U.S. patent application number 10/702497 was filed with the patent office on 2004-05-20 for method for treating tension-type headache.
Invention is credited to Bendtsen, Lars, Jensen, Rigmor, Madsen, Ulf, Olesen, Jes.
Application Number | 20040097562 10/702497 |
Document ID | / |
Family ID | 27363629 |
Filed Date | 2004-05-20 |
United States Patent
Application |
20040097562 |
Kind Code |
A1 |
Olesen, Jes ; et
al. |
May 20, 2004 |
Method for treating tension-type headache
Abstract
NMDA receptor antagonists, especially mirtazapine, can be used
to treat tension-type headaches.
Inventors: |
Olesen, Jes; (Hellerup,
DK) ; Bendtsen, Lars; (Slagelse, DK) ; Jensen,
Rigmor; (Virum, DK) ; Madsen, Ulf; (Horsholm,
DK) |
Correspondence
Address: |
BROWDY AND NEIMARK, P.L.L.C.
624 Ninth Street, N.W.
Washington
DC
20001
US
|
Family ID: |
27363629 |
Appl. No.: |
10/702497 |
Filed: |
November 7, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10702497 |
Nov 7, 2003 |
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09941855 |
Aug 30, 2001 |
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6649605 |
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09941855 |
Aug 30, 2001 |
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09304115 |
May 4, 1999 |
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6284794 |
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09941855 |
Aug 30, 2001 |
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PCT/DK97/00502 |
Nov 4, 1997 |
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60085413 |
May 14, 1998 |
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60030294 |
Nov 5, 1996 |
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Current U.S.
Class: |
514/352 |
Current CPC
Class: |
A61K 31/198 20130101;
A61K 31/00 20130101 |
Class at
Publication: |
514/352 |
International
Class: |
A61K 031/44 |
Claims
1. A method for treatment or prevention of tension-type headache in
a person in need of such treatment, comprising administering an
amount of an agent effective to interact with neuronal transmission
connected with pain perception, so as to prevent or reduce central
sensitization, with the proviso that said interaction is not
performed by administering ethyl
2-amino-6-(4-fluorobeznylamino)-3-pyridylcarbamate or an
arylglycinamide derivative as defined herein.
2. A method according to claim 1 for treatment of tension-type
headache in a person in need of such treatment, comprising
administering an amount of an agent effective to interact with
neuronal transmission connected with pain perception, so as to
prevent or reduce central sensitization.
3. A method according to claim 1 for prevention of tension-tape
headache in a person in need of such treatment, comprising
administering an amount of an agent effective to interact with
neuronal transmission connected with pain perception, so as to
prevent or reduce central sensitization.
4. A method according to claim 1, wherein the agent is an agent
which is capable of substantially normalizing a pathological
qualitatively altered stimulus-response function.
5. A method according to claim 1, wherein the agent is an agent
which is capable of substantially normalizing a pathological
abnormally low pain threshold.
6. A method according to claim 1, wherein the agent is an agent
which is capable of substantially reducing a pathological increased
pericranial muscle hardness.
7. A method according to claim 1, wherein the agent is an agent
which is capable of substantially reducing a pathological increased
pericranial myofascial tenderness.
8. A method according to claim 1, wherein the agent is an agent
which is capable of substantially preventing or reducing pain,
tenderness or hardness in pericranial muscle induced by
experimental tonic muscle contraction, or normalizing a
qualitatively altered stimulus-response function induced by
experimental tonic muscle contraction, or normalizing a reduced
pain threshold induced by experimental tonic muscle
contraction.
9. A method according to claim 1, wherein the agent is an agent
which is capable of substantially preventing or reducing pain,
tenderness or hardness in pericranial muscle induced by intra
muscular infusion of algogenic substances, or preventing or
normalizing a qualitatively altered stimulus-response function
induced by intra muscular infusion of algogenic substances or
normalizing a reduced pain threshold induced by intra muscular
infusion of algogenic substances.
10. A method according to claim 1, wherein the agent is an agent
which is capable of substantially preventing or reducing pain,
tenderness or hardness in pericranial muscle induced by stimulation
of nociceptive afferents in myofascial tissues or preventing or
normalizing a qualitatively altered stimulus-response function
induced by stimulation of nociceptive afferents in myofascial
tissues or normalizing a reduced pain threshold induced by
stimulation of nociceptive afferents in myofascial tissues.
11. A method according to claim 1, wherein the agent is an agent
which is capable of substantially preventing or reducing secondary
allodynia or secondary hyperalgesia induced by stimulation of
nociceptive afferents in myofascial tissues.
12. A method according to claim 1, wherein the agent is an agent
which is capable of substantially preventing or reducing wind-up
induced by repetitive stimulation of nociceptive afferents in the
pericranial region.
13. A method according to claim 1, wherein the agent is an agent
which is capable of substantially preventing or reducing secondary
allodynia or secondary hyperalgesia induced by nociceptive input in
an experimental animal model.
14. A method according to claim 1, wherein the agent is an agent
which is capable of substantially preventing or reducing wind-up
induced by repetitive stimulation of nociceptive afferents in an
experimental animal model.
15. A method according to claim 1, wherein the agent is an agent
which is capable of substantially preventing or reducing increased
receptive field size of second order neurons induced by nociceptive
input in an experimental animal model.
16. A method according to claim 1, wherein the agent is an agent
which is capable of substantially preventing or reducing an
increased excitability of the flexion reflex induced by nociceptive
input in an experimental animal model.
17. A method according to claim 1, wherein the agent is an agent
which is capable of substantially preventing or reducing central
sensitization induced by nociceptive input in an experimental
animal model.
18. A method according to claim 1 for treatment or prevention of
tension-type headache in a person in need of such treatment, the
patient having a qualitatively altered stimulus/response function
in connection with nociception, comprising administering an amount
of an agent effective to interact with neuronal transmission
connected with pain perception, so as to obtain a substantial
normalization of an otherwise qualitatively altered
stimulus/response function in connection with nociception.
19. A method according to claim 1, wherein the treatment or
prevention of tension-type headache is not accompanied by a
substantial reduction of muscle tension.
20. A method according to claim 1, wherein the interaction
comprises interaction with neuronal transmission connected with
second order nociceptive neurons.
21. A method according to claim 1, wherein the interaction
comprises a reduction of input to second order nociceptive
neurons.
22. A method for treating tension-type headache in a person which
comprises administering an agent in an amount effective to
alleviate said headache, said agent being an agent capable of
altering the relationship of pain intensity to pressure intensity
when the trapezoid muscle is palpated at different pressure
intensities in said person.
23. A method according to claim 22 wherein the relationship is
substantially linear in the untreated persons, and substantially
non-linear in the treated persons.
24. A method according to claim 23, wherein the relationship is
positively accelerating in the treated person.
25. A method according to claim 24, wherein the rate of
acceleration of pain intensity with pressure intensity is
substantially constant.
26. A method according to claim 25, wherein the relationship in the
treated persons is substantially the same as in control persons who
did not have tension-type headache and who were treated with a
placebo.
27. A method according to claim 1, wherein the interaction is one
which in a panel of test persons suffering from increased
myofascial tenderness with disorder of pericranial muscle in
connection with tension-type headache still transform a
substantially linear pain intensity perception in response to
pressure intensity in trapezius muscle into a curve (C) of which
the values of pain intensity are lower than the linear pain
intensity perception and wherein the curve (C) can be described
substantially as a power function and is a curve which is
substantially linear in a double logarithmic plot and wherein
substantially each of the values of curve (C) is at the most 20%
higher than the value of the corresponding curve produced for a
test panel of healthy controls.
28. A method according to claim 27, wherein substantially each of
the values of curve (C) is at the most 10% higher than the value of
the corresponding curve produced for a test panel of healthy
controls.
29. A method according to claim 1, wherein the interaction is
effected by administering an effective amount of an agent
interacting with neuronal transmission connected with pain
perception, the administration being performed substantially at
least once daily and being continued for a period of at least one
month.
30. A method according to claim 29, wherein the administration is
being continued for a period of at least one month and less than 10
years.
31. A method according to claim 29, wherein the administration is
being continued for a period of at least one month and less than 5
years.
32. A method according to claim 29, wherein the administration is
being continued for a period of at least one month and less than 2
years.
33. A method according to claim 29, wherein the administration is
being continued for a period of at least one month and less than 1
year.
34. A method for treatment or prevention of tension-type headache
in a person in need of such treatment comprising administering an
amount of an agent which, in the peripheral and/or central nervous
system, is effective to specifically interact with neuronal
transmission connected with pain perception by a) substantially
antagonizing the action of glutamate, 5-HT, GABA, nitric oxide,
nitric oxide synthase, guanylate cyclase, cyclic guanylate
monophosphate (cGMP), CGRP, substance P, neurokinin A, neurokinin
B, bradykinin, PACAB, adenosine, glycine, his tin, neurotrophins,
Na.sup.+ ions or Ca.sup.2+ ion channels, or by b) substantially
potentiating the action of adenosine, galanine or norepinephrine,
with the proviso that said agent is not ethyl
2-amino-6-(4-fluorobenzylamino)-3-pyridylcarbamate.
35. A method according to claim 34, wherein the agent is an agent
capable of interacting with neuronal transmission connected with
pain perception, so as to prevent or reduce central
sensitization.
36. A method according to claim 34, wherein the agent is an agent
capable of interacting with neuronal transmission connected with
pain perception, so as to obtain a substantial normalization of a
qualitatively altered stimulus/response function in connection with
nociception.
37. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially inhibiting the production of glutamate or
substantially inhibiting the release of glutamate or substantially
counteracting the action of glutamate or substantially inhibiting
the binding of glutamate to receptors for glutamate.
38. A method according to claim 34, wherein the agent comprises a
glutamate receptor antagonist.
39. A method according to claim 37, wherein the agent comprises a
glutamate receptor antagonist.
40. A method according to claim 39, wherein the agent comprises an
NMDA glutamate receptor antagonist.
41. A method according to claim 40, wherein the agent comprises a
competitive NMDA glutamate receptor antagonist.
42. A method according to claim 41, wherein the agent comprises a
nitrogen-containing heterocyclic compound selected from the group
consisting of diacidic piperidines, diacidic piperazines and
phosphono amino acids or derivatives of any of the above which are
competitive NMDA antagonists or prodrugs thereof.
43. A method according to claim 40, wherein the agent comprises a
non-competitive NMDA glutamate receptor antagonist.
44. A method according to claim 43, wherein the agent is selected
from a group consisting of polycyclic amines, tricyclic
antidepressants, adamantanamines, arylcyclohexylamines,
arylcyclohexylamines, opioid derivatives, glycylamides,
piperidinylethanols, piperidinylethanols, diguanidines,
g-aminobutyric acid derivatives, polycyclic amines or derivatives
of any of the above which are non-competitive NMDA antagonists or
prodrugs thereof.
45. A method according to claim 40, wherein the agent comprises a
tricyclic antidepressant or derivatives thereof which are NMDA
glutamate receptor antagonists or prodrugs thereof.
46. A method according to claim 40, wherein the agent is a selected
from the group consisting of .gamma.-aminobutyric acid derivatives,
polycyclic amines or derivatives of any of the above which are NMDA
glutamate receptor antagonists or prodrugs thereof.
47. A method according to claim 39, wherein the agent comprises a
non-NMDA glutamate receptor antagonist.
48. A method according to claim 47, wherein the agent comprises a
competitive non-NMDA glutamate receptor antagonist.
49. A method according to claim 47, wherein the agent comprises a
non-competitive non-NMDA glutamate receptor antagonist.
50. A method according to claim 47, wherein the agent comprises an
AMPA glutamate receptor antagonist.
51. A method according to claim 47, wherein the agent is a
competitive AMPA glutamate receptor antagonist.
52. A method according to claim 51, wherein the agent is selected
from the group consisting of quinoxalinediones, dihydraquinolones,
diacidic decahydroisoquinolines, amino acid isoxazoles,
indoleoximes or derivatives of any of the above which are
competitive AMPA receptor antagonists or prodrugs thereof.
53. A method according to claim 47, wherein the agent comprises a
non-competitive AMPA glutamate receptor antagonist.
54. A method according to claim 53, wherein the agent is selected
from the group consisting of 2,3-benzodiazepines, phthalazines or
derivatives of any of the above which are non-competitive AMPA
receptor antagonists or prodrugs thereof.
55. A method according to claim 47, wherein the agent comprises a
kainic acid receptor antagonist.
56. A method according to claim 55, wherein the agent comprises a
competitive kainic acid receptor antagonist.
57. A method according to claim 56, wherein the agent comprises an
indoleoxime or derivatives thereof which are competitive kainic
acid receptor antagonists or prodrugs thereof.
58. A method according to claim 55, wherein the agent comprises a
non-competitive kainic acid receptor antagonist.
59. A method according to claim 47, wherein the agent comprises a
metabotropic glutamate receptor antagonist.
60. A method according to claim 59, wherein the agent comprises a
competitive metabotropic glutamate receptor antagonist.
61. A method according to claim 59, wherein the agent comprises a
non-competitive metabotropic glutamate receptor antagonist.
62. A method according to claim 37, wherein the agent comprises a
metabotropic glutamate receptor agonist.
63. A method according to claim 62, wherein the agent is selected
from the group consisting of phenylglycines, amino acid indanes,
phosphono amino acids or derivatives of any of the above which are
metabotropic glutamate receptor agonists or prodrugs thereof.
64. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially inhibiting the production of 5-HT or substantially
inhibiting the release of 5-HT or substantially counteracting the
action of 5-HT or substantially inhibiting binding of 5-HT to
5H.sub.2,3 receptors.
65. A method according to claim 34, wherein the agent comprises a
5-HT.sub.2,3 receptor antagonist.
66. A method according to claim 64, wherein the agent comprises a
5-HT.sub.2,3 receptor antagonist.
67. A method according to claim 66, wherein the agent is selected
from the group consisting of tropan derivatives, polycyclic amines
or derivatives of any of the above which are 5-HT.sub.2,3 receptor
antagonists or prodrugs thereof.
68. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially enhancing the production of GABA or substantially
enhancing the release of GABA or substantially enhancing the action
of GABA or substantially activating receptors for GABA.
69. A method according to claim 68, wherein the agent comprises a
GABA activity enhancer.
70. A method according to claim 69, wherein the agent comprises a
benzodiazepine or a derivative thereof which is a GABA activity
enhancer or prodrugs thereof.
71. A method according to claim 34, wherein the agent comprises a
GABA uptake inhibitor.
72. A method according to claim 70, wherein the agent comprises a
GABA uptake inhibitor.
73. A method according to claim 72, wherein the agent is selected
from the group consisting of carboxypiperidine derivatives,
carboxypyridine derivatives, 3-hydroxyisoxazoles, nipecotic acid
derivatives, guvacine derivatives or derivatives of any if the
above which are GABA uptake inhibitors or prodrugs thereof.
74. A method according to claim 68, wherein the agent comprises a
GABA-A agonist.
75. A method according to claim 74, wherein the agent is selected
form the group consisting of .gamma.-aminobutyric acid derivatives,
3-hydroxyisoxazoles or derivatives of any of the above which are
GABA-A agonists or prodrugs thereof.
76. A method according to claim 68, wherein the agent comprises a
GABA transaminase inhibitor.
77. A method according to claim 76, wherein the agent comprises a
g-aminobutyric acid derivative or derivatives thereof which are
GABA transaminase inhibitors or prodrugs thereof.
78. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system is capable
of substantially inhibiting the production of nitric oxide or
substantially counteracting the action of nitric oxide or
substantially inhibiting the production of nitric oxide synthase
(NOS) or substantially counteracting the action of nitric oxide
synthase (NOS).
79. A method according to claim 34, wherein the agent comprises a
nitric oxide inhibitor.
80. A method according to claim 78, wherein the agent comprises a
nitric oxide inhibitor.
81. A method according to claim 34, wherein the agent comprises an
NOS inhibitor.
82. A method according to claim 8D, wherein the agent comprises an
NOS inhibitor.
83. A method according to claim 82, wherein the agent is selected
from the group consisting of arginine derivatives, citrulline
derivatives, indazoles, imidazolin-N-oxides, phenylimidazoles,
21-aminosteroids, biphenyls, piperidine derivatives or derivatives
of any of the above which are NOS inhibitors or prodrugs
thereof.
84. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially inhibiting the production of guanylate cyclase or
substantially counteracting the action of guanylate cyclase or
substantially inhibiting the production of cyclic guanylate
monophosphate (cGMP) or substantially counteracting the action of
cyclic guanylate monophosphate (cGMP) or substantially inhibiting
any further steps in the reaction induced by cyclic guanylate
monophosphate (cGMP).
85. A method according to claim 34, wherein the agent comprises a
guanylate cyclase inhibitor.
86. A method according to claim 84, wherein the agent comprises a
guanylate cyclase inhibitor.
87. A method according to claim 86, wherein the agent comprises a
quinoxaline or derivatives thereof which are guanylate cyclase
inhibitors.
88. A method according to claim 84, wherein the agent comprises a
cGMP inhibitor.
89. A method according to claim 84, wherein the agent comprises
capable of substantially counteracting the action of protein kinase
C.
90. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially inhibiting the production of CGRP or substantially
inhibiting the release of CGRP or substantially counteracting the
action of CGRP or substantially inhibiting the binding of CGRP to
receptors for CGRP.
91. A method according to claim 34, wherein the agent comprises a
CORP inhibitor.
92. A method according to claim 90, wherein the agent comprises a
CGRP inhibitor.
93. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially inhibiting the production of substance P or
substantially inhibiting the release of substance P or
substantially counteracting the action of substance P or
substantially inhibiting the binding of substance P to receptors
for substance P.
94. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially inhibiting the production of neurokinin A or
substantially inhibiting the release of neurokinin A or
substantially counteracting the action of neurokinin A or
substantially inhibiting the binding of neurokinin A to receptors
for neurokinin A.
95. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially inhibiting the production of neurokinin B or
substantially inhibiting the release of neurokinin B or
substantially counteracting the action of neurokinin B or
substantially inhibiting binding of neurokinin B to receptors for
neurokinin B.
96. A method according to claim 95, wherein the agent comprises an
NK2 receptor antagonist.
97. A method according to claim 96, wherein the agent comprises a
peptidomimetic or derivatives thereof which are NK2 receptor
antagonists or prodrugs thereof.
98. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially inhibiting the production of bradykinin or
substantially inhibiting the release of bradykinin or substantially
counteracting the action of bradykinin or substantially inhibiting
binding of bradykinin to receptors for bradykinin.
99. A method according to claim 34, wherein the agent comprises a
bradykinin antagonist.
100. A method according to claim 95, wherein the agent comprises a
bradykinin antagonist.
101. A method according to claim 100, wherein the agent comprises a
peptidomimetic or derivatives thereof which are bradykinin receptor
antagonists or prodrugs thereof.
102. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially inhibiting the production of PACAB or
substantially inhibiting the release of PACAB or substantially
counteracting the action of PACAB or substantially inhibiting
binding of PACAB to receptors for PACAB.
103. A method according to claim 34, wherein the agent comprises a
PACAB inhibitor.
104. A method according to claim 102, wherein the agent comprises a
PACAB inhibitor.
105. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially inhibiting the production of adenosine or
substantially inhibiting the release of adenosine or substantially
counteracting the action of adenosine or substantially inhibiting
binding of adenosine to adenosine A2 receptors.
106. A method according to claim 34, wherein the agent comprises an
A receptor antagonist.
107. A method according to claim 105, wherein the agent comprises
an A2 receptor antagonist.
108. A method according to claim 107, wherein the agent comprises a
xanthine derivative or derivatives thereof which are A2 receptor
antagonists or prodrugs thereof.
109. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially enhancing the production of adenosine or
substantially enhancing the release of adenosine or substantially
enhancing the action of adenosine or substantially activating
adenosine A1 receptors.
110. A method according to claim 34, wherein the agent comprises an
adenosine uptake inhibitor.
111. A method according to claim 109, wherein the agent comprises
an adenosine uptake inhibitor.
112. A method according to claim 111, wherein the agent comprises a
pyrimidine derivative or homopiperazine derivative or derivatives
of any of the above which are adenosine uptake inhibitors or
prodrugs thereof.
113. A method according to claim 34, wherein the agent comprises an
A1 receptor agonist.
