiety in a subject suffering from depression and/or from anxiety; c) the treatment of depression and/or of anxiety in a subject suffering from pain, preferably from neuropathic pain, more preferably from neuropathic pain due to lumbar radiculopathy; d) the inhibition of depression and/or of anxiety; e) the treatment of pain, preferably of neuropathic pain, more preferably of neuropathic pain due to lumbar radiculopathy, and the simultaneous treatment of depression and/or of anxiety; and/or f) the treatment of pain, preferably of neuropathic pain, more preferably of neuropathic pain due to lumbar radiculopathy, and simultaneous inhibition of depression and/or of anxiety.

A second aspect of the invention relates to a method for (i) the treatment of pain, preferably of neuropathic pain, more preferably of neuropathic pain due to lumbar radiculopathy, in a subject suffering from depression and/or from anxiety, and/or (ii) the treatment or the inhibition of depression and/or of anxiety, comprising the administration of an effective amount of tapentadol, with the proviso tapentadol is not administered in combination with an antiepileptic.

For the purpose of the specification, “tapentadol” is intended to include (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, its physiologically acceptable salts and solvates thereof. Suitable physiologically acceptable salts include salts of inorganic acids, such as hydrochloric acid (tapentadol HCl), hydrobromic acid and sulfuric acid, and salts of organic acids, such as methane sulfonic acid, fumaric acid, maleic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, lactic acid, citric acid, glutamic acid, acetylsalicylic acid, nicotinic acid, aminobenoic acid, □-liponic acid, hippuric acid and asparaginic acid. The preferred salt is the hydrochloride salt.

For the purpose of the specification, unless expressly stated otherwise, doses of tapentadol relate to the free base. Thus, when a physiologically acceptable salt of tapentadol is used instead, its dose has to be adapted to the equivalent dose of the free base. For example, a dose of “200 mg” means an amount of 200 mg of the free base or any equivalent amount of a physiologically acceptable salt or solvate corresponding to 200 mg of the free base (e.g. about 233 mg of the hydrochloride). If not expressly stated otherwise, doses are “per administration”, not “per day”.

The term “depression” is known to persons skilled in the art. Depression is a common mental disorder that presents with depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration. These problems can become chronic or recurrent and lead to substantial impairments in an individual\'s ability to take care of his or her everyday responsibilities. At its worst, depression can lead to suicide. Depression occurs in persons of all genders, ages, and backgrounds. In this regard it can further be referred e.g. to the International Classification of Diseases (ICD-10), particularly to its Chapter V. As used in the specification, the term “depression” preferably covers hereditary depressions and depressions, which represent a reaction of stressors in the environment, or both. Preferably, pain is regarded as stressor in the environment. Furthermore, the term “depression” also covers depressive disorders, such as mood disorder, major depressive disorder, and dysthymic disorder. Preferably, the term “depression” also relates to depression induced by pain, i.e. depression that arises from pain in a subject suffering from pain. The depression is typically caused by the chronic nature of the pain.

As used herein, the “depression score” is a value determining the degree of the depression. The scale of depression scores covers the range from 0 to 21, wherein the degree of the depression is high in case of high values and low in case of low values. In a group of tested subjects, typically the mean or mediate values of depression scores are determined. The mean value is the sum of all depression scores divided by the number of subjects. The mediate value is the middle depression score in the set of determined scores. Preferably, the “depression score” is defined as in the experimental section.

The term “anxiety” is known to the skilled person. Anxiety is one of the feelings one experiences when under stress; physical, social, economic, psychological. Anxiety results in a feeling of impending doom, fear (which can be intense), dryness of mouth, sweating, restlessness, racing heart, butterflies in the stomach, itching and tingling all over the body, shortness of breath, having to visit the bathroom repeatedly, inability to concentrate, make decisions, carry out work, eat or sleep. In this regard it can further be referred e.g. to the International Classification of Diseases (ICD-10), particularly to its Chapter V. As used herein, the term “anxiety” relates to an anxiety disorder. Preferably, the term “anxiety” also covers panic disorder, generalized anxiety disorder, and somatoform disorders. Preferably, the term “anxiety” also relates to anxiety induced by pain, i.e. anxiety that arises from pain in a subject suffering from pain. The anxiety is typically caused by the chronic nature of the pain.

