U.S. patent application number 14/502552 was filed with the patent office on 2015-01-15 for use of tapentadol for inhibiting and/or treating depression and anxiety.
The applicant listed for this patent is Gruenenthal GmbH. Invention is credited to Ulrich JAHNEL, Ilona STEIGERWALD, Thomas TZSCHENTKE.
Application Number | 20150018426 14/502552 |
Document ID | / |
Family ID | 44260882 |
Filed Date | 2015-01-15 |
United States Patent
Application |
20150018426 |
Kind Code |
A1 |
STEIGERWALD; Ilona ; et
al. |
January 15, 2015 |
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.
Inventors: |
STEIGERWALD; Ilona; (Aachen,
DE) ; JAHNEL; Ulrich; (Remscheid, DE) ;
TZSCHENTKE; Thomas; (Aachen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gruenenthal GmbH |
Aachen |
|
DE |
|
|
Family ID: |
44260882 |
Appl. No.: |
14/502552 |
Filed: |
September 30, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13458510 |
Apr 27, 2012 |
|
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14502552 |
|
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61480621 |
Apr 29, 2011 |
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Current U.S.
Class: |
514/654 |
Current CPC
Class: |
A61K 9/0053 20130101;
A61P 25/22 20180101; A61K 31/137 20130101; A61P 25/06 20180101;
A61P 1/04 20180101; A61P 25/00 20180101; A61P 25/04 20180101; A61P
17/00 20180101; A61P 25/20 20180101; A61P 25/24 20180101; A61P
29/00 20180101 |
Class at
Publication: |
514/654 |
International
Class: |
A61K 31/137 20060101
A61K031/137 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 29, 2011 |
EP |
11 003 508.6 |
Claims
1. A method of treating pain in a subject, said method comprising
administering to the subject a therapeutically effective amount of
tapentadol as the only pharmacologically active ingredient, wherein
the subject suffers from depression and/or anxiety.
2. (canceled)
3. (canceled)
4. The method according to claim 1, wherein the tapentadol is
administered orally.
5. The method according to claim 1, wherein the tapentadol is
administered once daily or twice daily.
6. The method according to claim 1, wherein the tapentadol is
administered at a daily dose within the range of from 25 to 600
mg.
7. The method of treating pain according to claim 1, wherein the
pain is moderate or severe.
8. The method of treating pain according to claim 1, wherein the
pain is chronic pain.
9. The method according to claim 8, wherein the chronic pain is
pain selected from the group consisting of cancer pain,
chemotherapy-induced pain, upper back pain, low back pain,
inflammatory pain including pain associated with rheumatic
diseases, arthritic pain, ankylosing spondylitis, myofascial pain,
pain associated with musculo-skeletal disorders, muscle pain,
skeletal pain, joint pain, chronic pain associated with
fibromyalgia, pain from strains or sprains, persistent
post-operative pain, persistent posttraumatic pain, renal colic,
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, 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 of two or more of the foregoing.
10. The method of treating pain according to claim 1, wherein the
pain is selected from the group consisting of neuropathic pain,
nociceptive pain, psychogenic pain, phantom pain and combinations
of two or more of the foregoing.
11. The method of treating pain according to claim 1, wherein the
pain is neuropathic pain.
12. The method according to claim 11, wherein 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, pain
associated with multiple sclerosis, AIDS-related neuropathy,
thalamic pain, paraplegic pain caused by myelopathy, anesthesia
dolorosa, low back pain, reflex sympathetic dystrophy/causalgia,
cancer pain, chemotherapy-induced pain, post-thoracotomy pain,
entrapment neuropathy, and peripheral neuropathy.
13-15. (canceled)
16. The method according to claim 1, wherein the tapentadol is used
for a) the treatment of pain in the subject suffering from
depression or from anxiety; e) the treatment of pain and the
simultaneous treatment of depression or anxiety; or f) the
treatment of pain and simultaneous inhibition of depression or
anxiety.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/458,510, filed Apr. 27, 2012, which claims priority from
U.S. provisional patent Application No. 61/480,621, filed Apr. 29,
2011, the entire disclosures of which are 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
[0002] 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.
[0003] 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).
[0004] Tapentadol is a centrally acting analgesic with a dual mode
of action consisting of .mu.-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.
[0005] 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).
[0006] 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).
[0007] 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.
[0008] 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.
[0009] 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.
[0010] Similarly, U.S. Pat. No. 7,868,043 discloses pharmaceutical
compositions comprising a mesophasic pregabalin prodrug and methods
of use thereof.
[0011] 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.
[0012] 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.
[0013] 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.
[0014] 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.
[0015] 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.
[0016] 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.
[0017] 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.
[0018] 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.
[0019] 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.
[0020] 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 OF THE INVENTION
[0021] 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.
[0022] 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.
[0023] 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.
[0024] In a first aspect, the invention is directed to the use of
tapentadol in [0025] (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 [0026] (ii) the treatment or inhibition of
depression and/or of anxiety, with the proviso tapentadol is not
administered in combination with an antiepileptic.
[0027] Thus, the invention relates to, inter alia, the use of
tapentadol in [0028] 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; [0029] b) the treatment of depression and/or of anxiety in
a subject suffering from depression and/or from anxiety; [0030] 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;
[0031] d) the inhibition of depression and/or of anxiety; [0032] 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
[0033] 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.
[0034] A second aspect of the invention relates to a method for
[0035] (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
[0036] (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.
[0037] 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, onic acid, hippuric acid and asparaginic acid.