114. A method according to claim 109, wherein the agent comprises
an A1 receptor agonist.
115. A method according to claim 114, wherein the agent is selected
from the group consisting of adenosine derivatives,
adeninglucosides or derivatives thereof which are A1 receptor
agonists or prodrugs thereof.
116. A method according to claim 1, wherein the agent is an agent
which, in the peripheral-and/or central nervous system, is capable
of substantially enhancing the production of galanine or
substantially enhancing the release of galanine or substantially
enhancing the action of galanine or substantially activating
receptors for galanine.
117. A method according to claim 34, wherein the agent comprises a
galanine receptor agonist.
118. A method according to claim 116, wherein the agent comprises a
galanine receptor agonist.
119. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially enhancing the production of norepinephrine or
substantially enhancing the release of norepinephrine or
substantially enhancing the action of norepinephrine or
substantially activating receptors for norepinephrine.
120. A method according to claim 34, wherein the agent comprises an
norepinephrine receptor agonist.
121. A method according to claim 119, wherein the agent comprises
an norepinephrine receptor agonist.
122. A method according to claim 121, wherein the agent comprises
an a-2 receptor agonist.
123. A method according to claim 122, wherein the agent is selected
from the group consisting of aminoimidazolines, thiazinamines,
imidazoles, or derivatives of any of the above which are a-2
receptor agonists or prodrugs thereof.
124. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially inhibiting the production of glycine or
substantially inhibiting the release of glycine or substantially
counteracting the action of glycine or substantially inhibiting
binding of glycine to receptors for glycine.
125. A method according to claim 34, wherein the agent comprises a
glycine antagonist.
126. A method according to claim 124, wherein the agent comprises a
glycine antagonist.
127. A method according to claim 126, wherein the agent is selected
from the group consisting of aminopyrrolidinones, kynurenic acid
derivatives, tetrahydroquinolines, kynurenic acid derivatives,
indoles, glycine derivatives, quinoxalinediones, dicarbamates or
derivatives of any of the above which are glycine antagonists or
prodrugs thereof.
128. A method according to claim 1, wherein the agent is an agent
which, in the peripheral and/or central nervous system, is capable
of substantially inhibiting the production of histamin or
substantially inhibiting the release of histamin or substantially
counteracting the action of histamin or substantially inhibiting
binding of histamine to receptors for histamin.
129. A method according to claim 1, wherein the agent is a agent
which, in the peripheral and/or central nervous system, is capable
of substantially inhibiting the production of neurotrophins or
substantially inhibiting the release of neurotrophins or
substantially counteracting the action of neurotrophins or
substantially inhibiting binding of neurotrophins to receptors for
neurotrophins.
130. A method according to claim 34, wherein the agent comprises a
neurotrophin receptor antagonist.
131. A method according to claim 129, wherein the agent comprises a
neurotrophin receptor antagonist.
132. A method according to claim 1, wherein the agent is capable of
substantially inhibiting the action of Na.sup.+ ion channels in the
peripheral and/or central nervous system.
133. A method according to claim 34, wherein the agent comprises a
Na.sup.+ channel blocker.
134. A method according to claim 132, wherein the agent comprises a
Na.sup.+ channel blocker.
135. A method according to claim 134, wherein the agent is selected
from the group consisting of triazines, diphenylmethylpiperazines,
hydantoins, aminopiperidines, benzthiazoles, dibenzazepines,
phenylamides, aminoethylanisoles or derivatives of any of the above
which are Na.sup.+ channel blockers or prodrugs thereof.
136. A method according to claim 1, wherein the agent is capable of
substantially inhibiting the action of Ca.sup.2+ ion channels in
the peripheral and/or central nervous system.
137. A method according to claim 34, wherein the agent comprises a
Ca.sup.2+ channel blocker.
138. A method according to claim 136, wherein the agent is a
Ca.sup.2+ channel blocker.
139. A method according to claim 138, wherein the agent is selected
from the group consisting of diphenylmethylpiperazines,
arylphosphonic esters or derivatives of any of the above which are
Ca.sup.2+ channel blockers or prodrugs thereof.
140. A method of treatment of tension-type headache comprising
administering to a person in need of such treatment an effective
amount of an agent which is capable of substantially inhibiting the
action of the enzyme nitric oxide synthase (NOS) and thereby
reduces chronic pain in connection with tension-type headache.
141. A method according to claim 140, wherein the agent is selected
from the group consisting of arginine derivatives, citrulline
derivatives, indazoles, imidazolin-N-oxides, phenylimidazoles,
biphenyls, piperidine derivatives or derivatives of any of the
above which are NOS inhibitors or prodrugs thereof.
142. A method of screening a drug for the ability to alleviate a
tension-type headache which comprises comparing the relationship of
pain intensity to pressure intensity when the trapezoid muscle is
palpated at different pressure intensities for (a) persons having
tension-type headaches after treatment with the drug, and (b)
persons having tension-type headaches, treated with a placebo, and
determining if the relationship is altered.
Description
[0001] This application is a nonprovisional claiming the benefit
under 35 USC .sctn.119(e) of provisional Serial No. 06/085,413,
filed 14 May 1998. This application is also a continuation-in-part
of PCT/DK97/00502, filed 4 Nov. 1997, a PCT application designating
the United States, which is a nonprovisional claiming the benefit
under 35 USC .sctn. 119(e) of provisional Serial No. 06/030,292,
filed 5 Nov. 1996. All of the above applications are hereby
incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a method of treatment or
prevention of tension-type headache in a human in need of such
treatment. In particular, the invention relates to a method of
treatment of tension-type headache comprising the administration of
an agent or agents effective for the prevention or reduction of
central sensitization
GENERAL BACKGROUND
[0003] Types of Clearly Defined Headache Disorders.
[0004] Previously, headache disorders were not clearly
distinguished and it was widely believed that they formed part of a
continuum and were strongly related. In 1988, The International
Headache Society, (IHS) via its ad hoc committee on classification
published a document entitled Classification and Diagnostic
Criteria for Headache Disorders, Cranial Neuralgias and Facial Pain
(Classification and Diagnostic Criteria for Headache Disorders,
1988). A new entity was here defined by name of tension-type
headache. This entity was practically the same as conditions
previously called tension headache, muscle contraction headache,
psycho-myogenic headache and idiopathic headache. The IHS
classification also defined a number of other specific headache
diseases. Today it therefore gives no meaning to talk about
headache in general. It would be the same as to discuss bellyache
and chest pain without specifying its type and etiology. Due to the
development in diagnostic accuracy research results obtained before
1988 have uncertain validity.
[0005] Tension-type headache was subdivided by the IHS
Classification Committee into an episodic form occurring less than
half of all days and a chronic form occurring half of all days or
more. Furthermore, both of these divisions were further subdivided
into a form with disorder of pericranial muscle and a form without
such disorder. It is thus crucial that research and patents specify
which of the subforms are included. Before the entity of
tension-type headache was created, it was widely believed that this
kind of headache was caused by muscle ischemia, a concept later
disproven by the present inventors (Langemark et al. 1990). The
term tension-type headache was created in order to indicate that
experts disagreed with the notion of tension-type headache being
simply a kind of muscle pain. In fact, the term idiopathic headache
was suggested There is only a moderate co-morbidity with neck pain
and low back pain in sufferers of tension-type headache.
Furthermore, Electromyography (EMG)-measurements have failed to
detect an increase of muscle contraction sufficient to cause pain
on a purely mechanical basis in tension-type headache patients
whereas central factors such as depression and anxiety have been
attributed a significant role. Finally, a genetic factor has
recently been shown to be involved in tension-type headache (.O
slashed.stergaard et al. 1996). From the point of view of
mechanisms and definition tension-type headache is thus a specific
entity which may or may not share mechanisms with muscle pain in
the head and in other parts of the body. The classification and
diagnostic criteria for tension-type headache are shown in Tables I
and II.
1TABLE I Classification of headache disorders, cranial neuralgias,
and facial pain (Headache Classification Committee 1988). 1.
Migraine 2. Tension-type headache 3. Cluster headache and chronic
paroxysmal hemicrania 4. Miscellaneous headaches unassociated with
structural lesion 5. Headache associated with head trauma 6.
Headache associated with vascular disorders 7. Headache associated
with non-vascular intra-cranial disorder 8. Headache associated
with substances or their withdrawal 9. Headache associated with
noncephalic infection 10. Headache associated with metabolic
disorder 11. Headache or facial pain associated with disorder of
cranium, neck, eyes, nose, sinuses, teeth, mouth or other facial or
cranial structures 12. Cranial neuralgias, nerve trunk pain and
deafferentation pain 13. Headache not classifiable
[0006]
2TABLE II Diagnostic criteria for episodic and chronic tension-type
headache (Headache Classification Committee 1988) II.1. Episodic
tension-type headache A. At least 10 previous headache episodes
fulfilling criteria B-D listed below. Number of days with such
headache <180/year (<15/month) B. Headache lasting from 30
minutes to 7 days C. At least 2 of the following pain
characteristics: 1. Pressing/tightening quality 2. Mild or moderate
severity (may inhibit, but does not prohibit activities) 3.
Bilateral location 4. No aggravation by walking stairs or similar
routine physical activity D. Both of the following: 1. No nausea or
vomiting (anorexia may occur) 2. Photophobia and phonophobia are
absent, or one but not the other is present E. At least one of the
following: 1. History, physical and neurological examinations do
not suggest one of the disorders listed in groups 5-11 2. History
and/or physical and/or neurological examinations do suggest such
disorders, but they are ruled out by appropriate investigations 3.
Such disorders are present, but tension-type headache does not
occur for the first time in close temporal relation to the disorder
II.2. Chronic tension-type headache A. Average headache frequency
15 days/month (180 days/year) for 6 months fulfilling criteria B-D
listed below B. At least 2 of the following pain characteristics:
1. Pressing/tightening quality 2. Mild or moderate severity (may
inhibit, but does not prohibit activities) 3. Bilateral location 4.
No aggravation by walking stairs or similar routine physical
activity C. Both of the following: 1. No vomiting 2. No more than
one of the following: Nausea, photophobia or phonophobia D. At
least one of the following: 1. History, physical and neurological
examinations do not suggest one of the disorders listed in groups
5-11 2. History and/or physical and/or neurological examinations do
suggest such disorders, but they are ruled out by appropriate
investigations 3. Such disorders are present, but tension-type
headache does not occur for the first time in close temporal
relation to the disorder
[0007] Epidemiological studies done by the inventors have shown
that chronic tension-type headache affects three percent of the
population at any given time, the lifetime prevalence being as high
as six percent (Rasmussen et al. 1991). Severe episodic
tension-type headache defined as persons having headache twice a
week or more occurs in approximately ten percent of the population.
Thus, tension-type headache is a serious problem with significant
socio-economic implications, involving enormous loss of workdays
and quality of life.
[0008] Previous Findings in General Pain Physiology and Pain
Pharmacology
[0009] The possible pathogenic mechanisms of tension-type headache
have previously been studied and discussed by Langemark et al.
(Langemark et al. 1987, 1988, 1989) and by the group of Jean
Schoenen (Schoenen et al. 1987, 1991a, b). The latter group have
mainly focused on electrophysiological recordings as
electromyography, and the jaw opening reflex as reflected by the
so-called exteroceptive silent period (ES2) (Schoenen et al. 1987).
On the basis of shortened ES2 periods in patients with chronic
tension-type headache compared to healthy controls a limbic
dysfunction was suggested, but these results have later been
disproven by more systematic investigations (Bendtsen et al. 1996a,
Lipchik et al 1996, Zwart and Sand, 1996). Schoenen and other
groups have also studied mechanical pain thresholds on the
extremities as well as in the cranial region and decreased
mechanical pain thresholds in severely affected patients with
chronic tension-type headache were reported (Schoenen et al. 1991a,
Langemark et al. 1989), whereas patients with the episodic form of
tension-type headache are reported to have normal thresholds
compared to healthy controls (Hatch et al. 1992, Goebel et al.
1992, Jensen et al. 1993b). These authors suggested that central
mechanisms may be involved in the chronic subform and that the
peripheral mechanisms played a role in the episodic form, but
provided no further clues or arguments about the underlying
mechanisms. One more recent congress presentation and two
scientific papers by the present inventors have focused on the
sensory mechanisms in tension-type headache as decreased thresholds
and tolerances were found in and outside the head of patients with
chronic tension-type headache indicating a generally increased
sensitivity to noxious and innocuous stimuli (Bendtsen et al.
1995b, 1996b and 1996c). Similarly a congress report and a
scientific paper present data from patients studied during and
outside a spontaneous tension-type headache episode (Jensen et al.
1995a and 1995b). Muscle tenderness was increased during the
headache episode, whereas mechanical pain thresholds remained
unchanged and the thermal pain tolerance decreased. It bias
concluded that a peripheral sensitization may be one of the primary
sources of pain and that central sensitization may contribute to
and maintain the pain in chronic tension-type headache. However,
these data did not provide any further clues for more specific
localizations of the sensitization, could not lead to a precise
experimental model and finally did not lead to guidance for
specific treatment of tension-type headache.
[0010] Peripheral Induction of Central Sensitization
[0011] One of the most exciting developments in pain research over
the past decades has been the recognition that the response
generated by the somatosensory system to a defined input is not
fixed or static. In particular, the increased knowledge on central
sensitization; i.e. increased excitability of neurons in the
central nervous system, has been a major breakthrough in the
understanding of chronic pain. In 1983 Woolf and colleagues (Woolf
1933) demonstrated for the first time that a prolonged noxious
input from the periphery is capable of sensitizing spinal dorsal
horn neurons. It has later been demonstrated that the central
sensitization is induced by repetitive C-fibre, but not A-fibre.,
input (Yaksh and Malmberg 1994). In the sensitized state, a
low-intensity stimulus can generate pain, the phenomenon of
allodynia. The low-intensity stimulus is mediated via low-threshold
afferents, A-b-fibres, which do not normally mediate pain, and it
has been suggested that the major cause of increased pain
sensitivity in the chronic pain condition is an abnormal response
to A-b-sensory input (Woolf and Doubell 1994). The original
findings by Woolf and colleagues on spinal dorsal horn
sensitization have later been confirmed by numerous independent
laboratories (Mense 1993), and a similar sensitization of
trigeminal brainstem nociceptive neurons following stimulation of
craniofacial muscle afferents has been reported by Hu et al. (Hu et
al. 1992). While central sensitization may be of relevance in many
different chronic pain conditions it is particular likely in muscle
pain, because input from muscle nociceptors is more effective in
inducing, prolonged changes in the behavior of dorsal horn neurons
than is input from cutaneous nociceptors (Wall and Woolf 1984).
SUMMARY OF THE INVENTION
[0012] The inventors of the present invention have discovered that
the central nervous system is sensitized in patients suffering from
increased myofascial pain in connection with tension-type headache
because of prolonged nociceptive input from myofascial tissues. The
present inventors were then able to devise, for the first time, an
effective treatment of tension-type headache, which comprises
interacting with neuronal transmission connected with nociception
so as to prevent or reduce central sensitization.
[0013] A better understanding of the principle of the invention can
be derived from the detailed description of the scientific
background in the scientific section below.
[0014] Scientific Section
[0015] Previous Findings in General Pain Physiology and Pain
Pharmacology and Previous Findings in Tension-Type Headache.
[0016] Pain physiology and pain pharmacology have mostly been
elucidated in animal studies. There are, however, no animal models
with any proven validity in tension-type headache. Furthermore,
these animal experimental studies are done in anaesthetized animals
while the sensation of pain by definition can only occur in awake
beings. Most of the experiments are also of an acute nature
stimulating for milliseconds and recording responses for seconds,
minutes or hours and are therefore of uncertain validity for
chronic tension-type headache. Finally, only few studies have been
done on myofascial tissues projecting via the trigeminal nerve
while the huge body of knowledge otherwise available deals with
mechanisms of the spinal cord. None of the experimental animal
studies mention any form of headache, neither do they suggest that
the results of these studies may be utilized for the treatment of
tension-type headache. However, after the crucial findings leading
to the present invention were made, it is clear that the
implications of the findings in relation to general pain physiology
can also'be utilized in relation to tension-type headache.
[0017] With respect to medicinal treatment of tension-type
headache, the prior art mentions a variety of substances. The
substance Flupirtin (ethyl
2-amino-6-(4-fluorobenylamino)-3-pyridylcarbamate), which is
suggested to work as an NMDA glutamate receptor antagonist
(Schwartz et al. 1981), has been suggested for use in the treatment
of chronic or episodic tension-type headache, as disclosed in EP 0
659 410 A2, and according to Worz et al., 1996, it has shown
positive effects. However, in these documents the substance is
described as a muscle relaxant, and the mechanism by which it is
proposed to exert its effect in the treatment of various
conditions, including tension-type headache, is by lowering muscle
tension. Thus, as opposed to the present inventors, the prior art
understands and explains tension-type headache as a condition
directly and primarily caused by muscle tension. WO 96/32386
concerns arylglycinamide derivatives which are antagonists of
neurokinins, and these compounds are broadly claimed for use in the
treatment of a wide variety of conditions in which neurokinins are
supposed to be implicated. Tension-type headache is mentioned as
such a condition, but there is no indication of what the mechanism
of neurokinin involvement might be. For all the above-mentioned
prior art documents, it can be said that the concept of central
sensitization in relation to tension-type headache as introduced by
the present inventors, is not described or contemplated at all.
Indeed, the prior art does not appear to be concerned with the
underlying physiological mechanisms of tension-type headache, but
seems to reflect presently held notions of pain physiology in
general.
[0018] In connection with the present invention, the term
"arylglycinamide derivative as disclosed in WO 96/32386" means a
compound as defined in any of claims 1-17 of WO 96/32386. As
appears from the claims herein, these arylglycinamide derivatives
are excluded from the definitions of all aspects of the present
invention. The excluded arylglycinamide derivatives of claims 1-17
of WO 96/32386 are all comprised by the definition given in claim 1
of WO 96/32386. Thus, whenever reference is made to an
"arylglycinamide derivative as disclosed in WO 96/32386", this
means an arylglycinamide derivative covered by the definition of
claim 1 of WO 96/32386, that is:
[0019] Arylglycinamide derivatives of the general formula I 1
[0020] and their pharmaceutically acceptable salts, in which
[0021] Ar is unsubstituted or 1-5 times substituted phenyl, or
unsubstituted or 1 or 2 times substituted naphtyl [the substituents
of phenyl and naphthyl independently of each other being halogen
(F, Cl, Br, J), OH, (C.sub.1-C.sub.4)alkyl,
O--(C.sub.1-C.sub.4)alkyl, CF.sub.3, OCF.sub.3 or NR.sup.9R.sup.10
(wherein R.sup.9 and R.sup.10 independently of each other are H,
methyl or acetyl)], or Ar is phenyl substituted with --OCH.sub.2O--
or --O(CH.sub.2).sub.2O--;
[0022] R.sup.1 and R.sup.2 together with the N to which the are
bound form a ring of the formula 2
[0023] wherein p is 2 or 3,
[0024] X means oxygen, N(CH.sub.2).sub.nR.sup.6 or CR.sup.7R.sup.8,
wherein
[0025] n is 0, 1 or 2,
[0026] R.sup.6 is (C.sub.3-C.sub.7)cycloalkyl, phenyl or naphthyl
each phenyl optionally being 1-3 times substituted with halogen (F,
Cl, Br, n), (C.sub.1-C.sub.4)allyl, O--(C.sub.1-C.sub.4)alkyl,
CF.sub.3, OCF.sub.3 or NR.sup.15R.sup.16 (wherein R.sup.15 and
R.sup.16 independently of each other are H, methyl or acetyl);
[0027] R.sup.7 and R.sup.8 have one of the following meanings
[0028] a) when R.sup.3 is unsubstituted or substituted phenyl, then
R.sup.7 and R.sup.8 are H,
[0029] b) when R.sub.8 is H, --CONH.sub.2, --NHC(O)CH.sub.3,
--N(CH.sub.3)C(O)CH.sub.3, CN, 3
[0030] or --C(O)N((C.sub.1-C.sub.3)alkyl).sub.2,
[0031] then R.sup.7 is phenyl, phenyl substituted with 1-3
substituents [wherein the substituents independently from each
other are halogen (F, Cl, Br, J), (C.sub.1-C.sub.4)alkyl,
O--(C.sub.1-C.sub.4)alkyl, CF.sub.3 or OCF.sub.3], piperidinyl.