As used herein, the “anxiety score” is a value determining the degree of the depression. The scale of anxiety scores covers the range from 0 to 21, wherein the degree of the anxiety is high in case of high values and low in case of low values. In a group of tested subjects, typically the mean or mediate values of anxiety scores are determined and referred to. The mean value is the sum of all anxiety scores divided by the number of subjects. The mediate value is the middle anxiety score in the set of determined scores. Preferably, the “anxiety score” is defined as in the experimental section.

As used herein the terms “inhibit” and “inhibition” refer only to a retarding or lessening of a condition.

As used herein the term “antiepileptic” relates to drugs used in the treatment of epilepsy. The term “antiepileptic” preferably also covers “anticonvulsants”, which are used in the treatment of epileptic seizures. Thus, the terms “antiepileptic”, “anticonvulsant” and “anti-seizure drug” are to be understood as synonyms. According to the ATC-index of the “WHO Collaborating Center for Drug Statistics Methodology” antiepileptics (N03A) cover barbiturates and derivatives, hydantoin derivatives, oxazolidine derivatives, succinimide derivatives, benzodiazepine derivatives, carboxamide derivatives, fatty acid derivatives and other antiepileptics such as pregabalin (N03AX16). According to US 2010/0297181 AMPA receptor antagonists such as 1,2-dihydropyridine compounds also exhibit an anti-seizure effect and are useful in the treatment of epilepsy. Thus, AMPA receptor antagonists also fall under the term “antiepileptic”. Dihydropyridine derivatives are also known as selective calcium channel blockers with mainly vascular effects (C08CA) according to the ATC-index of the “WHO Collaborating Center for Drug Statistics Methodology”. Thus, calcium channel blockers are also considered as being covered by the term “antiepileptic” in the specification.

As used herein, the term “psychogenic pain” preferably refers to painful symptoms, which are the result of internal psychological conflicts. These unconsciously expressed physical symptoms typically do not have an identifiable origin. Instead, the painful symptoms are the result of a somatoform disorder, also known as pain disorder. The “somatization” of pain belongs to painful symptoms of depressions and can be defined as the disease “pain predominant-type depression”, wherein the depression manifests itself predominantly in the “somatization” of pain. Preferably, the pain disorder, i.e. the “somatization of pain”, also includes hypersensitivity to pain. Furthermore, the pain disorder can be accompanied by hypochondriasis.

As used herein, the “pain score” is a value determining the degree of pain or a mixture of pains in a subject is suffering from pain. The scale of pain scores covers the range from 0 to 21, wherein the degree of pain is high in case of high values and low in case of low values. In a group of tested subjects, typically the mean or mediate values of pain scores are determined and referred to. The mean value is the sum of all pain scores divided by the number of subjects. The mediate value is the middle pain score in the set of determined scores. Accordingly, the “neuropathic pain score” is a value determining the degree of neuropathic pain, and the “nociceptive pain score” is a value determining the degree of nociceptive pain. Preferably, the “pain score” is defined as in the experimental section.

According to the invention, tapentadol is used in the (i) treatment of pain in a subject suffering from depression and/or from anxiety, and/or (ii) treatment or the inhibition of depression and/or of anxiety, with the proviso tapentadol is not administered in combination with an antiepileptic.

Preferably, tapentadol is used in the (i) treatment of neuropathic pain, more preferably of neuropathic pain due to lumbar radiculopathy, in a subject suffering from depression and/or from anxiety, and/or (ii) treatment or the inhibition of depression and/or of anxiety in a subject suffering from neuropathic pain, more preferably from neuropathic pain due to lumbar radiculopathy, preferably with the proviso that tapentadol is not administered in combination with an antiepileptic.

In one preferred embodiment, tapentadol is used in the treatment of pain in a subject suffering from depression and/or from anxiety, wherein the pain is neuropathic pain, preferably polyneuropathic pain, more preferably diabetic polyneuropathic pain.

In another preferred embodiment, tapentadol is used in the treatment of pain in a subject suffering from depression and/or from anxiety, wherein the pain is low back pain, preferably pain due to lumbar radiculopathy, having a neuropathic component, particularly a mononeuropathic component or a polyneuropathic component. The neuropathic component can be assessed e.g. by painDETECT positive (for further details, it is referred to the experimental section).

In a preferred embodiment, tapentadol is used in the treatment of pain in a subject that can be considered opioid naïve. In a preferred embodiment, tapentadol is used in the treatment of pain in a subject that has been pre-treated with opioids, preferably weak opioids.