The preferred salt is the hydrochloride salt.
[0038] 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".
[0039] 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.
[0040] 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.
[0041] 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.
[0042] 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 medite
value is the middle anxiety score in the set of determined scores.
Preferably, the "anxiety score" is defined as in the experimental
section.
[0043] As used herein the terms "inhibit" and "inhibition" refer
only to a retarding or lessening of a condition.
[0044] 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.
[0045] 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.
[0046] 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.
[0047] According to the invention, tapentadol is used in the [0048]
(i) treatment of pain in a subject suffering from depression and/or
from anxiety, and/or [0049] (ii) treatment or the inhibition of
depression and/or of anxiety, with the proviso tapentadol is not
administered in combination with an antiepileptic.
[0050] Preferably, tapentadol is used in the [0051] (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 [0052] (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.
[0053] 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.
[0054] 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).
[0055] In a preferred embodiment, tapentadol is used in the
treatment of pain in a subject that can be considered opioid naive.
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.
[0056] 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.
[0057] 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.
[0058] 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.
[0059] 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.
[0060] 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.
[0061] 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.
[0062] 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.
[0063] 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.
[0064] 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.
[0065] 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.
[0066] 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%).
[0067] 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%).
[0068] 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%).
[0069] 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%).
[0070] 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%).
[0071] 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.
[0072] 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.
[0073] 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.
[0074] 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.
[0075] Preferably, the tapentadol is used to treat moderate or
severe pain. More preferably, the tapentadol is used to treat
severe pain.
[0076] In another preferred embodiment, the pain is paroxysmal or
constant. Preferably, the tapentadol is used to treat pain which is
constantly present.
[0077] In another preferred embodiment, the pain is central or
peripheral. Preferably, the pain is central.
[0078] 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.
[0079] 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.
[0080] 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.
[0081] 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.
[0082] 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.
[0083] In another preferred embodiment, the pain is neuropathic
pain, nociceptive pain or a mixture thereof. More preferably, the
pain is neuropathic pain.
[0084] 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).
[0085] In one preferred embodiment, the neuropathic pain is
polyneuropathic pain. Preferably, the pain is diabetic
polyneuropathic pain.
[0086] 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.
TABLE-US-00001 E1 E2 E3 E4 E5 E6 Neuropathic .gtoreq.1 3 to 21 3 to
21 5 to 20 5 to 15 5 to 15 pain score Nociceptive .gtoreq.0 1 to 20
1 to 10 1 to 10 1 to 5 0 pain score
[0087] 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.
[0088] 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.
[0089] 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.
[0090] 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.
[0091] 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.
[0092] 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.
TABLE-US-00002 E7 E8 E9 E10 E11 E12 Depression score .gtoreq.1 3 to
21 3 to 15 5 to 10 5 to 12 5 to 10 Anxiety score .gtoreq.0 1 to 20
1 to 10 1 to 8 3 to 8 3 to 5
[0093] In a preferred embodiment, tapentadol is used in the
treatment of pain in a subject suffering from depression and/or
from anxiety, wherein the depression and/or anxiety is
simultaneously or sequentially treated, resulting in a reduction of
the depression and anxiety scores and the pain scores. The values
for the depression scores and anxiety scores as well as the pain
scores, i.e. neuropathic and nociceptive pain scores in a subject
are summarized as preferred embodiments E13 to E20 below.
TABLE-US-00003 E13 E14 E15 E16 E17 E18 E19 E20 Depression score
.gtoreq.1 3 to 21 3 to 15 5 to 10 5 to 12 5 to 10 5 to 10 5 to 10
Anxiety score .gtoreq.0 1 to 20 1 to 10 1 to 10 3 to 8 3 to 8 3 to
8 3 to 5 Neuropathic .gtoreq.1 3 to 21 3 to 21 5 to 20 5 to 15 5 to
15 5 to 10 5 to 10 pain score Nociceptive .gtoreq.0 1 to 20 1 to 15
1 to 10 1 to 5 0 0 0 pain score
[0094] Preferably, the reduction of anxiety is dependent on the
pain the anxiety is associated with. The values for the anxiety
scores before (initial) and after (final) the administration of
tapentadol to a subject suffering from anxiety are summarized as
preferred embodiments E21 to E25 below.
TABLE-US-00004 E21 E22 E23 E24 E25 Anxiety score initial: initial:
initial: initial: initial: associated with 2 to 20 2 to 20 2 to 9 4
to 7 5.9 (.+-.1) nociceptive final: <90% final: <80% final:
final: final: pain of initial of initial 1 to 8 3 to 6 4.5 (.+-.1)
value value Anxiety score initial: initial: initial: initial:
initial: associated with 2 to 20 2 to 20 4 to 11 6 to 9 7.9 (.+-.1)
neuropathic final: <80% final: <65% final: final: final:
(presumed of initial of initial 1 to 8 3 to 6 4.8 (.+-.1) pain
compo- value value nent) Anxiety score initial: initial: initial:
initial: initial: associated with 2 to 20 2 to 20 5 to 12 7 to 10
8.3 (.+-.1) neuropathic final: <80% final: <70% final: final:
final: (defined) of initial of initial 1 to 8 3 to 6 4.5 (.+-.1)
value value
[0095] Preferably, the time period between the determination of the
initial and the final anxiety score is 6 months, more preferably 3
months, still more preferably 30 days, yet more preferably 20 days,
most preferably 10 days. Furthermore, the daily dosage of
tapentadol is preferably within the range of from 25 to 600 mg,
preferably from 50 to 300 mg, more preferably from 50 to 150
mg.