1-methylpiperidinyl, 4
[0032] or
[0033] c) R.sup.7 and R.sup.8 together form the moiety 5
[0034] R.sup.3 is H, (C.sub.1-C.sub.4)alkyl, unsubstituted or 1-3
times substituted phenyl, wherein the substituents independently of
each other are halogen, (C.sub.1-C.sub.4)alkyl,
O--(C.sub.1-C.sub.4)alkyl, CF.sub.3, OCF.sub.3 or NR.sup.17R.sup.18
(wherein R.sup.17 and R.sup.18 independently of each other are H,
methyl or acetyl);
[0035] R.sup.4 is phenyl(C.sub.1-C.sub.4)alkyl or
naphthyl(C.sub.1-C.sub.4- )alkyl, wherein phenyl may be substituted
with 1-3 substituents: which substituents independently of each
other are halogen (F, Cl, Br, J), (C.sub.1-C.sub.4)alkyl,
O--(C.sub.1-C.sub.4)alkyl, CF.sub.3, OCF.sub.3 or NR.sup.19R.sup.20
(wherein R.sup.19 and R.sup.20 independently of each other are H,
methyl or ethyl, and
[0036] R.sup.5 is H, (C.sub.1-C.sub.4)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, CH.sub.2COOH, --CH.sub.2C(O)NH.sub.2,
--OH or phenyl(C.sub.1-C.sub.4)alky- l.
[0037] Novel Experimental Evidence for Neuronal Sensitization in
Tension-Type Headache.
[0038] As discussed, previous studies in tension-type headache have
in general terms indicated that there may be sensitization of
muscle and nociceptive afferents and also in a non-specific way
have suggested some kind of central sensitization. Whether one or
the other kind of sensitization is the more important or whether
indeed they both co-exist has not been clear. Recent series of
experiments by the present inventors have now clearly shown that
tension-type headache is indeed much more complicated than
previously anticipated; thus neither the phenomenon of peripheral
sensitization nor that of unspecific central sensitization does in
isolation explain the condition. The studies of the present
inventors have demonstrated that mechanical force due to
contraction of chewing muscles may induce peripheral sensitization
in chewing muscles and that this peripheral sensitization is an
important factor which may or may not induce headache (Jensen and
Olesen 1996). Whether this happens depends on the response of the
central nervous system. Further experiments have shown for the
first time that a qualitatively altered pain perception related to
sensitization of second order nociceptive neurons is chronically
present in subjects with tension-type headache (Bendtsen et al.
1996c). This is believed to be far the most important abnormality
in tension-type headache. Thirdly, recent studies by the present
inventors have demonstrated that in addition to sensitization of
second order nociceptive neurons, there is also a component of a
more unspecific sensitization of pain pathways at higher levels of
the central nervous system (Bendtsen et al. 1996b). While
sensitization of second order neurons is believed to be segmental
(located only in those segments of the spinal cord/trigeminal
nucleus which receive afferents from myofascial tissues), the
sensitization of higher centers is of a general nature and results
in increased pain sensitivity all over the body. It is anticipated
that the sensitization of supraspinal neurons is a consequence of
the considerably increased nociceptive input to these neurons
(Lamour et al. 1983) because of the sensitization at the level of
the spinal dorsal horn/trigeminal nucleus. Thus, the generalized
pain hypersensitivity reflects the sensitization of second order
neurons. Moreover, a recent study (Ashina et al. 1998a, Example 4
herein) by the inventors has demonstrated that the nitric oxide
synthase (NOS) inhibitor, L-N.sup.0 methyl arginine hydrochloride
(L-NMMA), is effective in the treatment of patients with chronic
tension-type headache. Since NOS inhibitors reduce spinal dorsal
horn sensitization induced by continues painful input from the
periphery (Mao et al. 1997) this study provides additional evidence
for central sensitization at the level of the spinal dorsal
horn/trigeminal nucleus in patients with tension-type headache.
Another recent study (Example 8 herein) by the inventors has
demonstrated that L-NMMA reduces muscle hardness in patients with
tension-type headache. Increased muscle hardness is anticipated to
reflect central sensitization, since it is known that central
sensitization may increase the drive to motor neurons both at the
supraspinal and at the segmental level (Woolf 1983), resulting in
increased muscle activity and thereby in increased muscle hardness.
This study, therefore, also points towards central sensitization in
tension-type headache. Finally, the present inventors have recently
demonstrated that experimental tooth clenching induces increased
tenderness of masticatory muscles in patients with tension-type
headache and that the increased tenderness precedes the induced
headache by several hours (Jensen and Olesen 1996), and that the
central nervous system is sensitized only in patients with tender
pericranial muscles and not in patients without tender pericranial
muscles (Jensen et al. 1998). Together these studies demonstrate
that the central nervous system is sensitized at the level of the
spinal dorsal horn/trigeminal nucleus in patients with tension-type
headache because of prolonged nociceptive input from myofascial
tissues. On the basis of the combined findings of thc inventors, a
novel and rather complex model of the mechanisms of tension-type
headache has been developed, as depicted in FIG. 1. In the
following the model is described in details and its significant
implications for devising successful future drug treatment of
tension-type headache are discussed.
[0039] The model is illustrated in FIG. 1, in which the
abbreviations have the following meaning:
[0040] V: Trigeminal nerve,
[0041] C2, C3: Second and third cervical segment of the spinal
cord,
[0042] PAG: Periaquaductal grey,
[0043] DRN: Dorsal raphe nuclei,
[0044] on-cells: cells in ventromedial medulla, which activate pain
pathways, for instance by reducing the threshold in the tail flick
test.
[0045] C, Ad, Ab: Fibers of the C, Ad, and Ab type
[0046] Model for the Development of Tension-Type Headache Involving
Neuronal Sensitization.
[0047] The main circuitry in FIG. 1 is the following:
[0048] Voluntary muscle activity is initiated by the supplementary
motor area. This activates the motor cortex which again activates
the motor nucleus of the trigeminal nerve and anterior horn cells
of the C2 and C3 segments of the spinal cord causing contraction of
chewing and neck muscles. Simultaneously with the activation of
motor cortex, the supplementary motor area also activates the
antinociceptive system. Therefore normal muscle activity, even when
vigorous, is not normally perceived as painful. Another way of
activating the motor pathways is via the limbic system which is
concerned with emotions. When this system is activated, as in
states of anxiety and stress it is envisaged that the motor cortex
and the pain facilitatory system are activated simultaneously.
Thus, emotionally induced involuntary muscle contraction usually
induces myofascial tenderness and pain. Both voluntary and
emotionally triggered muscle contraction via mechanical stress and
perhaps neurogenic inflammation increase afferent input from
myofascial tissues via C-fibers, A-d-fibers and A-b-fibers. C-fiber
input is responsible for slow pain and, when prolonged, causes the
so-called wind-up phenomenon in second order neurons located in the
nucleus of the trigeminal tract and in segments C2 and C3 of the
dorsal horn of the spinal cord. Wind-up is associated with
increased sensitivity of second order neurons and an increase of
their receptive fields. Furthermore, input via A-b-fibers becomes
painful which is called allodynia. Input from the periphery in a
state of wind-up causes a more intense pain than normally. With
repeated or chronic micro traumatic or inflammatory reactions in
myofascial tissues peripheral nociceptores, primarily projecting
via C-fibers, become sensitized. Substances involved in peripheral
sensitization include the potassium ion, bradykinin, histamine,
ATP, neurotrophins and possibly other growth factors (Meyer et al.,
1994).
[0049] Synaptic Mechanisms in the Spinal Dorsal Horn/Trigeminal
Nucleus Involved in Central Sensitization
[0050] How does repetitive C-fibre input to the spinal dorsal horn
result in abnormal responses to normal Ab-fibre inputs, i.e. in
central sensitization? The most likely answer is that C-fibre
released neurotransmitters increase the excitability of dorsal horn
neurons so that previously ineffective Ab-fibre inputs to
nociceptive dorsal horn neurons become effective (Woolf and
Thompson 1991). Several neurotransmitters are knows to be involved
in nociceptive transmission from C-fibre afferents to second order
neurons in the spinal dorsal horn. These neurotransmitters can
largely be divided into gases, into peptides, which are chains of
amino acids, or into excitatory or inhibitory amino acids, which
are chemically single amino acids and into excitatory or inhibitory
amines.
[0051] Gases
[0052] The freely diffusible gas nitric oxide (NO) is probably
released from C-fibres and acts after binding to the enzyme
guanylate cyclase in postsynaptic neurons. However, even though NO
is considered of major importance in central sensitization, its
exact role as a neurotransmitter is not yet clarified (Meller and
Gebhart 1993).
[0053] Neurokinins
[0054] Neurokinins are a fairly of related peptides, including
substance P, neurokinin A, neurokinin B and bradykinin which are
known to be released from C-fibres. Currently there are three known
subclasses of receptors for these peptides: neurokinin-1, (NK1)
NK.sub.2 and NK.sub.3 receptors.
[0055] PACAP
[0056] PACAP is expressed in abundant amounts in dorsal horn
neurons and is believed to play a significant role in pain
transmission or the modulation of pain transmission.
[0057] Calcitonin Gene-Related Peptide (CGRP)
[0058] The exact role of this peptide in pain transmission is not
known because of lack of selective receptor antagonists. However,
CGRP probably protracts the breakdown of substance P in the
synaptic cleft, thereby adding to the level of excitability of the
spinal cord (Dickenson 1996).
[0059] Other Peptides
[0060] Several other peptides such as somatostatin, neuropeptide Y
and galanin may be important, but their exact role in central
sensitization is not yet known.
[0061] Excitatory Amino Acids
[0062] It now appears that the excitatory amino acid glutamate
plays a dominant role in the development of central sensitization.
Glutamate is used by most neurons in the brain and spinal cord as
their major excitatory transmitter. The actions of glutamate are
mediated by 4 different receptor classes: the N-methyl-D-aspartate
(NMDA), the a-amino-3-hydroxy-5-methyl-4-isoxazolyl-propionic acid
(AMPA), the kainate receptors, and the metabotropic receptors. Of
these receptors, especially the NMDA receptors are considered to be
of crucial importance in central sensitization (Coderre et al.
1993).
[0063] Adenosine
[0064] The central terminals of primary afferent fibres do express
adenosine receptors (Levine and Taiwo 1994). Via these receptors,
adenosine can inhibit voltage-gated calcium channels via activation
of a G-protein resulting in an inhibition of transmitter release
from the primary afferent neuron (Rang et al. 1994). Adenosine
agonists may also act to inhibit the firing of wide-dynamic
neurons, probably through an increase in potassium conductance.
Furthermore, adenosine has been reported to block the release of
glutamate (Yaksh and Malmberg 1994). In support of these findings
intrathecal adenosine has been shown to increase the nociceptive
threshold (Yaksh and Malmberg 1994). Adenosine does also play a
role in the peripheral tissues. In the primary afferent nociceptor
adenosine acting at the A.sub.1-receptor inhibit hyperalgesia,
while adenosine acting at the A.sub.2-receptor produces
hyperalgesia via elevation of intracellular cAMP (Levine and Taiwo
1994).
[0065] Gamma Amino Butyric Acid (GABA)
[0066] GABA is an important inhibitory transmitter in the central
nervous system, and it has been suggested that the encoding of
low-threshold mechanical stimuli as innocuous depends completely
upon the presence of a tonic activation of intrinsic glycine and/or
GABAergic neurons (Yaksh and Malmberg 1994). Furthermore, it has
been demonstrated that the administration of GABA antagonists can
produce allodynia (Woolf 1994). GABA.sub.B agonists may act to
inhibit the firing of wide-dynamic neurons, probably through an
increase in potassium conductance (Yaksh and Malmberg 1994) and
GABA may also reduce the amount of transmitter release from the
central terminals of primary afferent fibres by opening of chloride
channels (Rang et al. 1994).
[0067] 5-hydroxytryptamine (5-HT)
[0068] 5-HT is a very important transmitter in the modulation of
pain. While 5-HT has both analgesic and algesic properties, it acts
mainly as an inhibitory pain transmitter in the central nervous
system (Roberts 1992). Thus, when 5-HT is applied directly to the
spinal cord, it produces analgesia (Fields and Basbaum 1994). The
antinociceptive effects of 5-HT are mediated via many different
5-HT receptor subtypes. Thus, it is known that both the 5-HT.sub.1,
5-HT.sub.2 and 5-HT.sub.3 receptors are involved in antinociception
(Fields and Basbaum 1994).
[0069] Norepinephrine (NE)
[0070] Like 5-HT, also norepinephrine (NE) plays an important role
as an endogenous antinociceptive transmitter. In general,
noradrenergic controls are mediated at the spinal level by the
action at the a-2-adrenergic receptor (Fields and Basbaum 1994).
The a-2-agonist clonidine has been shown to block the release of
transmitters and peptides in primary afferent terminals by
presynaptic action, and it is most likely that the analgesic
effects of the tricyclic antidepressants partly depend on their
inhibition of norepinephrine re-uptake (Boivie 1994).
[0071] Intracellular Mechanisms in the Spinal Dorsal
Horn/Trigeminal Nucleus Involved in Central Sensitization.
[0072] Why are the NMDA receptors considered so important? The
actions of many receptors on neuronal excitability are via opening
or closing of ion channels. The ion channel for the NMDA receptors
allows vast amounts of calcium into the neuron, so much that the
resultant increase in excitability exceeds that produced by all
other receptors (Dickenson 1996). The increase in intracellular
calcium initiates a cascade of biochemical events. Thus, calcium
activates a calmodulin-sensitive site on NO synthase, which results
in the production of NO. NO may thereafter act via at least three
different mechanisms: 1) it may act in the neuron where it is
produced, e.g. by increasing cyclic guanylate mono phososphate
(cGMP) levels which again will activate protein kinases or by
inducing the expression of immediate early genes. The protein
kinases and the protein products of immediate early genes may then
act as third messengers and control the expression of other genes
involved in the synthesis of growth factors, channel proteins,
peptides and enzymes; 2) it may act as a retrograde transmitter by
diffusion to the presynaptic neuron where it modulates excitability
and enhances synaptic connections; and 3) it may diffuse to
adjacent neurons, e.g. interneurons (Meller and Gebhart 1993).
Another important result of increased intracellular calcium is the
activation of phospholipase A.sub.2, leading to increases in
intracellular arachidonic acid and the subsequent formation of
cyclooxygenase and lipooxygenase products. Prostaglandins have been
shown to increase calcium conductance on dorsal root ganglion cells
and to increase the secretion of primary afferent peptides such as
substance P (Yaksh and Malmberg 1994). Activation of the NMDA
receptors thus has dramatic consequences and the receptors are
therefore usually blocked, such that they do not participate in
normal transmission. This channel block, which is mediated by
physiological levels of Mg.sup.2+ ions, can only be removed by
sufficient repeated depolarization of the membrane. It is suspected
that the neurokinins co-released with glutamate from C-fibres
contribute to the removal of Mg.sup.2+ ions. This important action
of the neurokinins is probably mediated via NK.sub.1 and NK.sub.2
receptors (Dickenson 1996). Also the protein kinases activated by
NO will feed back on the NMDA receptors, causing phosphorylation
and partial removal of the Mg.sup.2+ channel blockade (Woolf 1996).
Other glutamate receptors are probably also involved in central
sensitization, but the exact mechanisms are not yet known.
[0073] Altered Pain Perception after Central Sensitization
[0074] The increased excitability of neurons in the spinal dorsal
horn/trigeminal nucleus has dramatic consequences for the pain
perception in the individual patient. In the sensitized state, pain
can be generated by low-threshold Ab-fibres (allodynia) (Torebjork
et al. 1992), the response to activation of high-threshold
afferents is exaggerated (hyperalgesia) (Woolf 1994), and since the
receptive field of the dorsal horn neuron is increased, the central
sensitization will also be manifest as a spread of hypersensitivity
to uninjured sites (secondary hyperalgesia) (Torebjork et al.
1992).
[0075] Central Sensitization in the Brain
[0076] When noxious input is received in the nucleus of the
trigeminal tract, its further transmission to the thalamus and
sensory cortex depends on the intensity of the input and on the
balance between pain inhibiting and pain facilitating descending
systems originating from the brain stem. When the pain inhibiting
system is activated, it decreases the likelihood that incoming
stimuli are being transmitted to the thalamus and, alternatively,
when the facilitatory system is activated, it increases the
likelihood of this event. From the thalamus, nociception is
projected further to the sensory cortex. Via unknown mechanisms
pain causes a reflex increase in muscle tone. It is envisaged that
this response to pain is mediated via the limbic system because
pain and anxiety are closely interrelated. There is also a
cross-talk between nociception and motor activity at the level of
the trigeminal nucleus/spinal cord. Finally, pain activates the
sympathetic system causing release of noradrenaline. This again is
responsible for an increased pain sensation, so-called
sympathetically aggravated or maintained pain.
[0077] Detailed Model for the Progression of Tension-Type
Headache
[0078] The progression of episodic tension-type headache into
chronic tension-type headache often takes several years and happens
only in a minority of episodic tension-type headache sufferers. A
genetic disposition (.O slashed.stergaard et al. 1996) as well as
several environmental factors seem to be involved in the
development of chronicity. Despite the fact that the progression is
continuous, it is best illustrated by a number of scenarios.
[0079] Scenario 1: Mild and moderate muscle contraction in normals.
Voluntary muscle contraction in relation to normal functions such
as cheating or head holding is initiated from the supplementary
motor cortex. This is probably associated with only a minor
increase in nociception from myofascial tissues and no wind-up in
non-headache sufferers. Simultaneously the antinociceptive system
is activated such that no sensation of pain occurs.
[0080] Scenario 2: Forceful and/or long-lasting muscle activity in
normals. With particularly vigorous muscle activity and especially
when it is very protracted, the strain on myofascial tissues may be
such that nociception is rather marked and tenderness and local
pain may occur, but it is rapidly controlled by local reparative
mechanisms in myofascial tissues and a continuously active
antinociceptive system. Tenderness without spontaneous pain on the
day after exercise may be a result of this balance or may be a
purely local phenomenon.
[0081] Scenario 3: Involuntary muscle activity induced by the
limbic system in normals: In contrast to activation initiated by
the supplementary motor area, muscle contraction initiated by the
limbic system is not associated with an increased antinociceptive
activity. On the contrary it is proposed to be associated with
increased activity in the pain facilitatory system. An alternative
is a decrease in the activity of the antinociceptive system, but
this is unlikely because this system is normally not tonically
active. Limbic initiated muscle activity therefore causes pain even
with moderate degrees of contraction and also with relatively
short-lasting contractions. However, in normals the drive from the
limbic system is short lasting and so are the mild changes in
myofascial tissues induced by the motor activity. The headache is
therefore self limiting.
[0082] Scenario 4: Voluntary contraction in patients with severe
episodic--and chronic but not daily tension-type headache. In most
of these individuals voluntary muscle activity will be painful. In
part this is due to permanent sensitization of second order neurons
in the nucleus of the trigeminal tract, in part it is due to the
fact (Jensen and Olesen 1996) that the antinociceptive system is
not activated as normally. Contraction therefore aggravates
tenderness and causes pain from the myofascial structures (Jensen
and Olesen 1996) The process of reverting the system back to normal
may be more or less effective. This variable duration of the
initiating stimulus accounts for the variable duration of the
headache.
[0083] Scenario 5: Severe (daily) chronic tension-type
headache.
[0084] In severe chronic tension-type headache there is a state of
chronic sensitization in myofascial tissues and in central pain
pathways both at the second order neurons and at higher centers.
There is a minor constant elevation of EMG signal from cranial
muscles. In addition, the most severe cases also have a more
diffuse sensitization revealed in decreased pain thresholds
throughout the body (Bendtsen et al. 1996b). Chronically increased
muscle activity maintains a state of chronic peripheral
sensitization which again maintains a state of chronic
sensitization in the second order neurons in the nucleus of the
trigeminal tract (Bendtsen et al. 1996c). This causes steady inflow
of nociceptive signals to the thalamus and the perception of
chronic pain by the sensory cortex. This again activates the limbic
system and stimulates tonic involuntary muscle activity. In this
situation of chronic pain there is probably also activation of the,
sympathetic nervous system adding a component of sympathetically
mediated pain to the whole picture. On top of this chronic
situation of sustained pain, it is easy to see how additional
strain would result in increased and prolonged pain. A further
increase in muscle activity would for instance in the sensitized
peripheral myofascial tissues lead to a stronger than normal
nociceptive input to the already sensitized nucleus of the
trigeminal tract which would project to already sensitized
hemispheric pain centers. A vicious circle has been set up and it
may become permanent due to changes in gene transcription and
consequent structural changes in neurons and synapses.