In a preferred embodiment, tapentadol is used in the treatment of pain in a subject suffering from depression and/or from anxiety, wherein the pain is causative for depression and/or for anxiety, i.e. the pain induces depression and/or anxiety. Preferably, the pain and depression and/or anxiety are simultaneously or sequentially treated. More preferably, the pain, which is causative for depression and/or for anxiety is a mixture of nociceptive and neuropathic pain, and is simultaneously or sequentially treated with depression and/or anxiety. Most preferably, the pain, which is causative for depression and/or anxiety is neuropathic pain, and is simultaneously or sequentially treated with depression and/or anxiety.

In another preferred embodiment, tapentadol is used in the treatment of depression and/or of anxiety in a subject suffering from depression and/or from anxiety, which cannot be attributed to a pain. Preferably, the depression and/or anxiety can be attributed to a disability, to a chronic disease, to chemotherapy, to a hospital stay, to side effects of a medicament, and/or the like.

In another preferred embodiment, tapentadol is used in the treatment of depression and/or of anxiety in a subject suffering from pain, wherein depression and/or anxiety is causative for the pain, i.e. depression and/or anxiety occurs with pain symptoms. The pain symptoms may be regarded as psychogenic pain. Preferably, the psychogenic pain and depression and/or anxiety are simultaneously or sequentially treated.

In another preferred embodiment, tapentadol is used in the inhibition of depression and/or of anxiety. Preferably, depression and/or anxiety are expected to develop due to a disability, to a chronic disease, to chemotherapy, to a hospital stay, to side effects of a medicament, and/or the like.

In another preferred embodiment, tapentadol is used in the treatment of pain and the simultaneous treatment of depression and/or of anxiety. Preferably, the pain is chronic pain. More preferably, the pain is selected from the group consisting of neuropathic pain, nociceptive pain, psychogenic pain, phantom pain, and mixtures thereof. Still more preferably, the pain is a mixture of nociceptive and neuropathic pain. Most preferably, the pain is neuropathic pain.

In another preferred embodiment, tapentadol is used in the treatment of pain and the simultaneous inhibition of depression and/or of anxiety. Preferably, the pain is chronic pain. More preferably, the pain is selected from the group consisting of neuropathic pain, nociceptive pain, psychogenic pain, phantom pain, and mixtures thereof. Still more preferably, the pain is a mixture of nociceptive and neuropathic pain. Most preferably, the pain is neuropathic pain.

According to the invention, tapentadol is not administered in combination with an antiepileptic. This is advantageous because the use of antiepileptic drugs for the treatment of a subject suffering from depression and/or anxiety is undesired. It has been found that antiepileptic drugs can be associated with a significantly increased risk for suicide-related events in patients with depression. Preferably, tapentadol is not administered in combination with anticonvulsants and anti-seizure drugs. More preferably, tapentadol is not administered in combination with an antiepileptic selected from the group consisting of barbiturates and derivatives, hydantoin derivatives, oxazolidine derivatives, succinimide derivatives, benzodiazepine derivatives, carboxamide derivatives, fatty acid derivatives and other antiepileptics such as pregabalin. Most preferably, tapentadol is not administered in combination with pregabalin.

In another preferred embodiment, tapentadol is not administered in combination with AMPA receptor antagonists. AMPA receptor antagonists such as 1,2-dihydropyridines are classified as antiepileptics according to US 2010/0297181, which is incorporated by reference. Preferably, tapentadol is not administered in combination with any of the antiepileptic AMPA receptor antagonists mentioned in US 2010/0297181. More preferably, tapentadol is not administered in combination with 1,2-dihydropyridines or derivatives thereof. Dihydropyridines are also known as selective calcium channel blockers with mainly vascular effects (C08CA) according to the ATC-index of the “WHO Collaborating Center for Drug Statistics Methodology”. Consequently, tapentadol is preferably also not administered in combination with selective calcium channel blockers with mainly vascular effects. Most preferably, tapentadol is administered neither with an antiepileptic nor a calcium channel blockers.

In one preferred embodiment, tapentadol is administered as the only pharmacologically active ingredient in a medicament (medication). Preferably, tapentadol is administered via a route selected from the group consisting of orally, buccally, sublingually, transmucosally, intralumbally, intraperitoneally, transdermally, intraveneously, intramusculously, intragluteally, intracutaneously and subcutaneously. More preferably, tapentadol is administered orally.