[0096] Preferably, the reduction of depression is dependent on the
pain the depression is associated with. The values for the
depression scores before (initial) and after (final) the
administration of tapentadol to a subject suffering from depression
are summarized as preferred embodiments E21 to E25 below.
TABLE-US-00005 E26 E27 E28 E29 E30 Depression score initial:
initial: initial: initial: initial: associated with 2 to 20 2 to 20
3 to 10 5 to 8 6.1 (.+-.1) nociceptive final: final: final: final:
final: <95% of initial value <85% of initial value 1 to 8 3
to 6 4.9 (.+-.1) Depression score initial: initial: initial:
initial: initial: associated with 2 to 20 2 to 20 5 to 12 7 to 10
8.8 (.+-.1) neuropathic final: final: final: final: final:
(presumed <90% of initial value <75% of initial value 3 to 10
5 to 8 6.2 (.+-.1) pain component) Depression score initial:
initial: initial: initial: initial: associated with 2 to 20 2 to 20
5 to 12 7 to 10 8.3 (.+-.1) neuropathic final: final: final: final:
final: (defined) <90% of initial value <75% of initial value
2 to 9 4 to 7 5.8 (.+-.1)
[0097] Preferably, the time period between the determination of the
initial and the final depression score is 6 months, more preferably
3 months, still more preferably 30 days, yet more preferably 20
days, most preferably 10 days. Furthermore, the daily dosage of
tapentadol is preferably within the range of from 25 to 600 mg,
more preferably from 50 to 300 mg, most preferably from 50 to 150
mg.
[0098] In another preferred embodiment, tapentadol is used in the
treatment of depression and/or anxiety, wherein the depression and
anxiety scores are reduced. The reduction of the mean values for
the anxiety scores due to the administration of tapentadol over the
time periods of 10, 20 and 30 days are summarized as preferred
embodiments E31 to E35 below. Each %-value indicates the remaining
mean anxiety score after the defined time period relative to the
initial mean anxiety score.
TABLE-US-00006 Time E31 E32 E33 E34 E35 10 days <99% <95%
<90% <80% <75% 20 days <95% <90% <85% <60%
<50% 30 days <92% <85% <80% <50% <20%
[0099] Preferably, the daily dosage of tapentadol is within the
range of from 25 to 600 mg, preferably from 50 to 300 mg, more
preferably from 50 to 150 mg.
[0100] The reduction of the mean values for the depression scores
due to the administration of tapentadol over the time periods of
10, 20 and 30 days are summarized as preferred embodiments E36 to
E30 below. Each %-value indicates the remaining mean depression
score after the defined time period relative to the initial mean
depression score.
TABLE-US-00007 Time E36 E37 E38 E39 E40 10 days <99% <95%
<90% <80% <75% 20 days <95% <90% <85% <60%
<50% 30 days <92% <85% <80% <50% <20%
[0101] Preferably, the daily dosage of tapentadol is within the
range of from 25 to 600 mg, preferably from 50 to 300 mg, more
preferably from 50 to 150 mg.
[0102] Preferably, tapentadol is administered in form of a
pharmaceutical composition comprising tapentadol and at least one
pharmaceutically acceptable additive and/or auxiliary
substance.
[0103] Suitable pharmaceutically acceptable additives and/or
auxiliary substances in the context of this invention include all
the substances known to the expert from the prior art for realizing
galenical formulations. The choice of these auxiliary substances
and the amounts thereof to be employed depend on whether the
administration unit/dosage form is to be administered orally,
intravenously, intraperitoneally, intradermally, intramuscularly,
intranasally, buccally or locally. Formulations in the form of
tablets, chewable tablets, coated tablets, capsules, granules,
drops, juices or syrups are suitable for oral administration, and
solutions, suspensions, easily reconstitutable dry formulations and
sprays are suitable for parenteral, topical and inhalatory
administration. Suppositories for use in the rectum are a further
possibility. The use in a depot in dissolved form, a carrier film
or a patch, optionally with the addition of agents which promote
penetration through the skin, are examples of suitable forms for
percutaneous administration.
[0104] Examples of pharmaceutically acceptable auxiliary substances
and additives for orally administrable units or dosage forms
include disintegrating agents, lubricants, binders, fillers, mold
release agents, optionally solvents, flavorings, sugars, in
particular carrier agents, diluents, dyestuffs, antioxidants etc.
For suppositories, inter alia, waxes and fatty acid esters can be
used, and for compositions for parental administration carrier
substances, preservatives, suspension auxiliaries etc. can be
used.
[0105] The dosage forms comprise preferably 0.05 wt.-% to 99.5
wt.-% of tapentadol, more preferably 0.1 to 90 wt.-%, still more
preferably 0.5 to 80 wt.-%, most preferably 1.0 to 50 wt.-% and in
particular 5.0 to 20 wt.-%.