[0085] Rationale for the Novel Strategy According to the Invention
for the Treatment of Tension-Type Headache
[0086] Previous treatments have primarily been directed towards
reducing muscle contraction i.e. biofeedback treatment,
physiotherapy, dental treatment, exercises and muscle relaxants.
All of these treatments have had limited or no success. It follows
from the model according to the present inventors that therapeutic
intervention should be directed, primarily towards the afferent
system and above all against sensitization of second order neurons
in the nucleus of the trigeminal tract and upper cervical segments.
Furthermore, it follows that while intervention using peripherally
acting analgesics or other measures which reduce peripheral
nociceptive input is sufficient in episodic tension-type headache,
this is not so for severe episodic and chronic tension-type
headache, where sensitization of second order neurons occurs. In
these patients, desensitization of these neurons should be the
major target for drug intervention. It may, however, be difficult
to desensitize these neurons in face of an ongoing vigorous input
from the periphery. Therefore, drugs which reduce peripheral
sensitization may be needed in addition to the drugs which
desensitize second order nociceptive neurons, or drugs working at
both levels may be needed. Preferably treatment should be given
early enough to prevent sensitization of second order neurons.
Alternatively, if marked sensitization at the cortical level
occurs, the individual being hypersensitive to painful stimuli all
over the body, it may not be enough to intervene against the
sensitization of second order neurons. For such patients
intervention against cortical sensitization is recommended as an
additional measure.
[0087] The Novel Therapeutic Principle According to the Invention
for Treatment of Tension-Type Headache
[0088] According to the present invention, several means of
intervening against tension-tape headache can be envisaged,
depending on the level according to the above, at which the
intervention is aimed. In either case, be it in the periphery, the
second order neurons of the sensory trigeminal nucleus or the
cortex, the intervention must target the transmission of nerve
impulses. A number of different transmitter substances are involved
in this transmission at each level. Thus, the invention, in some of
its aspects, relate to the following therapeutic principles in
tension-type headache of the chronic type and of the severe
episodic type defined as having headaches ten or more days per
month:
[0089] Administration of agents or drugs (in the present
specification and claims, the terms agent and drug are used as
interchangeable) which prevent or reduce sensitization of second
order nociceptive neurons located in the nucleus of the descending
tract of the trigeminal nerve and in the C2 and C3 segments of the
dorsal cervical horn of the spinal cord. There are several known
types of assays indicating the capability of an agent to prevent or
reduce central sensitization. In the following, 13 such assays are
described.
[0090] Administration of agents or drugs which reduce supraspinal
pain sensitization to a normal level. These are agents or drugs
which normalize the response of pressure pain thresholds in the
temporal region to tooth clenching and drugs which normalize pain
thresholds in hand.
[0091] Administration of agents or drugs which reduce peripheral
sensitization defined as agents or drugs which prevent the
development of abnormal tenderness due to tooth clenching.
[0092] Administration of agents or drugs which normalize the pain
response to intra muscular infusion of bradykinin, 5-HT, histamine,
prostaglandines and/or nitroglycerine.
[0093] Administration of agents or drugs which normalize local
pressure pain threshold over myofascial tissues of the head.
[0094] Administration of agents or drugs which have more than one
of the above effects.
[0095] Administration of agents or drums which in a panel of test
patients with tension-type headache have one of the above effects
described one by one.
[0096] When targeting the transmission of nerve impulses according
to the invented model, it is preferred to interact with the
following substances relating to neurotransmission in connection
with pain:
[0097] Glutamate
[0098] Substance P
[0099] Nitric oxide
[0100] GABA
[0101] It is particularly preferred to:
[0102] Antagonize the effect of glutamic acid
[0103] Antagonize the effect of substance P
[0104] Antagonize the effect of nitric oxide
[0105] Stimulate the effect of GABA.
[0106] More specifically, it is preferred to use:
[0107] NMDA receptor antagonists
[0108] Inhibitors of neuronal nitric oxide synthase (NOS)
[0109] GABA A and GABA B receptor agonists
[0110] Counteraction of Central Sensitization of Second Order
Neurons
[0111] In order to counteract central sensitization of second order
neurons of the sensory trigeminal nucleus/dorsal horn, it will be
advantageous to cause a decrease in neuronal transmission involving
the pathways utilizing e.g. the transmitter substances glutamate,
nitric oxide, and the neurokinins (substance P, bradykinin,
neurokinin A, neurokinin B). Also, it will be of interest to
counteract the action of second messengers such as guanylate
cyclase, cGMP as well as any further steps in the action of cGMP in
second order sensory neurons receiving nociceptive input from the
head and neck.
[0112] Prevention of Central Sensitization of Second Order
Neurons
[0113] In order to prevent the occurrence of central sensitization
of second order neurons of the sensory trigeminal nucleus/dorsal
horn, it will be advantageous to normalize neuronal transmission in
the peripheral and/or central nervous system involving transmitter
substances such as glutamate, GABA, adenosine, nitric oxide, the
neurokinins (substance P, bradykinin, neurokinin A, neurokinin B),
neurotrophins and histamine. While it might have seemed
advantageous to use 5-HT.sub.1D receptor agonists because they
stabilize presynaptic nociceptive terminals, studies by the
inventors have shown that a compound of this class (sumatriptan) is
not effective to a clinically relevant extent in tension-type
headache although it is highly effective in migraine (Brennum et
al. 1992, 1996). Counteracting excitatory 5-HT receptors, such as
5-HT.sub.2 and 5-HT.sub.3 localized on second order neurons,
however, are contemplated to be effective in the treatment of
tension-type headache in accordance with the present invention
DETAILED DESCRIPTION OF TEE INVENTION
[0114] On the basis of their experimental discoveries and analyses,
the present inventors have devised, for the first time, a strategy
for the treatment or prevention of tension type headache. Up to
now, there has not been any effective treatment available for
tension type headache, which has been a very serious problem in
view of the very high prevalence of tension-type headache.
[0115] The present invention relates to a method of treatment or
prevention of tension-type headache in a person in need of such
treatment, the method comprising administering an amount of an
agent effective to interact with neuronal transmission connected
with pain perception so as to prevent or reduce central
sensitization.
[0116] The attainment of prevention or reduction of central
sensitization can be demonstrated by one of the following
assays:
[0117] 1) Normalization of a pathological qualitatively altered
stimulus-response function. The attainment of a normalization of a
qualitatively altered stimulus-response function in connection with
nociception (Bendtsen et al. 1996c, Example 1) can be demonstrated
by palpation of the trapezius muscle and recording of the degree of
pain corresponding to the intensity of palpation (Bendtsen et al.
1994). When a curve representing the stimulus/response function in
connection with nociception has changed in shape from being
substantially linear in a normal representation to being
substantially linear in a double logarithmic representation, a
normalization of the qualitatively altered stimulus/response
function has been obtained. In the present context, an agent which
normalizes a qualitatively altered stimulus-response function in
connection with nociception is an agent which, when administered to
a group of at least 20 patients suffering from tension-type
headache, will cause the curve representing the stimulus/response
function ion in connection with nociception to become substantially
linear when represented double logarithmically in at least 10 of
the patients. Preferably, the agent so defined has such an effect
in at least 12 of the patients. More preferably, the agent so
defined has such an effect in at least 14 of the patients.
[0118] 2) Normalization of a pathological abnormally low pain
threshold. Th attainment of a normalization of an abnormally low
pain threshold can be demonstrated by the measurement of the
pressure pain threshold in the extremities or in the pericranial
region with an electronic pressure algometer or by the measurement
of the electrical pain threshold with a constant current stimulator
as previously described (Bendtsen et al. 1996a). When the pain
threshold has changed from being significantly lower in a group of
patients with tension-type headache than in a group of healthy
controls to be not significantly different between the two groups,
a normalization of the abnormally low pain threshold has been
obtained. In the present context, an agent which normalizes an
abnormally low pain threshold is an agent which, when administered
to a group of at least 10 patients suffering from tension-type
headache, will change the pain threshold from being significantly
lower than that in a group of healthy controls to be not
significantly different between the two groups.
[0119] 3) Reduction of a pathological pericranial muscle hardness.
The attainment of reduction of pericranial muscle hardness can be
demonstrated by the measurement of hardness in the pericranial
muscles with a hardness meter as previously described (Ashina et
al. 1998a). When the muscle hardness is reduced significantly more
following the administration of a given agent than following the
administration of placebo, a reduction of muscle hardness has been
obtained. In the present context, an agent which reduces
pericranial muscle hardness is an agent which, when administered to
a group of at least 10 patients suffering from tension-type
headache, will reduce pericranial muscle hardness significantly
more than placebo. Such a reduction will typically be at least 10%.
Preferably the reduction will be at least 20%. More preferably the
reduction will be at least 30%.
[0120] 4) Reduction of a pathological increased pericranial
myofascial tenderness. The attainment of reduction of increased
pericranial myofascial tenderness can be demonstrated by the
measurement of the tenderness in the pericranial region using the
Total Tenderness Scoring system as previously described (Bendtsen
et al. 1995). Myofascial tenderness is considered to be increased
when the Total Tenderness Score or the Local Tenderness Score in
the pericranial region is above the 75% percentile of the Total
Tenderness Score or the Local Tenderness Score in a group of
healthy controls (Jensen and Rasmussen 1996). In the present
context, an agent which reduces increased pericranial myofascial
tenderness is an agent which, when administered to a group of at
least 10 patients suffering from tension-type headache, will reduce
the Total Tenderness Score or the Local Tenderness Score in the
pericranial region by at least 10% compared with the administration
of placebo. Preferably, the agent so defined will reduce the Total
Tenderness Score or the Local Tenderness Score in the pericranial
region by at least 20% compared with the administration of placebo.
More preferably, the agent so defined will reduce the Total
Tenderness Score or the Local Tenderness Score in the pericranial
region by at least 30% compared with the administration of
placebo.
[0121] 5) Prevention or reduction of pain, tenderness or hardness
in pericranial muscles, or prevention or normalization of a
qualitatively altered stimulus-response function or a reduced pain
threshold induced by experimental tonic muscle contraction. The
attainment of prevention or reduction of pain, tenderness or
hardness, or prevention or normalization of a qualitatively altered
stimulus-response function or a reduced pain threshold can be
demonstrated as described in assays 1-4 above. Experimental tonic
muscle contraction can be obtained by clenching of the molar teeth
for 30 minutes at 10% of the individual subject's maximal voluntary
contraction measured from electromyographic recordings of the
activity in the temporal or masseter muscles as previously
described (Jensen and Olesen 1996). In the present context, an
agent which prevents or reduces pain, tenderness or hardness, or
prevents or normalizes a qualitatively altered stimulus-response
function or a reduced pain threshold induced by experimental tonic
muscle contraction is an agent which, when administered to a group
of at least 10 human subjects, will prevent or reduce pain,
tenderness or hardness, or prevent or normalize a qualitatively
altered stimulus-response function or a reduced pain threshold
induced by experimental tonic muscle contraction to a significantly
higher degree than placebo.
[0122] 6) Prevention or reduction of pain, tenderness or hardness
in pericranial muscle, or prevention or normalization of a
qualitatively altered stimulus-response function or a reduced pain
threshold induced by intra muscular infusion of algogenic
substances. The attainment of prevention or reduction of pain,
tenderness or hardness, or prevention or normalization of a
qualitatively altered stimulus-response function or a reduced pain
threshold can be demonstrated as described in assays 1-4 above.
Intra muscular infusion of algogenic substances can be performed by
the use of a 0.4 mm needle as previously described (Jensen et al.
1990). Algogenic substances such as bradykinin, serotonin,
histamine, adenosine-tri-phosphate, prostaglandines, capsaicin,
hypertonic saline, potassium, nitroglycerine or combinations hereof
can be used. The algogenic substances can be injected either as a
single bolus injection (Jensen et al. 1990) or as a prolonged
infusion (Zhang et al. 1993). In the present context, an agent
which prevents or reduces pain, tenderness or hardness, or prevents
or normalizes a qualitatively altered stimulus-response function or
a reduced pain threshold induced by intra muscular infusion of
algogenic substances is an agent which, when administered to a
group of at least 10 human subjects, will prevent or reduce pain,
tenderness or hardness, or prevent or normalize a qualitatively
altered stimulus-response function or a reduced pain threshold
induced by intra muscular infusion of algogenic substances to a
significantly higher degree than placebo.
[0123] 7) Prevention or reduction of pain, tenderness or hardness
in pericranial muscle, or prevention or normalization of a
qualitatively altered stimulus-response function or a reduced pain
threshold induced by stimulation of nociceptive afferents in
myofascial tissues. The attainment of prevention or reduction of
pain, tenderness or hardness, or prevention or normalization of a
qualitatively altered stimulus-response function or a reduced pain
threshold can be demonstrated as described in assays 1-4 above.
Stimulation of nociceptive afferents in myofascial tissues can be
obtained by methods such as eccentric muscle contraction (Howell et
al. 1993), prolonged static muscle contraction, repeated monotonous
muscle work, ischemic muscle exercise (Myers and McCall Jr 1983),
electrical stimulation via needle electrodes inserted into the
muscles (Vecchiet et al. 1988) or mechanical pressure applied to
the muscles. In the present context, a substance which prevents or
reduces pain, tenderness or hardness, or prevents or normalizes a
qualitatively altered stimulus-response function or a reduced pain
threshold induced by stimulation of nociceptive afferents in
myofascial tissues is a substance which, when administered to a
group of at least 10 human subjects, oil prevent or reduce pain,
tenderness or hardness, or prevent or normalize a qualitatively
altered stimulus-response function or a reduced pain threshold
induced by stimulation of nociceptive afferents in myofascial
tissues to a significantly higher degree than placebo.
[0124] 8) Prevention or reduction of secondary allodynia or
secondary hyperalgesia induced by stimulation of nociceptive
afferents in myofascial tissues. The attainment of prevention or
reduction of secondary allodynia or secondary hyperalgesia can be
demonstrated by measuring pain sensitivity in the unaffected tissue
area that surrounds an area in which nociceptive afferents are
stimulated (Magerl et al. 1998). Pain sensitivity can be measured
by visual analogue scale recording of the pain intensity evoked by
stimuli such as mechanical pressures applied by an electronic
pressure algometer, manual palpation or pressure-controlled
palpation (Bendtsen et al. 1995; Bendtsen et al. 1996a), punctuate
mechanical stimuli applied by von Frey hairs (Magerl et al. 1998),
light touch stimuli applied by a soft cotton wisp (Magerl et al.
1998), thermal stimuli applied by the Marstock thermotest
(Norregaard et al. 1997) or electrical stimuli applied by surface
electrodes (Bendtsen et al. 1996a) or intra muscular needle
electrodes (Vecchiet et al. 1988) or by measuring the nociceptive
flexion reflex (Willer et al. 1984). Stimulation of nociceptive
afferents in myofascial tissues can be obtained as described in
assays 5-7 above. In the present context, an agent which prevents
or reduces secondary allodynia or secondary hyperalgesia induced by
stimulation of nociceptive afferents in myofascial tissues is an
agent which, when administered to a group of at least 10 human
subjects, will prevent or reduce secondary allodynia or secondary
hyperalgesia induced by stimulation of nociceptive afferents in
myofascial tissues to a significantly higher degree than
placebo.
[0125] 9) Prevention or reduction of wind-tip induced by repetitive
stimulation of nociceptive afferents in the pericranial region. The
attainment of prevention or reduction of wind-up can be
demonstrated by measuring pain sensitivity to repeated stimuli
(Magerl et al. 1998), since temporal summation of painful stimuli
is regarded as a psychophysical correlate of wind-up (Price et al.
1994). In the present context, wind-up is defined to be present
when repeated identical stimuli become increasingly painful
(Pedersen et al. 1998). Wind-up can be induced by stimuli such as
repeated electrical stimuli, e.g. five stimuli of 1 ms duration
with an intensity of 1.4 times the baseline pain threshold
delivered at 2 Hz by a constant current stimulator (Pedersen et al.
1998), or as repeated punctuate mechanical stimuli, e.g. five
stimuli delivered at 2 Hz with a 256 mN calibrated von Frey hair
(Magerl et al. 1998). The evoked pain intensity can be measured
using a visual analogue scale. In the present context, an agent
which prevents or reduces wind-up induced by stimulation of
nociceptive afferents in the pericranial region is an agent which,
when administered to a group of at least 10 human subjects, will
prevent or reduce wind-up induced by stimulation of nociceptive
afferents in the pericranial region to a significantly higher
degree than placebo.
[0126] 10) Prevention or reduction of secondary allodynia or
secondary hyperalgesia induced by nociceptive input in an
experimental animal model. The degree of secondary allodynia or
secondary hyperalgesia can be examined by measuring pain
sensitivity in the unaffected tissue area that surrounds an area in
which nociceptive afferents are stimulated (Magerl et al. 1998).
Pain sensitivity can be measured by recording the response of the
animal to well-defined stimuli, e.g. briskly stroking the skin
Faith the blunt point of a pencil (Magerl et al. 1998), mechanical
pressures applied by an electronic pressure algometer, manual
palpation, pressure-controlled palpation or calibrated von Frey
hairs (Hao et al. 1992), electrical stimuli or thermal stimuli (Hao
et al. 1992). The response of the animal can be measured by methods
such as: a) grading of the behavior of the animal to avoid a given
stimulus, e.g. as a score of 0: no response; 1: moderate efforts to
avoid the stimulus; and 2: vigorous efforts to escape the stimulus
(Hao et al. 1992); b) recording the time required for eliciting a
given response of the animal, e.g. withdrawal of an extremity, by a
given stimulus (Hao et al. 1992); c) recording the intensity of a
stimulus that elicits a given reaction, e.g. vocalization or
withdrawal or licking of an extremity (Hao et al. 1992); or d) by a
combination of the above-mentioned methods (Hao et al. 1992). The
induction of secondary allodynia or secondary hyperalgesia can be
performed as described above in assays 6 and 7 or by methods such
as the application to the skin of chemical irritants, e.g. mustard
oil (Woolf and King 1990), thermal stimuli (Hylden et al. 1989),
pinching, subcutaneous or intra muscular injections of complete
Freund's adjuvant (Hylden et al. 1989). In the present context, an
agent which prevents or reduces secondary allodynia or secondary
hyperalgesia induced by nociceptive input in an experimental animal
model is an agent which will prevent or reduce secondary allodynia
or secondary hyperalgesia induced by nociceptive input in an
experimental animal model to a significantly higher degree than
placebo.
[0127] 11) Prevention or reduction of wind-up induced by repetitive
stimulation of nociceptive afferents in an experimental animal
model. The degree of wind-up can be examined by measuring pain
sensitivity (Magerl et al. 1998) or the activity of second order
neurons to repeated stimuli (Woolf and Thompson 1991). In the
present context, wind-up is defined to be present when repeated
identical stimuli become increasingly painful (Pedersen et al.
1998) or potentiate the responses of second order neurons (Laird et
al. 1995). Pain sensitivity in animals can be recorded as described
above in assay 10, while the activity of second order neurons can
be measured using extra- and intracellular recordings of the
activity, in these neurons (Woolf and King 1990; Hu et al. 1992).
After exposure of the spinal cord via laminectomy, extracellular
recordings can be made using glass microelectrodes and
intracellular recordings can be made using potassium acetate
electrodes (Woolf and King 1990). Wind-up can be induced by stimuli
such as those described in assay 10. In the present context, an
agent which prevents or reduces wind-up induced by repetitive
stimulation of nociceptive afferents in an experimental animal
model is an agent which will prevent or reduce wind-up induced by
repetitive stimulation of nociceptive afferents in an experimental
animal model to a significantly higher degree than placebo.
[0128] 12) Prevention or reduction of increased receptive field
size of second order neurons induced by nociceptive input in an
experimental animal model. The receptive field size of second order
neurons can be measured using extra- and intracellular recordings
of the activity in these neurons (Woolf and King 1990; Hu et al.