In another preferred embodiment, tapentadol is administered once or twice daily and/or at a daily dose within the range of from 25 to 600 mg.

In another preferred embodiment, the dose of tapentadol to be administered once daily or twice daily in the course of each administration amounts to 50 mg (±75%), more preferably 50 mg (±50%), still more preferably 50 mg (±30%), yet more preferably 50 mg (±20%), most preferably 50 mg (±10%), and in particular 50 mg (±5%).

In another preferred embodiment, the dose of tapentadol to be administered once daily or twice daily in the course of each administration amounts to 100 mg (±75%), more preferably 100 mg (±50%), still more preferably 100 mg (±30%), yet more preferably 100 mg (±20%), most preferably 100 mg (±10%), and in particular 100 mg (±5%).

In still another preferred embodiment, the dose of tapentadol to be administered once daily or twice daily in the course of each administration amounts to 150 mg (±75%), more preferably 150 mg (±50%), still more preferably 150 mg (±30%), yet more preferably 150 mg (±20%), most preferably 150 mg (±10%), and in particular 150 mg (±5%).

In yet another preferred embodiment, the dose of tapentadol to be administered once daily or twice daily in the course of each administration amounts to 200 mg (±75%), more preferably 200 mg (±50%), still more preferably 200 mg (±30%), yet more preferably 200 mg (±20%), most preferably 200 mg (±10%), and in particular 200 mg (±5%).

In a preferred embodiment, the dose of tapentadol to be administered once daily or twice daily in the course of each administration amounts to 250 mg (±75%), more preferably 250 mg (±50%), still more preferably 250 mg (±30%), yet more preferably 250 mg (±20%), most preferably 250 mg (±10%), and in particular 250 mg (±5%).

In another preferred embodiment, tapentadol is used in the treatment of pain in a subject suffering from depression, wherein the pain is selected from the group consisting of pain being or being associated with panic disorder [episodic paroxysmal anxiety] [F41.0]; dissociative [conversion] disorders [F44]; persistent somatoform pain disorder [F45.4]; pain disorders exclusively related to psychological factors [F45.41]; nonorganic dyspareunia [F52.6]; other enduring personality changes [F62.8]; sadomasochism [F65.5]; elaboration of physical symptoms for psychological reasons [F68.0]; migraine [G43]; other headache syndromes [G44]; trigeminal neuralgia [G50.0]; atypical facial pain [G50.1]; phantom limb syndrome with pain [G54.6]; phantom limb syndrome without pain [G54.7]; acute and chronic pain, not elsewhere classified [G89]; ocular pain [H57.1]; otalgia [H92.0]; angina pectoris, unspecified [120.9]; other specified disorders of nose and nasal sinuses [J34.8]; other diseases of pharynx [J39.2]; temporomandibular joint disorders [K07.6]; other specified disorders of teeth and supporting structures [K08.8]; other specified diseases of jaws [K10.8]; other and unspecified lesions of oral mucosa [K13.7]; glossodynia [K14.6]; other specified diseases of anus and rectum [K62.8]; pain in joint [M25.5]; shoulder pain [M25.51]; sacrococcygeal disorders, not elsewhere classified [M53.3]; spine pain [M54.]; radiculopathy [M54.1]; cervicalgia [M54.2]; sciatica [M54.3]; low back pain [M54.5]; pain in thoracic spine [M54.6]; other dorsalgia [M54.8]; dorsalgia, unspecified [M54.9]; other shoulder lesions [M75.8]; other soft tissue disorders, not elsewhere classified [M79]; myalgia [M79.1]; neuralgia and neuritis, unspecified [M79.2]; pain in limb [M79.6]; other specified disorders of bone [M89.8]; unspecified renal colic [N23]; other specified disorders of penis [N48.8]; other specified disorders of male genital organs [N50.8]; mastodynia [N64.4]; pain and other conditions associated with female genital organs and menstrual cycle [N94]; mittelschmerz [N94.0]; other specified conditions associated with female genital organs and menstrual cycle [N94.8]; pain in throat and chest [R07]; pain in throat [R07.0]; chest pain on breathing [R07.1]; precordial pain [R07.2]; other chest pain [R07.3]; chest pain, unspecified [R07.4]; abdominal and pelvic pain [R10]; acute abdomen [R10.0]; pain localized to upper abdomen [R10.1]; pelvic and perineal pain [R10.2]; pain localized to other parts of lower abdomen [R10.3]; other and unspecified abdominal pain [R10.4]; flatulence and related conditions [R14]; abdominal rigidity [R19.3]; other and unspecified disturbances of skin sensation [R20.8]; pain associated with micturition [R30]; other and unspecified symptoms and signs involving the urinary system [R39.8]; headache [R51]; pain, not elsewhere classified [R52]; acute pain [R52.0]; chronic intractable pain [R52.1]; other chronic pain [R52.2]; pain, unspecified [R52.9]; other complications of cardiac and vascular prosthetic devices, implants and grafts [T82.8]; other complications of genitourinary prosthetic devices, implants and grafts [T83.8]; other complications of internal orthopaedic prosthetic devices, implants and grafts [T84.8]; other complications of internal prosthetic devices, implants and grafts, not elsewhere classified [T85.8]; wherein the information in brackets refers to the classification according to ICD-10.