[0106] Suitable pharmaceutically acceptable auxiliary substances
include, for example: water, ethanol, 2-propanol, glycerol,
ethylene glycol, propylene glycol, polyethylene glycol,
polypropylene glycol, glucose, fructose, lactose, sucrose,
dextrose, molasses, starch, modified starch, gelatine, sorbitol,
inositol, mannitol, microcrystalline cellulose, methylcellulose,
carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol,
polyvinylpyrrolidone, paraffins, waxes, naturally occurring and
synthetic gums, gum acacia, alginates, dextran, saturated and
unsaturated fatty acids, stearic acid, magnesium stearate, zinc
stearate, glyceryl stearate, sodium lauryl sulfate, edible oils,
sesame oil, coconut oil, groundnut oil, soya bean oil, lecithin,
sodium lactate, polyoxyethylene and polypropylene fatty acid
esters, sorbitan fatty acid esters, sorbic acid, benzoic acid,
citric acid, ascorbic acid, tannic acid, sodium chloride, potassium
chloride, magnesium chloride, calcium chloride, magnesium oxide,
zinc oxide, silicon dioxide, titanium oxide, titanium dioxide,
magnesium sulfate, zinc sulfate, calcium sulfate, potash, calcium
phosphate, dicalcium phosphate, potassium bromide, potassium
iodide, talc, kaolin, pectin, crospovidone, agar and bentonite.
[0107] The administration units/dosage forms according to the
invention may be controlled release, delayed release, prolonged
release/extended release, sustained release, repeat-action release,
etc. Prolonged release administration units/dosage forms are
preferred.
[0108] The administration units/dosage forms according to the
invention are prepared with the aid of means, devices, methods and
processes which are well-known in the prior art of pharmaceutical
formulation, such as are described, for example, in "Remington's
Pharmaceutical Sciences", ed. A. R. Gennaro, 17th ed., Mack
Publishing Company, Easton, Pa. (1985), in particular in part 8,
chapter 76 to 93.
[0109] Thus, e.g., for a solid formulation, such as a tablet,
tapentadol can be granulated with a pharmaceutical carrier, e.g.
conventional tablet constituents, such as maize starch, lactose,
sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or
physiologically acceptable gums, and pharmaceutical diluents, such
as e.g. water, in order to form a solid composition which comprises
tapentadol in homogeneous distribution. Homogeneous distribution is
understood here as meaning that tapentadol is uniformly distributed
over the entire composition, so that this can easily be divided
into unit dose forms, such as tablets, pills or capsules, having
the same activity. The solid composition is then divided into unit
dose forms. The administration units according to the invention can
also be coated or compounded in another manner in order to provide
a dose form with delayed release. Suitable coating compositions
are, inter alia, polymeric acids and mixtures of polymeric acids
with materials such as e.g. shellac, cetyl alcohol and/or cellulose
acetate.
[0110] Tapentadol can be released in a delayed or prolonged or
sustained manner from administration units/dosage forms which can
be used orally, rectally or percutaneously. Corresponding
formulations, in particular in the form of a "twice daily (bid)"
preparation which has to be taken only twice a day (bid), are
particularly preferred for the indication according to the
invention (cf. US-A-2005-58706).
[0111] Delayed or prolonged or sustained release of tapentadol may
be achieved by administration units/dosage forms which contain
tapentadol in a matrix, which contains e.g. 1 to 80% by weight, in
particular 5 to 80 by weight, of one or more hydrophilic or
hydrophobic polymers as physiologically acceptable matrix forming
agents and which comprise cellulose ethers and/or cellulose esters
having a viscosity (determined using a Pharm. Eu. capillary
viscosimeter) of 3,000 to 150,000 mPa s in a 2% by weight aqueous
solution at 20.degree. C. as physiologically acceptable matrix
forming agents. Preferred physiologically acceptable matrix forming
agents include polyethylene oxide having a molecular mass of more
than 0.5 mio g/mol, cellulose ethers and/or cellulose esters having
a viscosity between 10,000, in particular 50,000 mPa s, and 150,000
mPa s in a 2% by weight aqueous solution at 20.degree. C.
Particularly suitable physiologically acceptable matrix forming
agents may be selected from the group consisting of
hydroxypropylmethyl celluloses (HPMC), hydroxyethyl celluloses,
hydroxypropyl celluloses (HPC), methyl celluloses, ethyl celluloses
and carboxymethyl celluloses and are selected, in particular, from
the group consisting of HPMCs, hydroxyethyl celluloses and HPCs.
HPMCs having a viscosity of approximately 100,000 mPa s, measured
in a 2% by weight aqueous solution at 20.degree. C. are most
preferred.
[0112] The administration units/dosage forms according to the
invention can exist both as a simple tablet and as a coated tablet,
for example as a film tablet or dragee. The tablets are typically
round and biconvex, but oblong tablet shapes which allow the tablet
to be divided are also possible. Granules, spheroids, pellets or
microcapsules which are poured into sachets or capsules or may be
compressed to disintegrating tablets are also possible within the
scope of the invention.
[0113] Instead of a slow release matrix, it is also possible to use
a normal release matrix with a coating which retards release of the
pharmacologically active ingredient. For example, tapentadol can be
contained in a conventional matrix of microcrystalline cellulose
and optionally further pharmaceutical auxiliaries such as binders,
fillers, glidants, lubricants and flow regulators, which are
covered or coated with a material controlling the slow release of
tapentadol in an aqueous medium. Suitable coating agents include,
for example, water-insoluble waxes and polymers such as
polymethacrylates (Eudragit or the like) or water-insoluble
celluloses, in particular ethyl cellulose. The coating material can
optionally also contain water-soluble polymers such as polyvinyl
pyrrolidone, water-soluble celluloses such as hydroxypropylmethyl
cellulose or hydroxypropyl cellulose, other water-soluble agents
such as Polysorbate 80 or hydrophilic pore-forming agents such as
polyethylene glycol, lactose or mannitol.