1992) as described above in assay 11. The receptive fields can be
mapped using stimulation with, e.g., calibrated von Frey hairs,
blunt probes (Hylden et al. 1989), thermal stimuli (Hylden et al.
1989), serrated forceps or calibrated pinchers applied to the skin
(Woolf and King 1990). The induction of increased receptive field
size of second order neurons can be performed as described above in
assay 10. In the present context, an agent which prevents or
reduces increased receptive field size of second order neurons
induced by nociceptive input in an experimental animal model is an
agent which will prevent or reduce increased receptive field size
of second order neurons induced by nociceptive input in an
experimental animal model to a significantly higher degree than
placebo.
[0129] 13) Prevention or reduction of increased excitability of the
flexion reflex induced by nociceptive input in an experimental
animal model. The excitability of the flexion reflex can be
examined by measuring the activity in flexor motor neurons elicited
by a standard stimulus applied ipsilaterally to the recording of
flexor motor neuron activity (Woolf 1983). The examination can,
e.g., be performed by extracellular recordings of the activity from
flexor alpha motor neurons to the posterior biceps
femoris/semitendinosus muscles in the decerebrate rat (Woolf and
Thompson 1991). The flexion reflex can, e.g., be elicited by a
standard pinch applied to the ipsilateral toes (Woolf and Thompson
1991). The induction of increased excitability of the flexion
reflex can be performed as described above in assay 10. In the
present context, an agent which prevents or reduces increased
excitability of the flexion reflex induced by nociceptive input in
an experimental animal model is an agent which will prevent or
reduce increased excitability of the flexion reflex induced by
nociceptive input in an experimental animal model to a
significantly higher degree than placebo.
[0130] Prevention or reduction of central sensitization induced by
nociceptive input in an experimental animal model. The degree of
central sensitization in an experimental animal model can be
measured by other methods which are presumed to reflect central
sensitization but which are not mentioned in the above described
assays 10-13, i.e. measurement of cellular intermediate early genes
such as c-fos (Dubner and Ruda 1992). The induction of central
sensitization can be performed as described above in assay 10. In
the present context, an agent which prevents or reduces central
sensitization induced by nociceptive input in an experimental
animal model is an agent which sill prevent or reduce central
sensitization induced by nociceptive input in an experimental
animal model to a significantly higher degree than placebo.
[0131] In the present context the term "significantly higher degree
than placebo" should be taken to mean statistically significant
when the relevant statistical tests are applied to data relating to
an effect of an agent according to the invention compared to an
effect of placebo in any given assay or test.
[0132] The interaction with neuronal transmission connected with
pain perception will normally be interaction with neuronal
transmission connected with second order nociceptive neurons. This
interaction will normally involve prevention of sensitization by
way of a reduction of C-fiber input to the second order nociceptive
neurons or reversal of an already established sensitization of
second order nociceptive neurons.
[0133] Interaction with neuronal transmission connected with pain
perception can be exerted by increasing inhibitory synaptic stimuli
or it can be exerted by decreasing excitatory synaptic stimuli.
[0134] By the term "palpation" is meant the act of applying, with
the fingers, pressure to the surface of the body for the purpose of
determining the amount of pain elicited in the underlying tissue by
said pressure intensity.
[0135] In the present context, the term "qualitatively altered
stimulus/response function" in connection with nociception means
that the function describing the amount of pain elicited by a given
pressure intensity, sensed by a person being palpated, has changed
in shape from being positively accelerating to being substantially
linear, of Example 1.
[0136] By the term "tender muscle" is meant a muscle in which pain
is elicited by palpation with a clinically relevant pressure.
[0137] In the present context, by the term "central sensitization"
is meant that second order nociceptive neurons residing in the
central nervous system are rendered more sensitive than normally to
incoming synaptic stimuli. At the occurrence of central
sensitization such stimuli will elicit excitation of the said
central neurons at stimulation below the normal threshold for
excitation; thus, central neurons possess an increased
excitability.
[0138] In the present context, myofascial pain relates to pain in
the myofascial tissue, by which is meant muscular structures,
tendons and tendon insertions related to the pericranial and
cervical region.
[0139] In the context of the present invention second order
nociceptive neurons are neurons located in the nucleus of the
trigeminal tract and of C2 and C3 segments of medullary dorsal
horns, said neurons being involved in the processing of nociceptive
stimuli.
[0140] By the term "C-fibers" is meant a class unmyelinated
nociceptive fibers terminating on neurons in the nucleus of the
trigeminal tract/dorsal horn of the spinal cord.
[0141] The interaction with neuronal transmission connected with
pain perception, so as to obtain a substantial prevention or a
substantial normalization of an otherwise qualitatively altered
stimulus-response function in connection with nociception is
preferably performed by administering an effective amount of an
agent which prevents or normalizes an otherwise qualitatively
altered stimulus-response function in connection with
nociception.
[0142] In the present context, an agent which prevents or
normalizes an otherwise qualitatively altered stimulus-response
function in connection with nociception is an agent which, when
administered to a group of at least 20 patients suffering from
tension tape headache as defined above, will cause the curve
representing the stimulus/response function in connection with
nociception to become substantially linear when represented double
logarithmically in at least 10 of the patients. Preferably the
agent so defined has such an effect in at least 12 of the patients.
More preferably the agent so defined has such an effect in at least
14 of the patients.
[0143] A number of substances and classes of substances which
interact smith neuronal transmission to exert this function are
know, confer the detailed discussion thereof in the following.
[0144] In accordance with what is explained above, another way of
expressing the treatment according to the invention is by reference
to pain threshold in connection with chronic contraction of muscle,
in particular tooth clenching. Thus, according to this, the
invention can be expressed as a method for treatment of
tension-type headache in a person in need of such treatment,
comprising interacting with neuronal transmission connected with
pain perception so as to obtain a substantial increase of an
otherwise unresponsive pain threshold in connection with chronic
contraction of muscle, in particular tooth clenching.
[0145] Again, the interaction is preferably performed by
administering an agent which will interact with neuronal
transmission in a manner corresponding to what has been described
above. The agent can be characterized as a agent which performs
positively (as described above), in one or more of the assays
described above, such as the stimulus/response function test
described above, or as a agent which, in a group of at least 20
patients suffering from tension type headache as defined above,
will cause the effect of tooth clenching to be an increased pain
threshold instead of an abnormally low pain threshold in at least
10 of the patients, preferably at least 12 of the patients, more
preferably in at least 14 of the patients.
[0146] In another aspect, the invention relates to an agent having
the properties defined herein for use as a medicament, in
particular for the treatment of tension-type headache. This aspect
relates to those substances or substance classes discussed herein
which have not previously been used as medicaments or diagnostics.
In a further aspect, the invention relates to the use of an agent
having the properties described herein for the preparation of a
pharmaceutical composition for the treatment or prevention of
tension-type headache.
[0147] In one aspect of the present invention the treatment or
prevention of tension-type headache according to the invention is
not accompanied by a substantial reduction of muscle tension.
[0148] In an important aspect the present invention relates to a
method for treating tension-type headache in a person which
comprises administering an agent in an amount effective to
alleviate said headache, said agent being an agent capable of
altering the relationship of pain intensity to pressure intensity
when the trapezoid muscle is palpated at different pressure
intensities in said person. The relationship is typically
substantially linear in the untreated persons, and substantially
non-linear in the treated persons. Furthermore, the relationship
will typically be positively accelerating in the treated person. In
one embodiment of the present invention the rate of acceleration of
pain intensity with pressure intensity is substantially constant.
In one important embodiment of the present invention the
relationship in the treated persons is substantially the same as in
control persons who did not have tension-type headache and who were
treated with a placebo.
[0149] The agent interacting with neuronal transmission to
substantially normalize an otherwise qualitatively altered
stimulus/response function in connection with nociception is
preferably one which directly quantitatively lowers pain
perception, in that, in a panel of test persons suffering from
increased myofascial tenderness with disorder of pericranial muscle
in connection with tension-type headache, the administration of the
agent will result in transformation of a substantially linear pain
intensity perception in response to pressure intensity in trapezius
as well as other relevant pericranial muscles into a curve (C) of
which the values of pain intensity are lower than the linear pain
intensity perception.
[0150] The curve (C) is preferably a curve which can be described
substantially as a power function and is a curve which is
substantially linear in a double logarithmic plot.
[0151] It is preferred that substantially each of the values of
curve (C) is at the most 20% higher, preferably at the most 10%
higher, than the value of the corresponding curve produced for a
test panel of healthy controls.
[0152] In connection with any of the patient panel tests discussed
above it is noted that the treatment with the agent in question
should be performed by administration at least once daily to
maintain a therapeutic plasma level in the patients and should be
continued for a sufficient time to allow the agent to exert its
therapeutic effect, but that an agent is considered not to perform
according to the particular test if the effect is not obtained
within a treatment time of three months. This does not mean that it
will necessarily take three months for an agent to exert its
therapeutic effect; some compounds will show their therapeutic
effect after much shorter treatment periods, down to days or even
hours. In connection with testing of a new candidate agent, the
dosage of the agent will normally be kept as high as permitted by
the toxicity of the compound during initial tests and %% ill then
be reduced to a lower level which is still maximally effective
during the test proper.
[0153] Evaluation of the ability of an agent to provide an
effective treatment for tension-type headache, by interacting with
neuronal transmission according to the present invention, may also
be performed as an acute test, in which the agent is administered,
typically as a bolus or an infusion, to a group of patients
suffering from chronic tension-type headache. In such a test, the
pain connected to tension-type headache in these patients will
typically be scored by the patients, as described in example 4, at
various time points after administration of the agent, typically at
least every 15 min and subsequently monitored over a period of at
least 30 nun, typically at least 60 min, preferably at least 90,
more preferably at least 120 min. For the evaluation of a candidate
agent, an additional group of patients acutely suffering from
tension-type headache will receive placebo and serve as a control
group. The curves based on the pain scores of patients in both
groups will typically be compared, as shown in FIG. 14, and an
agent will be considered effective in treatment of tension-type
headache according to the present invention, if it is capable of
preventing or substantially preventing pain in connection with
tension-type headache when pain scores after administration of the
agent, when differering most from the corresponding score after
administration of placebo, are at least 10% lower than scores for
placebo, typically at least 20% lower, preferably at least 30%
lower, more preferably at least 40% lower. For an evaluation as
described here, the size of the participating groups of patients
will be at least 5 patients in each group, typically at least 7
patients in each group, preferably at least 10 patients in each
group, more preferably at least 12 patients in each group, even
more preferably at least 15 patients in each group.
[0154] Evaluation of the ability of an agent to provide an
effective prevention of tension-type headache by interacting with
neuronal transmission according to the present invention can be
performed as described above except that the parameter measured and
scored by headache patients will typically be duration of pain or
frequency of pain in connection with tension-type headache in
sufferers with an episodic form of the disease.
[0155] In the practical treatment of a patient, the administration
of an agent will normally be continued for at least one month,
preferably at least two months and more preferably at least three
months and in many cases indefinitely in order to establish and
maintain the normalization which is aimed at. If the desired
normalization occurs before one month of treatment, it is certainly
possible according to the invention to discontinue the treatment,
but this will increase risk of relapse and is normally not
preferred. The administration is performed using at least one dose
daily or at any rate substantially at least one dose daily (which
means that the treatment is not outside the scope of the invention
if it is just interrupted one or perhaps even (but not preferred) a
few days), and the dose of the particular agent is preferably
adapted so that it will maintain a therapeutic plasma level
substantially at any time. Notwithstanding the above statement to
the effect that the administration may in many cases be performed
indefinitely, it is contemplated that there will be cases where the
treatment period will be less than 10 years, such as less than 5
years or less than 2 years or even less than 1 year.
[0156] The interaction with neuronal transmission connected with
pain perception will normally be such an interaction with neuronal
transmission connected with second order nociceptive neurons which
involves substantially reducing excitation mediated through the
interaction between transmitter substances and their receptors on
second order nociceptive neurons.
[0157] The above-mentioned interaction will normally involve a
reduction of C-fiber, A-d-fiber and A-b-fiber input to the
nociceptive second order neurons, through a substantial reduction
of excitatory activity in synapses of C-fibers, A-d-fibers and
A-b-fibers on second order neurons, said activity mediated through
the interaction between the involved transmitter substances and
their receptors on second order nociceptive neurons.
[0158] The reduction of excitatory activity in synapses of
C-fibers, A-d-fibers and A-b-fibers on second order neurons
mediated through the interaction between the involved excitatory
transmitter substances and their receptors on second order
nociceptive neurons will preferably be performed by administration
of an effective amount of at least one agent which a) substantially
inhibits the production of said excitatory transmitter substance,
b) substantially inhibits the release of said excitatory
transmitter substance, c) substantially counteracts the action of
said excitatory transmitter substance, and/or d) substantially
inhibits the binding of said excitatory transmitter substance to
its relevant receptors.
[0159] Important examples of such excitatory transmitter substances
are selected from the group consisting of glutamate, nitric oxide,
neurokinins (substance P, neurokinin A, neurokinin B and
bradykinin), CGRP, adenosine working-through, A2 receptors, 5-HT
when working through 5-HT.sub.2,3 receptors and pituitary adenylate
cyclase actvating polypeptide (PACAP).
[0160] Agents which can interact with neuronal transmission
mediated by glutamate will typically comprise competitive or
non-competitive antagonists of ionotropic glutamate receptors,
including NMDA, AMPA and kainate receptors. Interaction with
glutamate neurotransmission can also be performed with antagonists
at the glycine site of the NMDA receptors or with antagonists or
inverse agonists at modulatory sites such as polyamine sites.
Interaction with metabotropic glutamate receptors can be performed
with agonists or antagonists depending-on whether they are
receptors located pre or postsynaptically and whether they belong
to the excitatory type I receptors (mGluR1,5) or the inhibitory
type II and type III receptors (mGluR2,3 and mGluR4,6-8,
respectively).
[0161] While sensitization of second order neurons is believed, as
explained above, to be an important cause of pain in connection
with tension type headache, it is clear that other elements of
neuronal transmission may also play a significant role and in some
cases even a predominant role as explained in the model described
in connection with FIG. 1. Based on this recognition, another, more
general, aspect of the present invention introduces, for the first
time, the use of a number of classes of substances for treatment of
tension type headache. This aspect relates to a method for
treatment or prevention of tension-type headache in a person in
need of such treatment, comprising administering an amount of an
agent which, in the peripheral and/or central nervous system, is
effective to specifically interact with neuronal transmission
connected with pain perception by
[0162] a) substantially antagonizing the action of glutamate, 5-HT,
GABA, nitric oxide, nitric oxide synthase, guanylate cyclase,
cyclic guanylate monophosphate (cGMP), CGRP, substance P,
neurokinin A, neurokinin B, bradykinin, PACAB, adenosine, glycine,
histamine, neurotrophins, Na.sup.+ ions or Ca.sup.2+ ion
channels,
[0163] or by
[0164] b) substantially potentiating the action of adenosine,
galanine or norepinephrine,
[0165] with the proviso that said agent is not ethyl
2-amino-(4-fluorobenzylamino)-3-pyridylcarbamate or an
arylglycineamide derivative as described herein.
[0166] An additional aspect of the present invention relates to a
method of treatment of tension-type headache comprising
administering to a person in need of such treatment an effective
amount of an agent which substantially inhibits the action of the
enzyme nitric oxide synthase (NOS) and thereby reduces chronic pain
in connection with tension-type headache. In many cases the effect
of treatment of tension-type headache with a NOS inhibitor will be
exerted through a decrease in existing central sensitization, but
also within the scope of the invention is treatment of tension-type
headache with NOS inhibitors whose effect on the reduction of pain
in connection with tension-type headache is mediated through a
mechanism not directly involving inhibition of central
sensitization. Such an alternative mechanism might possibly
comprise an alteration of pain modulation involving nitric
oxide.
[0167] A very important aspect of the present invention is a method
of screening a drug for the ability to alleviate a tension-type
headache which comprises comparing the relationship of pain
intensity to pressure intensity when the trapezoid muscle is
palpated at different pressure intensities for (a) persons having
tension-type headaches after treatment with the drug, and (b)
persons having tension-type headaches, treated with a placebo, and
determining if the relationship is altered. Also within the scope
of the present invention is a method of screening a drug for the
ability to alleviate tension-type headache comprising testing said
drug in one or more of the assays 1-13 described above and
determining effect in the test organism according to each assay.
The test organisms will typically be human patients and human
controls or relevant experimental animals, depending on the given
assay.
[0168] In the following discussion of substances or groups of
substances, numbers in parenthesis refer to the correspondingly
numbered structural formulas in the formula sheets below.
3 NMDA receptor antagonists competitive 6 CGS 19755 (1) 7 (R)-CPP
(2) 8 (R)-CPPene (3) 9 LY 235959 (4) non-competitive 10 MK-801 (5)
11 Metapramine (6) 12 Amitriptyline (7) 13 Imipramine (8) 14
Desipramine (9) 15 Mirtazapine (10) 16 Venlafaxine (11) 17
Memantine (12) 18 Ketamine (13) 19 Norketamine (14) 20
Dextromethorphan (15) 21 Remacemide (16) 22 Ifenprodil (17) 23
Eliprodil (18) 24 Synthalin (19) Glycine antagonists (NMDA
co-agonist site) 25 (R)-HA-966 (20) 26 7-CI-Kynurenic acid (21) 27
L-689,560 (22) 28 L-701,252 (23) 29 L-701,273 (24) 30 L-701,324
(25) 31 GV150526A (26) 32 ACPC (27) 33 MNQX (28) 34 ACEA 1021 (29)
35 DCQX (30) 36 Felbamate (31) AMPA receptor antagonists
competitive 37 CNQX (32) 38 NBQX (33) 39 PNQX (34) 40 YM90K (35) 41
L-698,544 (36) 42 LY 215490 (37) 43 AMOA (38) 44 NS-257 (39)
non-competitive 45 GYKI 52466 (40) 46 SYM 2206 (41) Kainic acid
receptor antagonist 47 NS-102 (42) Metabotropic glutamate receptor
ligands 48 4CPG (43) 49 UPF523 (44) 50 L-AP4 (45) Neurokinin A
(NK.sub.2) receptor antagonists 51 SR-48968 (46) 52 GR 159897 (47)
Bradykinin receptor antagonists D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser--
D-Tic-Oic Icatibant (48) 53 WIN 64338 (49) NO synthase inhibitors
54 L-NAME (50) 55 L-NMMA (51) 56 L-NIO (52) 57 L-NNA (53) 58
Dimethyl-L-arginine (54) 59 Thiocitruline (55) 60
(S)-Methylthiocitrulline (56) 61 7-Nitroindazole (57) 62 Potassium
carboxy-PTIO (58) 63 TRIM (59) 64 Tirilazad (60) 65
Diphenyleneiodonium chloride (61) 66 Paroxetine (62) Guanylat
cyclase inbibitor 67 ODQ (63) GABA-A receptor agonists 68
Gabapentin (64) 69 TACA (65) 70 Isonipenotic acid (66) 71 Midazolam
(69) 72 Isoguvacine (67) 73 THIP (68) GABA uptake inhibitors 74
(.+-.)-cis-4-Hydroxynipecotic acid (70) 75 Guvacine (71) 76 THPO
(72) 77 SKF 89976-A (73) 78 Tiagabine (74) 79 NO-711 (75) GABA
transaminase inhibitor 80 Vigabatrin (76) Adenosin receptor ligands
81 N.sup.6-Cyclopentyladenosine (77) 82 Adenosine (78) 83
Dipyridamole (79) 84 DMPX (80) 85 Dilazep (81) 5-HT.sub.2.3
receptor antagonists 86 Tropanserin (82) 87 Pizotyline (83)
.alpha.-2 Receptor agonists 88 Clonidine (84) 89 Apracionidine (85)
90 Xylazine (86) 91 Dexmedetomidine (87) Na.sup.+ channel blockers
92 Lamotrigine (88) 93 Lifarizine (89) 94 Phenytoin (90) 95
Lubeluzole (91) 96 Riluzole (92) 97 Carbamazepine (93) 98 Lidocaine
(94) 99 Tocainide (95) 100 Mexiletene (96) Ca.sup.2+ channel
blockers 101 Flunarizine (97) 102 Fostedil (98)
[0169] Agents which inhibit neuronal transmission mediated by
glutamate, in the central and/or peripheral nervous system, are
capable of a) substantially inhibiting the production of glutamate,
b) substantially inhibiting the release of glutamate, c)
substantially counteracting the action of glutamate and/or d)
substantially inhibiting the binding of glutamate to receptors for
glutamate.