In a preferred embodiment, the invention relates to the inhibition or treatment of pain selected from the aforementioned list of forms of pain according to ICD-10, irrespective of whether the subject simultaneously suffers from depression and/or anxiety or not.

In a particularly preferred embodiment, the invention relates to the inhibition or treatment of pain, preferably neuropathic pain, more preferably neuropathic pain due to lumbar radiculopathy, either in a subject simultaneously suffering from depression and/or anxiety; or in a subject simultaneously suffering neither from depression nor from anxiety.

Lumbar radiculopathy is a nerve irritation caused by damage to the discs between the vertebrae. Damage to the disc occurs because of degeneration of the outer ring of the disc, traumatic injury, or both. As a result, the central softer portion of the disc can rupture (herniate) through the outer ring of the disc and abut the spinal cord or its nerves as they exit the bony spinal column. This rupture is what causes the commonly recognized pain of “sciatica” that shoots down the leg.

Preferably, the tapentadol is used to treat moderate or severe pain. More preferably, the tapentadol is used to treat severe pain.

In another preferred embodiment, the pain is paroxysmal or constant. Preferably, the tapentadol is used to treat pain which is constantly present.

In another preferred embodiment, the pain is central or peripheral. Preferably, the pain is central.

In another preferred embodiment, the pain is chronic pain. Preferably, the subject has experienced the pain for at least a week, preferably at least a month, more preferably at least three months, still more preferably at least six months, and most preferably at least a year. More preferably, the pain has increased during the time the subject has experienced the pain. Most preferably, the pain has had an intermittent course during this time.

In a preferred embodiment, the chronic pain is selected from the group consisting of cancer pain, chemotherapy-induced pain, upper back pain, back pain, inflammatory pain including pain associated with rheumatic diseases, arthritic pain, ankylosing spondylitis pain, myofascial pain, pain associated with musculo-skeletal disorders, muscle pain, skeletal pain, joint pain, chronic pain associated with fibromyalgia, pain from strains/sprains, persistent post-operative pain, persistent posttraumatic pain, renal colic pain, irritable bowel syndrome-related pain, gastrointestinal pain, pelvic pain, abdominal pain, ischemic pain, angina pain, pain associated with claudication, pain accompanying myocardial infarction, vascular pain, pain associated with central nervous system trauma, facial pain, migraine-related pain, headache-related pain, orofacial pain, persistent pain deriving from damaged or inflamed somatic tissue, and combinations thereof. Preferably, the chronic pain is back pain, more preferably low back pain. Preferably, the chronic low back pain is nociceptive pain, neuropathic pain, or a mixture thereof, more preferably, the chronic low back pain is nociceptive mixed with neuropathic low back pain.

In another preferred embodiment, the pain is selected from neuropathic pain, nociceptive pain, psychogenic pain, phantom pain and mixtures thereof. Nociceptive pain may be causative for depression and/or for anxiety, i.e. induce depression and/or anxiety, whereas neuropathic pain, and phantom pain may be either causative for or resulting from depression and/or anxiety. Psychogenic pain typically results from depression and/or from anxiety, i.e. psychogenic pain may be regarded as a symptom of depression and/or anxiety.