[0114] As an alternative or a supplement to the possibilities of a
slow release matrix in the delayed release or prolonged release or
sustained release dosage forms or of a normal release matrix with a
coating which retards the release of tapentadol, an osmotically
driven release system can also be used to achieve a slow release.
Embodiments and examples of the actual production of osmotically
driven release systems can be found in U.S. Pat. No. 4,765,989,
U.S. Pat. No. 4,783,337, and U.S. Pat. No. 4,612,008.
[0115] The following examples further illustrate the invention but
are not to be construed as limiting its scope.
EXAMPLE
Aim and Design
[0116] The effectiveness of tapentadol hydrochloride PR and
tapentadol hydrochloride IR in the treatment of pain in a subject
suffering from depression and/or from anxiety, and in the treatment
of depression and/or of anxiety has been demonstrated in a clinical
study in subjects with severe and chronic nociceptive, mixed with
neuropathic low back pain. A subgroup suffering from neuropathic
pain due to lumbar radiculopathy was also investigated.
[0117] This was a multicenter, multinational, open-label,
effectiveness phase IIIb trial to evaluate effectiveness and safety
of tapentadol prolonged release treatment in patients with
inadequately managed, severe chronic low back pain with or without
a neuropathic pain component. Patients taking WHO Step II
analgesics discontinued those analgesics before starting study
medication; patients taking Step I analgesics and/or centrally
acting co-analgesics continued on the same dose. Patients who
enrolled in the study and were taking WHO Step I or II analgesics
had an average pain intensity score of >5 on an 11-point NRS-3
(average pain over 3 days prior to assessment) at screening;
patients who were taking no regular analgesic treatment had an
average pain intensity score (NRS-3) of >6. All patients
received tapentadol prolonged release (50-250 mg bid) for up to 12
weeks (5-week titration period and a 7-week maintenance period).
Tapentadol immediate release (IR) 50 mg (.ltoreq.twice a day,
.gtoreq.4 hours apart) was permitted (combined total daily dose of
tapentadol prolonged release and tapentadol IR, .ltoreq.500
mg/day). The primary efficacy endpoint was the change from Baseline
to Week 6 (when tapentadol prolonged release doses were stable) in
average pain intensity on the 11-point NRS-3 using the last
observation carried forward (LOCF) for imputing missing scores. The
painDETECT questionnaire was used to evaluate the likelihood of a
neuropathic pain component of low back pain; patients were
classified as painDETECT "negative," "unclear," or "positive." The
population of patients classified as painDETECT negative was
limited to approximately 30% of the total population.
[0118] In the painDETECT positive trial population the "diagnosis
of lumbar radiculopathy" was evaluated which was defined per study
protocol according following criteria: [0119] typical dermatomal
pain (radiating beyond the knee towards the foot, pain evoked by
stretching within distribution of the ischiadic/femoral nerve)
[0120] signs of root dysfunction: [0121] such as sensory
impairment, motor symptoms from compression of lumbar nerve root
(L4, L5, S1). [0122] and/or absent or diminished quadriceps femoris
or triceps surae reflexes. [0123] and/or quantitative sensory
testing (QST) deficit and pain distribution present in the same
dermatomal area.
[0124] In subjects with neuropathic pain further characterization
of the symptoms was performed. These additional assessments
referred explicitly to the neuropathic component of the LBP
(Neuropathic Pain Symptom Inventory (NPSI), Short Form McGill Pain
Questionnaire (SF-MPQ).NRS-3 for pain radiating towards or into the
leg).
[0125] All subjects completed Short Form-36 (SF-36) and EuroQoi-5
Dimension (EQ-5D) questionnaires and the Hospital Anxiety and
Depression Scale (HADS). The Patient Global Impression of Change
(PGIC) and Clinical global impression of change (CGIC) were also
used as secondary endpoints. For both tests, patients completed the
statement, "since I began trial treatment, I would rate my overall
condition as," using 7 possible responses ("very much worse" to
"very much improved"). Adverse events were recorded throughout the
trial. Furthermore, 51.8% of the painDETECT positive trial
population had a "diagnosis of lumbar radiculopathy" as defined per
study protocol.
Results
[0126] Short Form 36.RTM. Health Survey (SF-36.RTM.) scores: SF-36
physical functioning, bodily pain, general health, role-emotional
and physical component summary scores improved from Baseline to
Week 12 for patients who were painDETECT negative or
unclear/positive (all P<0.05); for those who were
unclear/positive, role-physical, vitality, social functioning,
mental health, reported health transition and mental component
summary scores also improved (all P<0.05).
[0127] EuroQol-5 Dimension (EQ-5D) scores: the mean (SD) change
from Baseline to Week 12 in the EQ-5D health status index score was
0.18 (0.25; P=0.0022) for patients who were painDETECT negative and
0.36 (0.32); P<0.0001) for those positive.
[0128] Hospital Anxiety and Depression Scale (HADS): Baseline mean
(SD) HADS depression (6.5[3.96] vs. 8.5[4.27]) and anxiety
(6.2[4.10] vs. 8.4[4.26]) scores were lower for patients with a
painDETECT negative vs. an unclear/positive result, respectively.
HADS depression and anxiety scores improved steadily from Baseline
to Week 12 for patients who were painDETECT unclear/positive
(P<0.0001 at Visit 12 for depression and anxiety), but not
significantly for those with a negative result. HADS depression and
anxiety scores improved steadily from Baseline to Week 12 for
patients with positive diagnosis of lumbar
radiculopathy-neuropathic pain subset (0.0023 at Visit 12 for
depression, p=0.0105 at Visit 12 for anxiety).