[0170] Examples of competitive NMDA receptor antagonists are
nitrogen-containing heterocyclic compounds selected from diacidic
piperidines, such as CGS 19755 (1), diacidic piperazines, such as
(R)-CPP (2) and (R)-CPPene (3), phosphono amino acids such as LY
235959 (4) and derivatives of any of the above which are
competitive NMDA antagonists or prodrugs thereof.
[0171] Examples of non-competitive NMDA receptor antagonists are
polycyclic amines, such as MK-801 (5); tricyclic antidepressants,
such as Metapramine (6), Amitriptyline (7), Imipramine (8),
Desipramine (9), Mirtazapine (10) or Venlafaxine (11);
adamantanamines, such as Memantine (12); arylcyclohexylamines, such
as Ketamine (13); arylcyclohexylamines, such as Norketamine (14):
opioid derivatives, such Dextromethorphan (15); glycylamides, such
as Remacemide (16); piperidinylethanols, such as Ifenprodil (17):
piperidinylethanols, such as Eliprodil (18); diguanidines, such as
Synthalin (19); .gamma.-aminobutyric acid derivatives, such as
Gabapentin (64); polycyclic amines, such as Pizotyline (83) or
derivatives of any of the above which are non competitive NMDA
antagonists or prodrugs thereof.
[0172] Mirtazapine (10) and Venlafaxine (11) are conventionally
known to have .alpha.-2 receptor antagonist effects, and their
efficacy as antidepressants are thought to be exerted through a
decrease in noradrenergic neutrotransmission. However, it is
presently believed that Mirtazapine and Venlafaxine may also have
an effect on glutamate neurotransmission, potentially as
non-competitive NMDA receptor antagonists. It is through this
mechanism that the two substances are presumed to provide a method
of treatment of tension-type headache according to the present
invention.
[0173] Examples of Glycine antagonists are aminopyrrolidinones,
such as (R)-HA-966 (20); kynurenic acid derivatives, such as
7-Cl-Kynurenic acid (21); tetrahydroquinolines, such as L-689,560
(22); kynurenic acid derivatives, such as L-701,252 (23), L-701,273
(24), L-701,324 (25); indoles such as GV150526A (26); glycine
derivatives, such as ACPC (27); quinoxalinediones, such as MNQX
(28), ACEA 1021 (29) and DCQX (30); dicarbamates, such as Felbamate
(31) and derivatives of any of the above which are glycine
antagonists or prodrugs thereof.
[0174] Examples of competitive AMPA receptor antagonists are
quinoxalinediones, such as CNQX (32), NBQX (33), PNQX (34) and
YM90K (35); dihydroquinolones, such as L-698,544 (36); diacidic
decahydroisoquinolines, such as LY 215490 (37); amino acid
isoxazoles, such as AMOA (38); indoleoximes, such as NS-257 (39)
and derivatives of any of the above which are competitive AMPA
receptor antagonists or prodrugs thereof.
[0175] Examples of non-competitive AMPA receptor antagonists are
2,3-benzodiazepines, such as GYKI 52466 (40); phthalazines, such as
SYM 2206 (41) and derivatives of any of the above which are
non-competitive AMPA receptor antagonists or prodrugs thereof.
[0176] Examples of competitive kainate receptor antagonists are
indoleoximes, such as NS-102 (42) and derivatives thereof which are
competitive kainic acid receptor antagonists or prodrugs
thereof.
[0177] Examples of metabotropic receptor agonists are
phenylglycines, such as 4CPG (43); amino acid indanes, such as
UPF523 (44); phosphono amino acids, such as L-AP4 (45) and
derivatives of any of the above which are metabotropic glutamate
receptor agonists or prodrugs thereof.
[0178] Agents which inhibit neuronal transmission mediated by 5-HT,
in the central and/or peripheral nervous system, are capable of a)
substantially inhibiting the synthesis of 5-HT, b) substantially
inhibiting the release of 5-HT, c) substantially counteracting the
action of 5-HT and/or d) substantially inhibiting the binding of
5-HT to excitatory 5-HT 5-HT.sub.2,3 receptors.
[0179] Examples of 5-HT.sub.2,3 receptor antagonists are tropan
derivatives, such as Tropanserin (82); polycyclic amines, such as
Pizotyline (83) and derivatives of any of the above which are
5HT.sub.2,3 receptor antagonists or prodrugs thereof.
[0180] It is presently believed that Pizotyline (83) may also have
effect on glutamate neurotransmission, potentially as a
non-competitive NMDA receptor antagonist, as mentioned above. This
mechanism is presumed, in addition to the 5-HT receptor antagonism,
to provide a method of treatment of tension-type headache according
to the present invention.
[0181] Agents which can inhibit neuronal transmission mediated by
adenosine, in the central and/or peripheral nervous system, are
capable of a) substantially inhibiting the synthesis of adenosine,
b) substantially inhibiting the release of adenosine, c)
substantially counteracting the action of adenosine, and/or d)
substantially functioning as antagonists at adenosine A2
receptors.
[0182] Examples of adenosine A2 receptor antagonists are xanthine
derivatives, such as DMPX (80) and derivatives thereof which are A2
receptor antagonists or prodrugs thereof.
[0183] Examples of adenosine uptake inhibitors are homopiperazine
derivatives, such as Dilazep (81) and derivatives thereof which are
adenosine uptake inhibitors or prodrugs thereof.
[0184] Agents which can inhibit neuronal transmission mediated by
substance P, in the central and/or peripheral nervous system are
capable of a) substantially inhibiting the synthesis of substance
P, b) substantially inhibiting the release of substance P, c)
substantially counteracting the action of substance P, and/or d)
substantially inhibiting binding of substance P to receptors for
substance P.
[0185] Agents which can inhibit neuronal transmission mediated by
neurokinin A, in the peripheral and/or central nervous system, are
capable of a) substantially inhibiting the synthesis of neurokinin
A, b) substantially inhibiting the release of neurokinin A, c)
substantially counteracting the action of neurokinin A, and/or d)
substantially inhibiting binding of neurokinin A to receptors for
neurokinin A (NK.sub.2 receptors).
[0186] Examples of neurokinin A (NK.sub.2) receptor antagonists are
peptidomimetics, such as SR-48968 (37); peptidomimetics, such as GR
159897 (38) and derivatives thereof which are NK2 receptor
antagonists or prodrugs thereof.
[0187] Agents which can inhibit neuronal transmission mediated by
bradykinin, in the peripheral and/or central nervous system, are
capable of a) substantially inhibiting the production of
bradykinin, b) substantially inhibiting the release of bradykinin,
c) substantially counteracting the action of bradykinin and/or d)
substantially inhibiting binding of bradykinin to receptors for
bradykinin.
[0188] Examples of bradykinin receptor antagonists are
peptidomimetics, such as Icatibant (48) and WIN 64338 (49) and
derivatives of any of the above which are bradykinin receptor
antagonists or prodrugs thereof.
[0189] Agents which can inhibit neuronal transmission mediated by
CGRP, in the peripheral and/or central nervous system, are capable
of a) substantially inhibiting the production of CGRP, b)
substantially inhibiting the release of CGRP, c) substantially
counteracting the action of CGRP and/or d) substantially inhibiting
the binding of CORP to receptors for CGRP.
[0190] Examples of GCRP receptor antagonists are GCRP 8-37.
[0191] Agents which can inhibit neuronal transmission mediated by
PACAP, in the peripheral and/or central nervous system are capable
of a) substantially inhibiting the synthesis of PACAP, b)
substantially inhibiting the release of PACAP, c) substantially
counteracting the action of PACAP and/or d) substantially
inhibiting binding of PACAP to receptors for PACAP.
[0192] Agents which can inhibit neuronal transmission mediated by
nitric oxide, in the peripheral and/or central nervous system, are
capable of a) substantially inhibiting the production of nitric
oxide, b) substantially counteracting the action of nitric oxide,
c) substantially inhibiting the production of nitric oxide synthase
(NOS) and/or d) substantially counteracting the action of nitric
oxide synthase (NOS).
[0193] The interaction with neuronal transmission connected with
pain perception connected with second order nociceptive neurons can
comprise interaction with intracellular substances involved in this
neuronal transmission, said interaction involving excitation
mediated through the interaction with enzymes and second messengers
in second order nociceptive neurons.
[0194] Preferred examples of the above mentioned intracellular
substances are NOS, guanylate cyclase, and cGMP.
[0195] The interaction with neuronal transmission connected with
pain perception, comprising interaction with NOS will preferably be
performed by the administration of an effective amount of at least
one agent which can substantially inhibit the production of the
NOS, and/or substantially counteract the action of NOS.
[0196] Examples of NOS inhibitors are arginine derivatives, such as
L-NAME (50), L-NMMA (51), L-NIO (52), L-NNA (53) and
Dimethyl-L-arginine (54); citrulline derivatives, such as
Thiocitrulline (55) and (S)-Methylthiocitrulline (56); indazoles,
such as 7-Nitroindazole (57); imidazolin-N-oxides, such as
Potassium carboxy-PTIO (58); phenylimidazoles, such as TRIM (59);
21-aminosteroids, such as Tirilazad (60); biphenyls, such as
Diphenyleneiodinium chloride (61); piperidine derivatives, such as
Paroxetine (62) and derivatives of any of the above which are NOS
inhibitors or prodrugs thereof.
[0197] The interaction with neuronal transmission connected with
pain perception, comprising interaction with guanylate cyclase can
be performed by the administration of an effective amount of at
least one agent which substantially inhibits the production of
guanylate cyclase and/or substantially counteracts the action of
guanylate cyclase.
[0198] Examples of guanylate cyclase inhibitors are quinoxalines,
such as ODQ (63) and derivatives thereof which are guanylate
cyclase inhibitors.
[0199] The interaction with neuronal transmission connected with
pain perception comprising interaction with cGMP can be executed by
the administration of an effective amount of at least one agent
which, in the peripheral and/or central nervous system, is capable
of a) substantially inhibiting the production of guanylate cyclase,
b) substantially counteracting the action of guanylate cyclase, c)
substantially inhibiting the production of cyclic guanylate
monophosphate (cGMP), d) substantially counteracting the action of
cyclic guanylate monophosphate (cGMP) and/or e) substantially
inhibiting any further steps in the reaction induced by cyclic
guanylate monophosphate (cGMP), such as protein kinase C.
[0200] The activity of C-fibers, A-d-fibers and A-b-fibers on
second order nociceptive neurons involves inhibitor
neurotransmitter substances. Reduction of activity of C-fibers on
second order neurons Hill normally be performed by administration
of an effective amount of at least one agent which is capable of a)
substantially inhibiting the enzymatic degradation of said
inhibitory transmitter substance, b) substantially enhancing the
release of said inhibitory transmitter substance, c) substantially
enhancing the action of said inhibitory transmitter substance
and/or substantially activating the relevant receptor for said
inhibitory transmitter substance.
[0201] Preferred examples of such inhibitory transmitter substances
are selected from the group consisting of GABA, galanine, adenosine
working through A.sup.1 receptors, and norepinephrine.
[0202] Agents which can stimulate neuronal transmission mediated by
GABA, in the peripheral and/or central nervous system, are capable
of a) substantially enhancing the production of GABA, b)
substantially inhibiting the enzymatic degradation of GABA, c)
substantially enhancing the release of GABA, d) substantially
enhancing the action of GABA and/or e) substantially activating
receptors for GABA.
[0203] An example of a substance with GABA-enhancing activity is
benzodiazepines, such as Midazolam (69) and derivatives thereof
which are GABA activity enhancers or prodrugs thereof.
[0204] Examples of GABA-A receptor agonists are
.gamma.-aminobutyric acid derivatives, such as Gabapentin (64) and
TACA (65): Isonipecotic acid (66) and Isoguvacine (67);
3-hydroxylisoxazoles, such as THIP (68) and derivatives of any of
the above which are GABA-A agonists or prodrugs thereof.
[0205] Gabapentin is conventionally known to have GABA-A receptor
agonist activity, though this mechanism has been questioned.
However, it is presently believed that Gabapentin may also have
antagonist effect on glutamate transmission, indirectly or
directly, potentially as a non-competitive NMDA receptor
antagonist, as mentioned above. It is through this mechanism, in
addition to its gabaergic activity, that Gabapentin is presumed to
provide a method of treatment of tension-type headache according to
the present invention.
[0206] Examples of GABA uptake inhibitors are carboxypiperidine
derivatives, such as (.+-.)-cis-4-Hydroxynipecotic acid (70);
carboxypyridine derivatives, such as Guvacine (71);
3-hydroxyisoxazoles, such as THPO (72); nipecotic acid derivatives,
such as SKF 89976-A (73) and Tiagabine (74); guvacine derivatives,
such as NO-711 (75) and derivatives of any if the above which are
GABA uptake inhibitors or prodrugs thereof.
[0207] Examples of GABA transaminase inhibitors are
.gamma.-aminobutyric acid derivatives, such as Vigabatrin (76) and
derivatives thereof which are GABA transaminase inhibitors or
prodrugs thereof.
[0208] Agents which can stimulate neuronal transmission mediated by
galanine, in the peripheral and/or central nervous system, are
capable of a) substantially inhibiting the enzymatic degradation of
galanine, b) substantially enhancing the release of galanine, c)
substantially enhancing the action of galanine and/or d)
substantially functioning as agonists at galanine receptors.
[0209] Agents which can stimulate neuronal transmission mediated by
adenosine, in the peripheral and/or central nervous system, are
capable of a) substantially inhibiting the enzymatic degradation of
adenosine, b) substantially enhancing the release of adenosine, c)
substantially enhancing the action of adenosine and/or d)
substantially functioning as agonists at A.sup.1receptors.
[0210] Examples adenosine A.sup.1 receptor agonists are adenosine
derivatives, such as N.sup.5-Cyclopentyladenosine (77);
adeninglucosides, such as Adenosine (78) and derivatives thereof
which are A1 receptor agonists or prodrugs thereof.
[0211] An example of an enhancer of the action of adenosine is
pyrimidine derivatives, such as Dipyridamole (79) and derivatives
thereof which are adenosine uptake inhibitors or prodrugs
thereof.
[0212] Agents which can stimulate neuronal transmission mediated by
norepinephrine, in the peripheral and/or central nervous system,
are capable of a) substantially inhibiting the enzymatic
degradation of norepinephrine, b) substantially enhancing the
release of norepinephrine, c) substantially enhancing the action of
norepinephrine and/or c) substantially functioning as agonists at
norepinephrine .alpha.-2 receptors.
[0213] Examples of a-2 receptor agonists are aminoimidazolines,
such as Clonidine (84); aminoimidazolines, such as Apraclonidine
(85); thiazinamines, such as Xylazine (86); imidazoles, such as
Dexmedetomidine (87) and derivatives of any of the above which are
.alpha.-2 receptor agonists or prodrugs thereof.
[0214] Reduction of activity of C-fibers on second order
nociceptive neurons can be performed by administration of an
effective amount of at least one agent which substantially blocks
ion channels for Na.sup.+ or Ca.sup.2+ ions.
[0215] Examples of Na.sup.+ channel blockers are triazines, such as
Lamotrigine (88); diphenylmethylpiperazines, such as Lifarizine
(89); hydantoins, such as Phenytoin (90); aminopiperidines, such as
Lubeluzole (91); benzthiazoles, such as Riluzole (92);
dibenzazepines, such as Carbamazepine (93); phenylamides, such as
Lidocaine (94); phenylamides, such as Tocainide (95);
aminoethylanisoles, such as Mexiletene (96) and derivatives of any
of the above which are Na.sup.+ channel blockers or prodrugs
thereof.
[0216] Examples of Ca.sup.2+ channel blockers are
diphenylmethylpiperazine- s, such as Flunarizine (97);
arylphosphonic esters, such as Fostedil (98) and derivatives of any
of the above which are Ca.sup.2+ channel blockers or prodrugs
thereof.
[0217] In accordance with normal usage, the term "agent", as used
herein, is intended to designate an active substance per se,
whether administered as such or in the form of a prodrug thereof,
as well as a pharmaceutical composition comprising the substance or
prodrug.
[0218] In addition to the specific substances mentioned above,
derivatives thereof which show an activity of the same kind as the
substance specifically mentioned are also useful for the purpose of
the present invention. The kind of derivatives which come into
consideration will, of course, depend on the specific character of
the substance in question, but as general examples of derivatives
which may be relevant for many of the substances may be mentioned
introduction of or chance of alkylsubstituents (typically with a
chain length from one to five carbon atoms) on aliphatic chains,
cycloalkanes, aromatic and heterocyclic ring systems, introduction
of or change of substituents such as halogens or nitro groups,
change of ringsize for cycloalkanes, change of aromatic or
heterocyclic ringsystems, change of alkylsubstituents on O- and
N-atoms, change of the alcohol part of ester groups, and
bioisosteric replacement of functional groups, especially use of
carboxylic acid bioisosteres such as phosphonic acids, phosphinic
acids, tetrazoles, 3-hydroxyisoxazoles, sulphonamiders and
hydroxyamic acids. Salts of acidic or basic compounds will be
equally useful compared to the free acids or free bases. In case of
racemic compounds, can racemates as well as pure enantiomeres and
diastereoisomeres be used, and in the case of substances
interacting with antagonist action be required. Of course,
derivatives to be used should be derivatives which, in addition to
their desired activity, show an acceptably low toxicity, and, in
general, the derivates should, just as the substances themselves,
be pharmaceutically acceptable.
[0219] The agent used according to the invention may be
administered as such or in the form of a suitable prodrug thereof.
The term "prodrug" denotes a bioreversible derivative of the drug,
the bioreversible derivative being therapeutically substantially
inactive per se but being able to convert in the body to the active
substance by an enzymatic or non-enzymatic process.
[0220] Thus, examples of suitable prodrugs of the substances used
according to the invention include compounds obtained by suitable
bioreversible derivatization of one or more reactive or
derivatizable groups of the parent substance to result in a
bioreversible derivative. The derivatization may be performed to
obtain a higher bioavailability of the active substance, to
stabilize an otherwise unstable active substance, to increase the
lipophilicity of the substance administered, etc.
[0221] Examples of tapes of substances which may advantageously be
administered in the form of prodrugs are carboxylic acids, other
acidic groups and amines, which may be rendered more lipophilic by
suitable bioreversible derivatization. As examples of suitable
groups may be mentioned bioreversible esters or bioreversible
amides. Amino acids are typical examples of substances which, in
their unmodified form, may have a low absorption upon
administration. Suitable prodrug derivatives of amino acids will be
one or both of the above-mentioned types of bioreversible
derivatives.
[0222] For the administration to a patient, a substance having any
of the activities as defined above or a prodrug thereof is
preferably formulated in a pharmaceutical composition containing
one or more substances having any of the activities as defined
above or prodrugs thereof and one or more pharmaceutically
acceptable excipients.
[0223] The substance or substances to be administered may be
formulated in the compositions in pharmaceutically acceptable
media, the character of which are adapted to the chemical character
of the substance. The compositions may be adapted for
administration by any suitable method, for example by oral, buccal,
sublingual, nasal, rectal or transdermal administration. Substances
which are suitable for oral administration may be formulated as
liquids or solids, such as syrups, suspensions or emulsions,
tablets, capsules and lozenges. A liquid compositions will normally
comprise a suspension or solution of the substance in a suitable
liquid carrier or suitable liquid carriers, for example an aqueous
solvent such as water, ethanol or glycerol, or a non-aqueous
solvent, such as polyethylene glycol or an oil. The composition may
also contain a suspending agent, preservative, flavouring or
colouring agent. A composition in the form of a tablet can be made
using any suitable pharmaceutical carrier or carriers used for
preparing solid formulations, for example pharmaceutical grades of
mannitol, lactose, starch, magnesium stearate, sodium saccharin,
talcum, cellulose, glucose, sucrose, magnesium carbonate, and the
like. For oral administration, a pharmaceutically acceptable
non-toxic composition may be formed by incorporating normally used
excipients, such as those carriers previously listed, and generally
1-95% of active ingredient, that is, a substance used according to
the invention or a prodrug thereof, often preferably 25-75% of the
substance of the prodrug. A composition iii the form of a capsule
can be prepared using conventional encapsulation procedures. Thus,
e.g., pellets containing the substance or prodrug in question may
be prepared using any suitable carriers and then filled into a hard
gelatin capsule, or a dispersion or suspension can be prepared
using any suitable pharmaceutical carrier or carriers, such as
aqueous gums, celluloses, silicates or oils and the dispersion or
suspension can be filled into a soft gelatin capsule.