Nociceptive pain is caused by stimulation of peripheral nerve fibers that respond only to stimuli approaching or exceeding harmful intensity (nociceptors), and may be classified according to the mode of noxious stimulation; the most common categories being “thermal” (heat or cold), “mechanical” (crushing, tearing, etc.) and “chemical” (iodine in a cut, chili powder in the eyes). Nociceptive pain may also be divided into “visceral,” “deep somatic” and “superficial somatic” pain. Visceral pain originates in the viscera (organs) and often is extremely difficult to locate, and nociception from some visceral regions produces “referred” pain, where the sensation is located in an area distant from the site of the stimulus. Deep somatic pain is initiated by stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae and muscles, and is dull, aching, poorly-localized pain. Examples include sprains and broken bones. Superficial pain is initiated by activation of nociceptors in the skin or superficial tissues, and is sharp, well-defined and clearly located. Examples of injuries that produce superficial somatic pain include minor wounds and minor (first degree) burns.

Neuropathic pain is believed to be caused by a primary lesion or dysfunction in the nervous system. Neuropathic pains have been categorized as peripheral neuropathic pain, due to lesion of the peripheral nervous system and central pain following lesions of the central nervous system. The prevalence of neuropathic pain is estimated to be about 1%. Neuropathic pain has been shown to be rather therapy resistant. Accordingly, neuropathic pain has a high potential of inducing depressions in a subject experiencing neuropathic pain.

In another preferred embodiment, the pain is neuropathic pain, nociceptive pain or a mixture thereof. More preferably, the pain is neuropathic pain.

In a preferred embodiment, the neuropathic pain is selected from the group consisting of diabetic neuralgia, monoradiculopathies, trigeminal neuralgia, post-herpetic neuralgia, persistent postoperative or posttraumatic pain, hyperalgia, allodynia, fibromyalgia, complex regional pain syndrome (CRPS), pain associated with multiple sclerosis, AIDS-related neuropathy, thalamic pain, paraplegic pain caused by myelopathy, anesthesia dolorosa, low back pain, reflex sympathetic dystrophy/causalgia (nerve trauma), cancer pain, chemotherapy-induced pain, post-thoracotomy pain, entrapment neuropathy (e.g., carpal tunnel syndrome), and peripheral neuropathy (widespread nerve damage).

In one preferred embodiment, the neuropathic pain is polyneuropathic pain. Preferably, the pain is diabetic polyneuropathic pain.

In another preferred embodiment, the pain is a mixture of neuropathic and nociceptive pain, wherein the neuropathic pain score is higher than the nociceptive pain score. Preferred values for the neuropathic pain scores and nociceptive pain scores are summarized as preferred embodiments E1 to E6 below.

E1 E2 E3 E4 E5 E6 Neuropathic ≧1 3 to 21 3 to 21 5 to 20 5 to 15 5 to 15 pain score Nociceptive ≧0 1 to 20 1 to 10 1 to 10 1 to 5 0 pain score

In another preferred embodiment, the pain is mainly neuropathic pain, wherein neuropathic pain score is preferably in the range of from 1 to 21, still more preferably from 3 to 21, yet more preferably from 5 to 20, most preferably from 5 to 15.

In another preferred embodiment, the depression and/or anxiety is induced by pain in a subject suffering from pain, wherein the pain is preferably as defined above.

In another preferred embodiment, the depression and/or anxiety induces psychogenic pain. Preferably, the psychogenic pain is back pain, chest pain, headache, muscle pain or a non-specific pain or ache, and can be regarded as a symptom for depression and/or anxiety.

In another preferred embodiment, the depression and/or anxiety induces one or more symptoms selected from the group consisting of depressed affect, anxiety, insomnia, suicidal thoughts, social inhibition, loss of energy, hopelessness, anhedonia, mood disturbances, irritability, disability, gastrointestinal disturbances, skin reactions, back pain, chest pain, headache, muscle pain and non-specific pains and aches.

The depression and/or anxiety a subject suffers from can be determined by the depression and/or the anxiety scores respectively. The initial depression and anxiety scores can be compared to the respective scores after the administration of certain amounts of tapentadol. Furthermore, the depression and anxiety scores can be assigned to certain pains. The mean and the mediate values for the depression and anxiety scores can be determined for a number of subjects. A reduction of these values indicates a decrease of depression and/or anxiety respectively.

In a preferred embodiment, the depression score is higher than the anxiety score. The values for the depression scores and anxiety scores are summarized as preferred embodiments E7 to E12 below.

E7 E8 E9 E10 E11 E12 Depression score ≧1

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