[0129] Patient Global Impression of Change: The percentage of
patients reporting a rating of "very much improved" or "much
improved" on the PGIC increased from 15.1% (26/172) at Week 1 to
48.6% (67/138) at Week 6 and 67.1% (61/91) at Week 12.
[0130] Clinical global impression of change (CGIC): The percentage
of patients reporting a rating of "very much improved" or "much
improved" on the CGIC increased from 15.1% (26/172) at Week 1 to
50.7% (70/138) at Week 6 and 68.2% (62/91) at Week 12.
[0131] Subject satisfaction with previous/new treatment: The
percentage of patients reporting a rating of "excellent" or "very
good" increased from 0.0% (0/175) at Baseline to 29.7 (41/138) at
Week 6 and 52.8% (48/91) at Week 12.
[0132] In the following [0133] (i) N is the number of subjects of
the specified diagnosis group, [0134] (ii) n is the number of
subjects with data available, [0135] (iii) "Mean" is the mean score
of the subjects, i.e. the sum of all scores is divided by the
number of subjects, [0136] (iv) SD is the standard deviation,
[0137] (v) "Median" is the median score of the subjects, i.e. the
middle score in the set of scores, [0138] (vi) "Range" is the range
of scores of the subjects, i.e. the range defined by the lowest and
the highest score of the set of scores. First, the depression
scores are presented. The total number of subjects in the clinical
study: N=175
TABLE-US-00008 [0138] Depression score n Mean (SD) Median Range
Screening 174 7.9 (4.37) 8.0 1-20 Baseline 173 7.9 (4.27) 8.0 0-21
Visit 1 164 7.8 (4.47) 7.0 0-20 Visit 5 141 6.9 (4.26) 6.0 0-18
Visit 6 130 6.6 (4.41) 6.0 0-19 Visit 7 127 6.1 (4.40) 6.0 0-18
Visit 8 119 6.2 (4.16) 6.0 0-17 Visit 9 87 6.1 (4.48) 6.0 0-17
Visit 10 85 6.2 (4.66) 6.0 0-21 Visit 11 85 5.9 (4.59) 5.0 0-17
Visit 12 89 5.7 (4.35) 5.0 0-18
Total number of subjects with nociceptive pain: N=49
TABLE-US-00009 Depression score n Mean (SD) Median Range Screening
48 6.8 (4.17) 6.0 1-16 Baseline 49 6.5 (3.96) 6.0 0-15 Visit 1 43
6.1 (3.90) 5.0 0-15 Visit 5 37 5.6 (3.68) 5.0 0-13 Visit 6 34 5.3
(4.03) 4.0 1-15 Visit 7 35 5.0 (3.63) 4.0 1-14 Visit 8 32 5.5
(3.90) 4.5 0-16 Visit 9 25 5.4 (3.49) 5.0 1-12 Visit 10 24 5.5
(3.34) 5.5 1-12 Visit 11 23 5.6 (4.04) 5.0 0-14 Visit 12 23 4.9
(3.13) 4.0 0-11
Total number of subjects with presumed neuropathic pain component:
N=41
TABLE-US-00010 Depression score n Mean (SD) Median Range Screening
41 7.4 (3.69) 7.0 1-17 Baseline 40 7.9 (3.84) 7.5 1-17 Visit 1 38
8.8 (4.59) 8.5 1-18 Visit 5 33 7.5 (4.59) 7.0 0-18 Visit 6 30 7.5
(4.60) 7.5 0-17 Visit 7 32 7.0 (4.71) 6.5 0-18 Visit 8 28 6.4
(4.24) 6.0 1-14 Visit 9 19 6.4 (4.32) 6.0 0-15 Visit 10 19 6.4
(5.34) 5.0 0-21 Visit 11 20 6.4 (5.11) 5.0 0-17 Visit 12 21 6.2
(4.66) 5.0 0-17
Total number of subjects with defined neuropathic pain: N=85
TABLE-US-00011 Depression score n Mean (SD) Median Range Screening
85 8.9 (4.63) 9.0 1-20 Baseline 84 8.7 (4.46) 8.5 0-21 Visit 1 83
8.3 (4.51) 8.0 1-20 Visit 5 71 7.3 (4.29) 7.0 1-17 Visit 6 66 6.8
(4.41) 6.0 0-19 Visit 7 60 6.2 (4.56) 6.0 0-16 Visit 8 59 6.4
(4.28) 6.0 1-17 Visit 9 43 6.5 (5.06) 6.0 0-17 Visit 10 42 6.5
(5.04) 6.0 0-19 Visit 11 42 5.9 (4.70) 5.5 0-15 Visit 12 45 5.8
(4.76) 5.0 0-18
Total number of subjects with presumed or defined neuropathic pain
component: N=126
TABLE-US-00012 Depression score n Mean (SD) Median Range Screening
126 8.4 (4.38) 8.0 1-20 Baseline 124 8.5 (4.27) 8.0 0-21 Visit 1
121 8.5 (4.52) 8.0 1-20 Visit 5 104 7.4 (4.37) 7.0 0-18 Visit 6 96
7.1 (4.46) 7.0 0-19 Visit 7 92 6.5 (4.61) 6.0 0-18 Visit 8 87 6.4
(4.24) 6.0 1-17 Visit 9 62 6.5 (4.81) 6.0 0-17 Visit 10 61 6.5