[0224] Examples of parenteral compositions are solutions or
suspensions of the substances or prodrugs in a sterile aqueous
carrier or parenterally acceptable oil, such as polyethylene
glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
The compositions may contain pharmaceutically acceptable auxiliary
substances as required to approximate physiological conditions,
such as buffering agents, wetting agents, detergents, and the like.
Additives may also include additional active ingredients, e.g.
bactericidal agents, or stabilizers. If desired, the solution or
suspension can be lyophilized and reconstituted with a suitable
carrier such as a sterile aqueous carrier prior to
administration.
[0225] Compositions for nasal administration can be formulated,
e.g., as aerosols, drops, gels and powders. For aerosol
administration, the substance or prodrug is preferably supplied in
finely divided form along with a surfactant and propellant. Typical
percentages of the substance or prodrug are 0.01-20% by weight,
preferably 1-10%. The surfactant must, of course be non-toxic, and
preferably soluble in the propellant. Representative of such
surfactants are the esters or partial esters of fatty acids
containing from 6 to 22 carbon atoms, such as caproic, octanoic,
lauric, palmitic, stearic, linoleic, linoleic, olesteric and oleic
acids with an aliphatic polyhydric alcohol or its cyclic anhydride
such as, for example, ethylene glycol, glycerol, erythritol,
arbitol, mannitol, sorbitol, the hexitol anhydrides derived from
sorbitol, and the polyoxyethylene and polyoxypropylene derivatives
of these esters. Mixed esters, such as mixed or natural glycerides
may be employed. The surfactant may constitute 0.1-20% by weight of
the composition preferably 0.25-5%. The balance of the composition
is ordinarily propellant. Liquified propellants are typically gases
at ambient conditions, and are condensed under pressure. Among
suitable liquified propellants are the lower alkanes containing up
to 5 carbons, such as butane and propane; and preferably
fluorinated or fluorochlorinated alkanes. Mixtures of the above may
also be employed. In producing the aerosol, a container equipped
with a suitable valve is filled with the appropriate propellant,
containing the substance according to the invention and surfactant.
The ingredients are thus maintained at an elevated pressure until
released by action of the valve.
[0226] Compositions for buccal or sublingual administration are,
for example, tablets, lozenges and pastilles, in which the
substance or the prodrug is formulated with a carrier such as sugar
and acacia, tragacanth or gelatin and glycerol. Compositions for
rectal administration are suitably in the form of suppositories
containing a suppository base such as cocoa butter. Compositions
for transdermal application are for example ointments, gels and
transdermal patches.
[0227] The compositions are preferably in unit dosage form such as
a tablet capsule or ampoule. Each dosage unit for oral
administration will normally contain from 1 to 500 mg (and for
parenteral administration preferably from 0.1 to 25 mg) of a
substance used according to the invention or a prodrug therefor,
calculated as the free active substance.
[0228] The physiologically acceptable substances or prodrugs are
normally administered in a daily dosage of between 1 mg and 500 mg
for a adult person, usually between 10 mg and 400 mg, such as
between 10 mg and 250 mg orally or an intravenous, subcutaneous or
intramuscular dose of between 0.1 mg and 100 mg, preferably between
0.1 and 50 mg, such as between 1 mg and 25 mg of the substance. The
substance or prodrug is preferably administered 1 to 4 times daily.
As mentioned above, the administration is normally aimed at
maintaining a therapeutically effective serum concentration of the
substance for at least one month, preferably at least two months or
at least three months. Controlled release tape compositions will
often be suitable for maintaining an effective serum concentration
with a small number of daily unit dosages.
LEGENDS TO FIGURES
[0229] FIG. 1 shows the model for the development of tension-type
headache.
[0230] Abbreviations; V: Trigeminal nerve, C2 and C3. Second and
third cervical segment of the spinal cord. PAG: Periaquaductal
grey, DRN: Dorsal raphe nuclei, on-cells: cells in ventromedial
medulla, which activate pain pathways, for instance by reducing the
threshold in the tail flick test. C: C fibers. Ad: A-d-fibers. Ab:
A-b-fibers.
[0231] FIG. 2 depicts stimulus-response functions in trapezius
muscle.
[0232] Stimulus-response functions for pressure versus pain in the
trapezius muscle in 40 patients with chronic tension-type headache
(dots) and in 40 control subjects (triangles)(mean .+-.SE).
Patients were significantly more tender than controls, P=0.002. In
patients, the stimulus-response function was approximately linear
with a slope (b)=0.50.+-.0.04 mm/U, P=0.00004 (FIG. 2A). In
contrast pain intensities increased in a positively accelerating
fashion with increasing pressure intensities in controls, a
relation that was well described by a power function. This was
demonstrated by obtaining an approximately linear relation between
pressure and pain in a double logarithmic plot, b=3.8.+-.0.61
logmm/logU, P=0.002 (FIG. 2B).
[0233] FIG. 3 depicts stimulus-response functions in temporal
muscle.
[0234] Stimulus-response functions for pressure versus pain in the
temporal muscle in 40 patients (dots) and in 40 controls
(triangles) (mean .+-.SE). Patients were slightly more tender than
controls, but the difference was not statistically significant,
P=0.42. In both groups pain intensities increased in a positively
accelerating fashion with increasing pressure intensities. This was
demonstrated by obtaining approximately linear relations between
pressure and pain in a double logarithmic plot: patients
b=3.0.+-.0.36 logmm/logU. P=0.0002; controls b=6.7.+-.0.36
logmm/logU, P=0.00001 (FIG. 3B).
[0235] FIG. 4 depicts stimulus-response functions in trapezius
muscle.
[0236] Stimulus-response functions for pressure versus pain in the
trapezius muscle in the 20 most tender patients (diamonds) and in
the 20 least tender patients (squares)(mean .+-.SE). In the most
tender patients, the stimulus-response function was linear,
b=0.69.+-.0.03 mm/U, P<0.00001. In contrast, pain intensities
increased in a positively accelerating fashion with increasing
pressure intensities in the least tender patients. This was
demonstrated by obtaining a linear relation between pressure and
pain in a double logarithmic plot, b=4.0.+-.0.18 logmm/logU,
P<0.00001 (FIG. 4B).
[0237] FIG. 5 shows Total Tenderness Scores in patients.
[0238] The Total Tenderness Scores (TTS) in patients outside and
during a headache episode and in controls. Median values are given
(*** indicate p<10.sup.-5 and ** indicate p=0.01, Wilcoxon's
test).
[0239] FIG. 6 shows Pressure Pain Thresholds (PPDT) and Pressure
Pain Tolerances (PPTO) in patients. Pressure Pain Thresholds (PPDT)
and Pressure Pain Tolerances (PPTO) in patients outside (closed
bars) and during a headache episode (open bars). Mean values of
left and right side are given in kPa with SD as vertical bars (*
indicate p<0.05, Wilcoxon's test).
[0240] FIG. 7 shows thermal thresholds in the hands and temporal
(Temp) regions of patients.
[0241] Thermal thresholds in the hands and temporal (Temp) regions
of patients outside (closed bars) and during a headache episode
(open bars). WD indicate warmth detection, HPD heat pain detection
and HPTO heat pain tolerance thresholds. Mean values of left and
right side are given in .degree. C. with SD as vertical bars (*
indicate p<0.05, Wilcoxon's test).
[0242] FIG. 8 depicts EMG-amplitude levels from the temporal and
trapezius muscles of patients. EMG-amplitude levels from the
temporal and trapezius muscles of patients outside (closed bars)
and during a headache episode (open bars). Part A indicates the
resting condition and part B the maximal voluntary contraction.
Mean values of left and night side are given in uV with SD as
vertical bars.
[0243] FIG. 9 depicts pain intensities in patients and
controls.
[0244] Pain intensities in those patients (filled circles) and
controls (open circles) who developed tension-type headache after a
30 minutes sustained clenching procedure. The ordinate indicates
the mean pain intensity in mm as recorded on a 100 mm visual
analogue scale. The abscissa indicates the time after the clenching
procedure (* p<0.05, Mann-Whitney's test)
[0245] FIG. 10 shows Total Tenderness Scores (TTS) in patients and
in controls.
[0246] Total Tenderness Scores (TTS) in patients and in controls
before and 90 minutes after experimental tooth clenching with
respect to development of headache. Median values with quartiles
are given. (** indicate p<0.01, *** p<0.003, Wilcoxon's
test).
[0247] FIG. 11 shows Pressure Pain Detection Thresholds and
Pressure Pain Tolerances in patients and controls.
[0248] Part A shows the Pressure Pain Detection Thresholds and Part
B the Pressure Pain Tolerances from fingers (F), temporal (T) and
parietal (P) regions from patients and controls before (filled
bars) and after clenching (open bars) with respect to development
of headache Mean values of right and left side with SD are given in
kPa. (* indicate p<0.05, as p<0.01, Wilcoxon's test).
[0249] FIG. 12 shows thermal thresholds in the temporal region of
patients and controls.
[0250] Thermal thresholds in the temporal region of patients and
controls before (filled bars) and after clenching (open bars) with
respect to headache development. WD indicate warmth detection, PD
heat pain detection and PTO heat pain tolerance. Mean values of
right and left side with SD are given in .degree. C.
[0251] FIG. 13 shows EMG-amplitudes in temporal and trapezius
muscles of patients and controls.
[0252] Part A shows the EMG-amplitudes (Root Mean Square-values)
during resting condition and part B during the maximal voluntary
contraction in temporal (temp) and trapezium (trap) muscles from
patients and controls before (filled bars) and after clenching
(open bars) with respect to headache development. Mean values of
left and right side with SD are given in uV (* indicate p<0.05,
** p<0.01 and p<0.001, Wilcoxon's test).
[0253] FIG. 14 shows changes in pain intensity and treatment.
[0254] Post infusion changes in pain intensity (VAS) relative to
pre-treatment pain intensity in 16 patients with chronic pain.
L-NMMA reduced pain significantly more than placebo (p=0.007).
[0255] FIG. 15 shows Pressure Pain Thresholds (PPDT) and Pressure
Pain Tolerances (PPTO) in patients with chronic tension-type
headache associated with muscular disorders (MUS) (filled bars) or
unassociated with such disorders (non-MUS) (open bars). Mean values
from the fingers, temporal (Temp) and Parietal (Par) regions are
given in kPa with SE as vertical bars
[0256] (*** indicate p<0.001,* indicate p=0.04).
[0257] FIG. 16 shows Pressure Pain Thresholds (PPDT) and Pressure
Pain Tolerances (PPTO) in patients with episodic tension-type
headache associated pith muscular disorders (MUS) (filled bars) or
unassociated with such disorders (non-MUS) (open bars). Mean values
from fingers, temporal (Temp) and Parietal (Par) regions are given
in kPa with SE as vertical bars.
[0258] No significant differences were detected.
[0259] FIG. 17 shows the percentage of change in muscle hardness.
Muscle hardness was significantly more reduced following treatment
with L-NMMA (dots) than with placebo (triangles) in patients with
chronic myofascial pain. * denotes p<0.05 compared with baseline
(time=0). The plots represent mean scores.
[0260] FIG. 18 shows the percentage of change in Total Tenderness
Scoring (TTS). The TTS tended to be reduced following treatment
with L-NMMA (dots) compared with placebo (triangles) (p=0.11).
Within each treatment, the TTS was significantly reduced at 60 and
120 minutes after start of the infusion of L-NMMA, while there was
no significant changes at any time after treatment with placebo. **
denotes p<0.01 compared with baseline (time=0). The plots
represent mean scores.
[0261] FIG. 19 shows the percentage of change from baseline pain
intensity on a 100 mm Visual Analog Scale. The pain intensity was
significantly more reduced during treatment with L-NMMA (dots) than
with placebo (triangles) (p=0.006). * denotes p<0.05 compared
with baseline (time=0). Tile plots represent mean scores (copyright
from Lancet).
EXAMPLE 1
[0262] Experimental Evidence for Central Sensitization in Chronic
Myofascial Pain
[0263] The study was performed in order to investigate the
pathophysiology of myofascial tenderness, which has consistently
been reported to be increased in patients with tension-type
headache (Lous and Olesen 1982; Langemark and Olesen 1987, Jensen
et al. 1993b). Recently, it was suggested that myofascial
tenderness may be the result of a lowered pressure pain threshold,
a stronger response to pressures in the noxious range (as
illustrated by a steeper stimulus-response function) or a
combination of both (Jensen 1990b). The aim of the study therefore
was to investigate the stimulus-response function for pressure
versus pain in patients with tension-type headache. The methods and
the results of the study will be described in the following.
[0264] Materials and Methods
4Table III Clinical data on headache patients and controls Patients
Controls Number 40 40 Sex (Females/males) 25/15 25/15 Age, years
40.0 (18-60) 39.8 (18-60) Frequency of TH, 24.6 (16-28) <1
days/4 weeks
[0265] Patients and Controls
[0266] Forty patients with chronic tension-type headache diagnosed
according to the criteria of the International Headache Society
(1988) were examined during a typical episode of tension-type
headache (Table III). Seven patients with coexisting infrequent
migraine (<one day/month) were accepted. The patients were
recruited from the out-patient headache clinic at Glostrup Hospital
without respect to presence or absence of myofascial tenderness.
All patients undercount a general physical and a neurological
examination and completed a diagnostic headache diary (Russell et
al. 1992) during a 4-week run-in period. The patients were not
allowed to take analgesics on the day of examination. Patients
suffering from serous somatic or psychiatric diseases and abusers
of analgesics were excluded. Forty healthy, age- and sex-matched
volunteers served as controls. Only controls who did not have a
headache on the day of examination and had less than 12 days with
headache a year were used. All subjects gave written informed
consent to participate in the study, which was approved by the
local ethics committee.
[0267] Apparatus
[0268] A palpometer (Bendtsen et al. 1994) was used to investigate
the stimulus-response function for pressure versus pain. The
palpometer consists of a Force Sensing Resistor.TM. (FSR) connected
to a meter, a principle first described by Atkins et al. (Atkins et
al. 1992). The FSR is a commercially available polymer film device,
which exhibits a decreasing electrical resistance pith increasing
force applied to the device. If the force is concentrated on a
small area the resistance is further decreased, i.e. the properties
of the FSR lies somewhere between a force transducer and a pressure
transducer. The FSR is 0.33 mm thick and circular with a diameter
of 10 mm. The FSR is attached with thin adhesive tape
(Micropore.RTM.) to the tip of the palpating finger. The force
applied to the FSR is displayed on the meter scale, which is
divided into arbitrary units from 60 to 200 arbitrary units (U). To
improve the readability of the meter, the readout is filtered using
a low-pass filter. The relation between the forces applied to the
plastic film and the palpometer output is linear in the range from
80 to 200U (Bendtsen et al. 1994). This range is equivalent to a
force range from 235 gm to 1550 gm. The intra- and inter-observer
variations for recordings of pressure intensity have previously
found to be 3.1% and 7.2%, respectively (Bendtsen et al. 1994).
Detailed information on the palpometer has been published earlier
(Bendtsen et al. 1994).
[0269] Methods
[0270] The examination was performed in a standardized manner by
the same investigator, a trained technician (HA), throughout the
whole study. The subjects were examined sitting in a dental chair
with headrest.
[0271] Total Tenderness
[0272] Tenderness of specified pericranial regions was recorded
according to the Total Tenderness Scoring system, which has
previously proved to be reliable (Bendtsen et al. 1995a). Five
pairs of muscles (masseter, temporal, frontal, sternocleidomastoid
and trapezius muscles) and three pairs of tendon insertions
(coronoid and mastoid processes and neck muscle insertions) were
palpated. Palpation was performed with small rotating movements of
the observer's second and third fingers. Pressure was sustained for
4-5 seconds. Prior to the study, the palpometer was used to train
the observer to exert a palpation pressure of moderate intensity
(140 U). The tenderness was scored on a 4-point (0-3) scale as
follows: 0=denial of tenderness, no visible reaction; 1=verbal
report of discomfort or mild pain, no visible reaction 2=verbal
report of moderate pain, with or without visible reaction; 3=verbal
report of marked pain and visible expression of discomfort. The
values from left and right sides were summed to a Total Tenderness
Score (maximum possible score=48).
[0273] Stimulus-Response Functions
[0274] Stimulus-response functions for pressure versus pain were
recorded during pressure-controlled palpation. i.e. palpation with
controlled pressure intensity by means of the palpometer.
Pressure-controlled palpation has previously proved to be a
reliable method of tenderness recording (Bendtsen et al. 1995a).
Palpation was performed with small rotating movements of the
observer's second finger. Pressure was sustained for 4-5 seconds.
The subjects were palpated at the trapezius and temporal muscles at
the non-dominant side. These muscles haste previously been found to
represent a highly tender and a largely normal muscle respectively
in patients with tension-type headache (Jensen et al. 1993b).
Palpation was performed with seven different pressure intensities
chosen in random order in the range from 80 to 200 U. At each
pressure intensity the subject indicated the corresponding pain
intensity on a visual analogue scale blinded for the observer. The
visual analogue scale consisted of a 100-mm line with endpoints
designated "no pain" and "unbearable pain": The degree of
tenderness elicited in each subject was calculated as the area
under the stimulus-response curve (AUC) according to the trapezium
rule (Matthews et al. 1990).
[0275] Statistics
[0276] Results are presented as mean .+-.SE. Data were analyzed
with Mann-Whitney's test and simple linear regression. Five percent
was accepted as level of significance.
[0277] Results
[0278] Total Tenderness
[0279] The Total Tenderness Score in patients was 17.7.+-.1.7 and
significantly higher than 3.4.+-.0.53 in controls,
p<0.00001.
[0280] Stimulus-Response Functions
[0281] The stimulus-response functions for pressure versus pain in
the trapezius muscle in patients and in controls are shown in FIG.
2. Calculating the area under the stimulus-response functions
revealed that patients were significantly more tender
(AUC=3370.+-.423 mmU) than controls (AUC=1693.+-.269 mmU), P=0.002.
In controls, pain intensities increased in a positively
accelerating fashion with increasing pressure intensities. The
stimulus-response function was well described by a power function.
This was demonstrated by obtaining an approximately linear relation
between pressure and pain in a double logarithmic plot, slope
(b)=3.8.+-.0.61 logmm/logU, P=0.002 (FIG. 2B). In contrast, the
stimulus-response function was approximately linear in patients,
b=0.50.+-.0.04 mm/U, P=0.00004. Thus, the stimulus-response
functions in controls and in patients were qualitatively
different.
[0282] The stimulus-response functions for pressure versus pain in
the temporal muscle are shown in FIG. 3. Patients were slightly
more tender (AUC=2139.+-.327 mmU) than controls (AUC=1722.+-.257
mmU), but the difference was not statistically significant, P=0.42.
In controls, pain intensities increased in a positively
accelerating fashion with increasing pressure intensities. In a
double logarithmic plot the relation between pressure and pain was
linear, b=6.7.+-.0.36 logmm/logU, P=0.00001 (FIG. 3B). In patients,
pain intensities increased in a positively accelerating fashion
with increasing pressure intensities. However, the curve was
irregular partly resembling a linear function. The regression
function was approximately linear in a double logarithmic plot
b=3.0.+-.0.36 logmm/logU, P=0.0002 (FIG. 3B).
[0283] To explore whether the abnormal stimulus-response function
in the trapezius muscle was related to the increased tenderness or
to the diagnosis of tension-type headache, the patients were
subgrouped on the basis of their degree of tenderness. The
stimulus-response functions for the 20 most tender patients
(AUC=5359.+-.538 mmU) and for the 20 least tender patients
(AUC=1381.+-.176 mmU) are shown in FIG. 4. In the 20 most tender
patients, the stimulus-response function was linear, b=0.69.+-.0.03
mm/U, P<0.00001. In contrast, pain intensities increased in a
positively accelerating fashion with increasing pressure
intensities in the 20 least tender patients. In a double
logarithmic plot the relation between pressure and pain was linear,
b=4.0.+-.0.18 logmm/logU, P<0.00001 (because none of the
patients reported any pain at the lowest stimulus intensity (U=80),
a value of 1 mm was added to all pain intensities in order to
perform this analysis) (FIG. 4B).