(5.09) 6.0 0-21 Visit 11 62 6.0 (4.80) 5.0 0-17 Visit 12 66 5.9
(4.70) 5.0 0-18
Total number of subjects with positive diagnosis of lumbar
radiculopathy-neuropathic pain subset: N=44
TABLE-US-00013 Depression score n Mean (SD) Median Range Screening
44 8.5 (4.70) 8.5 2-20 Baseline 44 8.2 (4.09) 8.0 0-17 Visit 1 44
7.5 (3.69) 7.5 1-15 Visit 5 40 6.7 (3.77) 6.0 1-14 Visit 6 38 6.3
(3.67) 6.0 1-13 Visit 7 34 5.4 (3.85) 5.0 0-14 Visit 8 35 5.8
(3.71) 6.0 1-14 Visit 9 24 6.2 (4.63) 7.5 1-14 Visit 10 25 6.2
(4.50) 7.0 0-13 Visit 11 26 6.0 (4.69) 6.5 0-14 Visit 12 27 5.3
(4.09) 5.0 0-12
Second, the anxiety scores are presented. The total number of
subjects: N=175
TABLE-US-00014 Anxiety score n Mean (SD) Median Range Screening 174
8.1 (3.99) 8.0 1-19 Baseline 173 7.8 (4.32) 7.0 0-18 Visit 1 164
7.6 (4.28) 7.0 0-18 Visit 5 141 6.8 (3.94) 7.0 0-17 Visit 6 130 6.6
(4.02) 6.0 0-18 Visit 7 127 5.9 (3.99) 6.0 0-18 Visit 8 119 5.6
(3.95) 5.0 0-18 Visit 9 87 5.7 (4.10) 4.0 0-19 Visit 10 85 5.6
(4.16) 5.0 0-19 Visit 11 85 5.4 (3.91) 5.0 0-14 Visit 12 89 5.2
(3.73) 4.0 0-13
Total number of subjects with nociceptive pain: N=49
TABLE-US-00015 Anxiety score n Mean (SD) Median Range Screening 48
6.7 (3.80) 6.5 1-15 Baseline 49 6.2 (4.10) 5.0 0-16 Visit 1 43 5.9
(4.19) 6.0 0-18 Visit 5 37 6.1 (3.80) 5.0 0-14 Visit 6 34 5.8
(4.68) 5.0 0-18 Visit 7 35 5.6 (4.15) 5.0 0-18 Visit 8 32 5.4
(4.40) 4.0 0-18 Visit 9 25 4.6 (3.34) 4.0 0-13 Visit 10 24 4.7
(3.21) 4.0 0-11 Visit 11 23 4.8 (3.77) 4.0 0-14 Visit 12 23 4.5
(3.65) 3.0 0-13
Total number of subjects with presumed neuropathic pain component:
N=41
TABLE-US-00016 Anxiety score n Mean (SD) Median Range Screening 41
8.3 (3.68) 8.0 1-17 Baseline 40 8.3 (4.15) 7.0 2-17 Visit 1 38 7.9
(4.52) 7.0 2-17 Visit 5 33 6.7 (4.22) 7.0 0-15 Visit 6 30 6.9
(3.99) 6.0 1-16 Visit 7 32 5.9 (4.08) 5.5 0-13 Visit 8 28 4.9
(4.04) 4.0 0-14 Visit 9 19 6.1 (5.10) 6.0 0-19 Visit 10 19 5.5
(5.46) 4.0 0-19 Visit 11 20 5.1 (4.25) 4.0 0-13 Visit 12 21 4.8
(3.67) 4.0 0-12
Total number of subjects with defined neuropathic pain: N=85
TABLE-US-00017 Anxiety score n Mean (SD) Median Range Screening 85
8.9 (4.07) 9.0 1-19 Baseline 84 8.5 (4.33) 8.5 0-18 Visit 1 83 8.3
(4.01) 8.0 0-18 Visit 5 71 7.2 (3.89) 8.0 0-17 Visit 6 66 6.9
(3.66) 6.0 0-16 Visit 7 60 6.1 (3.91) 6.0 0-16 Visit 8 59 6.0
(3.66) 5.0 0-14 Visit 9 43 6.1 (3.99) 5.0 1-16 Visit 10 42 6.1
(3.98) 6.0 0-16 Visit 11 42 5.9 (3.84) 5.5 0-13 Visit 12 45 5.7
(3.80) 5.0 0-13
Total number of subjects with presumed or defined neuropathic pain
component: N=126
TABLE-US-00018 Anxiety score n Mean (SD) Median Range Screening 126
8.7 (3.94) 9.0 1-19 Baseline 124 8.4 (4.26) 8.0 0-18 Visit 1 121
8.2 (4.16) 8.0 0-18 Visit 5 104 7.0 (3.98) 7.0 0-17 Visit 6 96 6.9
(3.75) 6.0 0-16 Visit 7 92 6.0 (3.95) 6.0 0-16 Visit 8 87 5.7
(3.80) 5.0 0-14 Visit 9 62 6.1 (4.32) 5.0 0-19 Visit 10 61 5.9
(4.46) 5.0 0-19 Visit 11 62 5.6 (3.96) 5.0 0-13 Visit 12 66 5.4
(3.76) 5.0 0-13
Total number of subjects with positive diagnosis of lumbar
radiculopathy-neuropathic pain subset: N=44
TABLE-US-00019 Anxiety score N Mean (SD) Median Range Screening 44
8.9 (4.06) 9.0 1-17 Baseline 44 8.6 (4.23) 9.0 0-18 Visit 1 44 8.7
(3.64) 9.0 1-18 Visit 5 40 6.8 (3.39) 7.5 1-15 Visit 6 38 7.1
(3.46) 7.5 1-13 Visit 7 34 6.1 (3.85) 6.0 0-15 Visit 8 35 5.9
(3.74) 5.0 0-13 Visit 9 24 6.2 (4.01) 5.0 1-13 Visit 10 25 6.1
(3.85) 6.0 0-13 Visit 11 26 6.3 (4.25) 6.5 0-13 Visit 12 27 5.7
(3.59) 6.0 0-11
[0139] The foregoing clinical data clearly demonstrate that
tapentadol exhibits a significant efficacy against depression and
anxiety.
[0140] The changes from baseline at visits 6, 8 and 12 are
summarized in the following tables:
Depression:
TABLE-US-00020 [0141] presumed or presumed defined lumbar defined
nociceptive neuropathic neuropathic radiculopathy neuropathic total
Visit 6 n 34 29 65 38 94 128 Mean (SD) -1.0 (3.15) -0.4 (3.55) -1.7
(3.43) -1.7 (3.23) -1.3 (3.50) -1.2 (3.40) Median -1.0 -0.0 -2.0
-1.0 -1.0 -1.0 Min, Max -11, 5 -12, 4 -10, 8 -9, 4 -12, 8 -12, 8
95% CI [-2.1; 0.1] [-1.8; 0.9] [-2.6; -0.9] [-2.7; -0.6] [-2.0;
-0.6] [-1.8; -0.6] p-value# 0.0813 0.5354 0.0002 0.0027 <0.0005
<0.0001 Visit 8 n 32 27 58 35 85 117 Mean (SD) -0.8 (2.31) -1.0
(3.13) -2.3 (3.33) -2.1 (3.54) -1.9 (3.30) -1.6 (3.09) Median -1.0
-1.0 -1.5 -1.0 -1.0 -1.0 Min, Max -8, 4 -12, 3 -12, 3 -10, 3 -12, 3
-12, 4 95% CI [-1.6; 0.0] [-2.2; 0.2] [-3.2; -1.4] [-3.3; -0.9]
[-2.6; -1.2] [-2.1; -1.0] p-value# 0.0551 <0.1084 <0.0001
0.0014 <0.0001 <0.0001 Visit 12 n 23 21 45 27 66 89 Mean (SD)
-0.5 (2.86) -1.5 (3.30) -2.2 (3.31) -2.1 (3.30) -2.0 (3.30) -1.6
(3.24) Median 0.0 -2.0 -2.0 -1.0 -2.0 -2.0 Min, Max -5, 4 -10, 6
-9, 6 -9, 3 -10, 6 -10, 6 95% CI [-1.7; 0.8] [-3.0; 0.0] [-3.2;
-1.2] [-3.5; -0.8] [-2.8; -1.2] [-2.3; -0.9] p-value# 0.4309 0.0534
0.0001 0.0023 <0.0001 <0.0001
Anxiety:
TABLE-US-00021 [0142] presumed or presumed defined lumbar defined
nociceptive neuropathic neuropathic radiculopathy neuropathic total
Visit 6 n 34 29 65 38 94 128 Mean (SD) -0.3 (2.93) -1.6 (3.58) -1.4
(3.44) -1.4 (3.88) -1.5 (3.47) -1.2 (3.36) Median 0.0 -1.0 -1.0
-0.5 -1.0 -1.0 Min, Max -7, 5 -9, 9 -10, 5 -10, 5 -10, 9 -10, 9 95%
CI [-1.3; 0.7] [-2.9; -0.2] [-2.3; -0.6] [-2.6; -0.1] [-2.2; -0.7]
[-1.7; -0.6] p-value# 0.5242 0.0271 0.0015 0.0361 <0.0001 0.0002
Visit 8 n 32 27 58 35 85 117 Mean (SD) -0.7 (3.88) -2.9 (3.11) -2.2
(3.77) -2.4 (4.23) -2.4 (3.57) -1.9 (3.72) Median -1.0 -2.0 -2.0
-1.0 -2.0 -2.0 Min, Max -7, 14 -11, 2 -13, 5 -13, 5 -13, 5 -13, 14
95% CI [-2.1; 0.7] [-4.1; -1.7] [-3.2; -1.2] [-3.9; -1.0] [-3.2;
-1.6] [-2.6; -1.3] p-value# 0.3027 <0.0001 <0.0001 0.0018
<0.0001 <0.0001 Visit 12 n 23 21 45 27 66 89 Mean (SD) -0.8
(2.82) -3.1 (3.16) -2.3 (4.14) -2.2 (4.11) -2.5 (3.85) -2.1 (3.67)
Median -1.0 -3.0 -2.0 -2.0 -2.0 -2.0 Min, Max -9, 4 -13, 0 -11, 6
-10, 4 -13, 6 -13, 6 95% CI [-2.0; 0.4] [-4.5; -1.7] [-3.5; -1.0]
[-3.8; -0.6] [-3.5; -1.6] [-2.9; -1.3] p-value# 0.1744 0.0002
0.0006 0.0105 <0.0001 <0.0001
[0143] The foregoing description and examples have been set forth
merely to illustrate the invention and are not intended to be
limiting. Since modifications of the described embodiments
incorporating the spirit and substance of the invention may occur
to persons skilled in the art, the invention should be construed
broadly to include all variations within the scope of the appended
claims and equivalents thereof.
* * * * *