[0284] Discussion
[0285] Possible physiological mechanisms leading to myofascial pain
include: a) sensitization of peripheral myofascial nociceptors, b)
sensitization of second order neurons at the spinal/trigeminal
level, c) sensitization of supraspinal neurons, and d) decreased
antinociceptive activity from supraspinal structures. These
mechanisms may be investigated by relating the intensity of
mechanical pressure applied to deep tissues to the response
recorded from sensory neurons. Such studies on animal models have
provided important information on deep tissue pain (Ness and
Gebhart 1987; Cervero and Sann 1989; Yu and Mense 1990; Jnig and
Koltzenburg 1991), but till now the relation between pressure and
pain has not been investigated in patients with chronic myofascial
pain.
[0286] Previously the stimulus-response function for-pressure
versus pain had been studied in 30 subjects with tender pericranial
muscles (15 headache patients and 15 volunteers) (Bendtsen et al.
1995a). In the trapezius muscle, an approximately linear
stimulus-response function virtually identical to the one recorded
in patients in the present study was found. The finding of almost
identical results in two different but comparable populations
obtained by two different observers, indicates that the employed
method for recording of stimulus-response functions is
reliable.
[0287] Before the present investigation, the stimulus-response
function in normal muscle was expected by the inventors to be
qualitatively similar to the stimulus-response ruction in tender
muscle, i.e. linear, but with a less steep slope or with a parallel
shift to the right as hypothesized by Jensen (Jensen 1990).
Surprisingly, the relation between palpation pressure and pain in
normal muscle and in highly tender muscle differed markedly. In the
trapezius and temporal muscles of controls, pain intensities
increased in a positively accelerating fashion with increasing
pressure intensities, a relation that was well described by a power
function. The same was found in patients in the temporal muscle
which was only slightly to moderately tender. The patients were
subgrouped on the basis of their degree of tenderness, the
stimulus-response function was linear in the most tender patients,
while it was well described by a power function in the least tender
patients. Thus, the stimulus-response function becomes increasingly
linear with increasing degrees of tenderness and die qualitatively
changed stimulus-response function is related to actual tenderness
and not to the diagnosis of tension-type headache. The possibility
that the linear stimulus-response function was due to a shift to
the left of the normal stimulus-response function such that the
patients were on the steep part of the curve already at low
pressures can be excluded. If so, the patients would have been much
more tender than controls also at the lowest stimulus-intensities,
which was not the case.
[0288] The present finding of a qualitatively altered response to
nociceptor stimulation in tender muscle demonstrates for the first
time that myofascial pain has a physiological basis and that
myofascial pain, at least in part, is caused by qualitative changes
in the processing of sensory information. These changes may be
located to peripheral nerve endings, to the spinal cord or to
higher order neurons.
[0289] Spinal dorsal horn neurons that receive input from deep
myofascial tissues can be classified as high-threshold
mechanosensitive (HTM) neurons requiring noxious intensities of
stimulation for activation and as low-threshold mechanosensitive
(LTM) neurons, which are activated b) innocuous stimuli (Mense
1993). Yu and Mense (Yu and Mense 1990) have shown that HTM dorsal
horn neurons have a positively accelerating stimulus-response
function, whereas the stimulus-response-function of LTM neurons is
approximately linear. This indicates that the linear
stimulus-response function in tender human muscle may be caused by
activity in LTM afferents. LTM afferents do not normally mediate
pain, but strong input from peripheral nociceptors can remodel the
circuitry of the dorsal horn by unmasking previously ineffective
synapses and by forming novel synaptic contacts between LTM
afferents and dorsal horn neurons that normally receive input from
HTM afferents (Wall 1977; Wall and Woolf 1984; Cervero and Jnig
1992; Hu et al. 1992; Woolf et al. 1992; Dense 1993; McMahon et al.
1993; Mayer and Gebhart 1994; Hoheisel et al. 1994). In this way
LTM afferents can mediate pain (Woolf and Thompson 1991). While the
above-mentioned studies have been performed on animal models
(Torebjork et al. 1992). Torebjork et al. have demonstrated similar
changes in the central processing of inputs from LTM afferents in
humans following intradermal injection of capsaicin. It therefore
seems probable that the present findings can be explained by
changes in neuronal behavior at the spinal/trigeminal level.
Support for this explanation was provided by a simultaneous
investigation of pain thresholds in the same subjects by means of
an electronic pressure algometer. Patents had significantly lower
pressure pain detection and tolerance thresholds in fingers than
controls (Bendtsen et al. 1996a). This indicates that the pain
perception is centrally disturbed. A decrease of the supraspinal
descending inhibition probably does not explain the present
findings, because it has been reported that the descending
inhibition acts via a parallel shift or via a decreased slope of
the stimulus-response curve (Ness and Gebhart 1987; Yu and Mense
1990), while it does not change the shape of the stimulus-response
curve. Sensitization of normally active peripheral-nociceptors
would probably induce a quantitative rather than a qualitative
change of the stimulus-response curve (Koltzenburg et al.
1992).
[0290] The results thus demonstrate for the first time that
nociceptive processes are qualitatively altered in patients with
chronic tension-type headache, and that the central nervous system
is sensitized at the spinal/trigeminal level in these patients.
[0291] Recent Studies from the Present Inventors Indicating that
the Central Sensitization is Induced by Prolonged Muscle Pain
[0292] As mentioned above, the information obtained from basic pain
research suggests that the central sensitization in chronic
tension-type headache is induced and probably maintained by
prolonged noxious input from the periphery. Prolonged muscle pain
is, in particular, likely to induce central sensitization, because
input from muscle nociceptors is more effective in inducing
prolonged changes in the behavior of dorsal horn neurons than is
input from cutaneous nociceptors (Wall and Woolf 1984). Recent
research from the present inventors does for the first time support
that there is a clear relation between central pain sensitivity and
the increased muscle pain in patients with tension-type headache,
and that the increased central pain sensitivity is induced by the
increased muscle pain. Thus, it has recently been demonstrated that
patients with chronic tension-type headache have decreased pain
thresholds to various types of stimuli both at cephalic and at
extra-cephalic locations (Bendtsen et al. 1996b), indicating a
state of central hypersensitivity, and that there is a significant
correlation between, cephalic as well as extra-cephalic pain
thresholds and the total pericranial tenderness recorded by manual
palpation (Bendtsen et al. 1996a). These findings demonstrate that
there is a close relationship between the increased pericranial
tenderness and the central hypersensitivity in chronic tension-type
headache, but it does not reveal the cause and effect relationship
between these abnormalities. However, since it is known that
patients with episodic tension-type headache have normal pain
thresholds (Jensen et al. 1993b) and that chronic tension-type
headache usually evolves from the episodic form (Langemark et al.
1958), and since experimentally induced tenderness of masticatory
muscles precedes the induced headache by several hours in patients
with tension-type headache (Jensen and Olesen 1996), it is most
likely that increased myofascial tenderness precedes central
hypersensitivity.
EXAMPLE 2
[0293] Mechanisms of Spontaneous Tension-Type Headaches.
[0294] An Analysis of Tenderness, Pain Thresholds and EMG
[0295] Pericranial muscle tenderness, EMG-levels and thermal and
mechanical pain thresholds were studied in 28 patients with
tension-type headache and in 30 healthy controls. Each patient was
studied during as well as outside a spontaneous episode of
tension-type headache. Outside of headache muscle tenderness and
EMG-levels were significantly increased compared to values in
controls subjects, while mechanical and thermal pain thresholds
were largely normal. During headache muscle tenderness evaluated by
blinded manual palpation increased significantly, while pressure
pain thresholds remained normal and pressure pain tolerances
decreased. Thermal pain detection and tolerance threshold decreased
significantly in the temporal region, but remained normal in the
hand. EMG-levels were unchanged during headache. The findings
indicate that one of die primary sources of pain in tension-type
headache may be a local and reversible sensitization of nociceptors
in the pericranial muscles. In addition, a segmental central
sensitization may contribute to the pain in frequent sufferers of
tension-type headache. The present study, for the first time,
examines the same patients both during headache and outside of a
headache episode with the following tests: EMG, pericranial
palpation, mechanical and thermal pain thresholds. The aim was to
analyze the relative importance of central and peripheral
nociceptive factors.
[0296] Subjects and Methods
[0297] Subjects
[0298] Twenty eight patients, 11 males and 17 females, with
frequent episodic or chronic tension-type headache fulfilling the
IHS-criteria (HCCIHS 1988) were included (Table IV). The patients
were recruited from the out-patient headache clinic at Gentofte
Hospital, Denmark. 9 patients with frequent episodic tension-type
headache (ETH).sup.3 8 days per month and 19 patients with chronic,
but not daily, tension-type headache (CTH) (HCCIHS 1988) were
included. The reason for this selection was that patients had to
have frequent headaches as well as frequent days without headache
in order to be studied in both states. Further inclusion criteria
were frequent headaches during at least one year and an age between
18 and 70 years. The exclusion criteria were: Daily headache,
migraine more than 1 day per month, cluster headache or trigeminal
neuralgia, other neurological, somatic or psychiatric disorders,
concurrent ingestion of major medications including migraine
prophylactics, any form of drug abuse or dependency including large
amounts of plain analgesics. A diagnostic headache diary had to be
filled out during a 4 week run-in period to ensure that patients
fulfilled the inclusion criteria. A complete physical and
neurological examination was performed before entry. Thirty age-
and sex-matched healthy subjects without tension-type headache
(<14 days TH/year) were used as controls (Table IV). Informed
consent vas obtained and the study was approved by the local
ethical committee.
[0299] Methods
[0300] The patients were examined randomly during and outside a
typical episode of tension-tape headache. The intensity of the
headache was recorded initially on a 100 mm Visual Analogue Scale
(VAS), where 0 indicated no pain at all and 100 mm indicated the
worst imaginable pain. Examinations were separated by at least one
week and performed at the same time of the day in order to
eliminate diurnal variations. Patients were not allowed to take any
medication on the days of examination. Healthy controls were
investigated once.
[0301] Examination
[0302] The examination was performed in a standardized fashion by
the same investigator, a trained technician (LH), throughout the
whole study. The technician was blinded to the subjects' headache
history and presence or absence of a possible muscular factor.
Before measuring pain thresholds each individual was carefully
instructed to apply the same interpretation of `painfhl` throughout
the study. Initial test sessions were applied to all subjects in
order to familiarize them with the test conditions.
[0303] Palpation Method
[0304] Pericranial tenderness was evaluated by palpation of 9 pairs
of muscles and tendon insertions in a standardized way. Each
patient was examined by the technician and the physician in random
order. Tenderness was scored at each location according to a four
point scale from 0 to 3, and scores from all sites were summated.
The maximally possible score was thus 54 points. This Total
Tenderness Score system (TTS) has previously proved to be reliable
(Bendtsen et al. 1996).
[0305] Pressure Pain Threshold
[0306] The mechanical pain thresholds and tolerances were evaluated
bilaterally on the distal dorsal part of the second finger.
Similarly, 2 cranial locations, one with interposed muscle, the
anterior part of the temporal muscle (temp) and one without
interposed muscle; the parietal region (par) were examined
(Petersen et al. 1992). A standardized and previously evaluated
method was applied using an electronic pressure algometer (Somedic
AB, Sweden) with a 0.79 cm. circular probe (Jensen et al. 1986,
Brennum et al. 1989). The Pressure Pain Detection Threshold (PPDT)
was defined as the threshold, where the pressure sensation became
painful, whereas the Pressure Pain Tolerance (PPTO) was the
threshold where the patient would no longer tolerate the pain
(Petersen et al. 1992). By pressing a hand-held button the subjects
indicated that the pain threshold was reached and the pressure was
immediately released. If patients did not activate the button, the
experiment was terminated when reaching 800 kPa in the cranial
region and 1500 kPa in the fingers. Each threshold was calculated
as the median value of 3 consecutive recordings.
[0307] Thermal Thresholds
[0308] Thermal thresholds were evaluated with a computerized
version of the Thermotest (Somedic AB, Sweden) (Fruhstorfer et al.
1976). The thermode consisted of series-coupled Peltier elements
and measured 25.times.50 mm. Two locations, the thenar region of
the hand and the anterior part of the temple were examined
bilaterally. Three parameters were recorded in each region i.e. the
Warm Detection (WD) defined as the lowest temperature detected as
warm, the Heat Pain Detection (HPD) defined as the temperature
where the heat sensation became painful, and the Heat Pain
Tolerance (HPTO) defined as the highest temperature tolerated
(Langemark et al. 1989, Jamal et al. 1985). A baseline temperature
of 32.degree. C. and a 1.0.degree. C./sec rate of temperature
change was used (Langemark et al. 1989). Heat stimulation was
terminated when reaching 52.degree. C. if the patients had not
responded before. By pressing a hand-held button the subjects
indicated, when the thresholds were reached. The thermode was
immediately removed from the area, the exact value was recorded in
the computer and the stimulator returned to baseline. Each
threshold was calculated as the average of 5 determinations
performed with intervals of 10-15 seconds.
[0309] Electromyography
[0310] A standardized, preciously described method was used (Jensen
et al. 1993a, Jensen et al. 1994). The EMG signals from the
temporal and trapezius muscles were recorded bilaterally using a
4-channels electromyograph (Counterpoint, Dantec, Copenhagen). Data
were collected during 2 conditions i.e. resting in the supine
position in 20 one second periods interrupted by 5 second interval
and during maximal voluntary contraction (MVC). The MVC lasted a
maximum of 5 seconds and was repeated 5-6 times with 30 second
intervals. MVC recording sessions lasting one second were analyzed
and the highest value of Root Mean Square (RMS) of the EMG was
selected (Jensen et al. 1993a, Jensen et al. 1994). The power
spectrum of each of the 1 second measurement sessions was
calculated for the frequency range 0 to 1 kHz and Mean Frequency
was extracted (Jensen et al. 1993a).
[0311] Statistics
[0312] Wilcoxons rank sum test (Wilc.) was used to compare paired
data from headache subjects. Mann-Whitneys test (M-W.) was used to
compare data between controls and patients. Mean values of right
and left sided observations are presented. Five percent level of
significance was used.
[0313] Results
[0314] Subjects
[0315] All the included patients and healthy controls completed the
study. There were no significant differences in age and
sex-distribution between healthy subjects and patients (Table
IV).
[0316] Headache
[0317] The headaches examined fulfilled the diagnostic criteria for
tension-type headache (HCCIHS 1988). Seventy one percent (20/28)
had a bilateral headache, whereas 29% (8/28) had a unilateral
headache. The median VAS score was initially 35 mm (range 17-75
mm).
[0318] Variation between Observers
[0319] The Total Tenderness Scores (TTS) as recorded by the 2
observers (LH, RJ) at the initial examination were comparable in
patients (Wilc. p=0.38) and in healthy controls (Wilc. p=0.27).
[0320] Side to Side Relation
[0321] The side to side variations were tested in patients as well
as in controls, and results corresponded to previous methodological
studies (Petersen et al. 1992, Jensen et al. 1986, Jamal et al.
1985, Jensen et al. 1993a).
[0322] Relation between controls and patients free of headache
[0323] Tenderness
[0324] Median TTS in TH patients free of headache was 13 and
significantly higher than 4 in healthy controls
(M-W.p<10.sup.-5) (FIG. 5).
[0325] Pressure Pain Thresholds
[0326] Pressure Pain Detection Thresholds and Pain Tolerance
Thresholds in patients were not significantly different from those
in healthy controls in any of the examined regions (Table V).
[0327] Thermal Thresholds
[0328] The warm detection threshold, the heat pain detection and
tolerance thresholds in the hands did not differ between patients
and controls. In the temporal regions of headache free patients the
warm detection (WD) and heat pain thresholds (HPD) were increased
compared to healthy controls (Table VI) (M-W, WD:p<0.001;
HPD:p=0.047). The heat pain tolerances were similar in the 2 groups
(Table VI).
[0329] EMG
[0330] During rest amplitude-levels were higher in patients in the
headache free condition as compared to healthy controls (M-W.
m.temp:p<0.001; m.trap p=0.016). No other significant
differences or tendencies were detected (Table VII).
[0331] Relation to the Headache State
[0332] Tenderness
[0333] The total tenderness score increased from 13 (range 0-29)
outside of headache to 16 (range 1-34) during headache
(Wilc.p<0.01) (FIG. 5)
[0334] Pressure Pain Thresholds
[0335] No significant differences in pressure pain detection
thresholds were found when results during headache were compared to
the headache free condition. Pressure pain tolerances in the
parietal regions decreased significantly during the headache (Wilc.
p=0.03), whereas the pressure pain tolerances from other locations
were unaffected (FIG. 6).
[0336] Thermal Thresholds
[0337] Heat pain detection (Wilc.p=0.011) and tolerances
(Wilc.p=0.016) were lower in the temporal region during headache as
compared to the headache free condition. No differences were seen
in the hand (FIG. 7).
[0338] EMG
[0339] No significant variations appeared when EMG parameters
during the headache episode were compared to the headache free
condition (FIGS. 8A+B).
[0340] Discussion
[0341] Comparison of Headache-Free Patients and Control
Subjects
[0342] Myofascial tissue has been considered an important source of
nociception in tension-type headache by some investigators (Travell
et al. 1983, Drummond et al. 1987), whereas others favor
alterations in central pain processing resulting in a state of
hypersensitivity to incoming stimuli from myofascial and other
cephalic tissues (Schoenen et al. 1991a, Schoenen et al. 1991b).
Previous findings of increased cranial and peripheral sensitivity
in patients with chronic tension-type headache support such central
mechanisms (Langemark et al. 1989, Schoenen et al. 1991b). However,
normal cranial pressure pain thresholds have recently been
described in subjects with chronic tension-type headache from a
general population (Jensen et al. 1993b) and in patients pith
episodic tension-type headache from headache clinics (Goebel et al.
1992. Eovim et al. 1992). Comparing groups of headache patients to
normal controls involves many confounding factors. These are
greatly diminished in studies comparing the headache state and the
non-headache state in the same individuals. The same patients were
studied both during and outside of headache. The headache
mechanisms were analyzed by means of EMG, pericranial palpation,
thermal and mechanical pain sensitivity.
[0343] The present study confirms that pericranial muscles of these
patients outside of headache are more tender than in healthy
subjects (Jensen et al. 1993, Hatch et al. 1992, Langemark et al.
1987). More importantly it is demonstrated, for the first time,
that tenderness increases during the headache phase. Are these
findings due to central or peripheral hypersensitivity? Normal
pressure pain thresholds and pressure pain tolerances outside
headache both in the cranial region and in the hands indicates that
central pain perception is not generally affected in these
patients. The warm detection and heat pain detection thresholds
were increased, not decreased, in the temporal region and normal in
the hands. Thus, decreased sensitivity to noxious heat can be due
to either a local factor in the skin which decreases the cutaneous
receptor sensitivity or central factors inhibiting the incoming
stimuli. No studies have addressed this issue before and the
finding needs further clarification. Higher EMG-amplitude values
during rest were recorded in headache free patients as compared to
normal controls. These findings correspond with a recent population
study where amplitude levels from the temporal and the frontal
muscles were increased in subjects pith chronic tension-type
headache (Jensen et al. 1994). These findings indicate that the
muscles are insufficiently relaxed. Whether this is causative or
secondary to the headache has been much debated, but lack of
correlation to the pain state (see below) indicates that it may be
a secondary characteristic. In the study presented in example 3 it
is described that sustained tooth clenching may be an initiating
event of tension-type headache, but the present results suggests
that other mechanisms are responsible for maintaining it.
[0344] Relation to the Headache State
[0345] During headache pericranial tenderness increased, indicating
peripheral or central sensitization of myofascial nociception
(Jensen et al 1990). EMG-levels were unchanged during headache
which makes it unlikely that pain elicited activity in pericranial
muscles can explain the increased tenderness. Pressure pain
thresholds were unaffected by the headache state whereas thermal
pain detection and tolerance thresholds decreased selectively in
the temporal region indicating that the actual headache episode may
be associated with a segmental central sensitization and/or a
decreased antinociception. A more generally defective central pain
modulation, as previously suggested (Schoenen et a. 1991a), is less
likely, because pressure pain thresholds and tolerances in the
hands were completely normal. A possible segmental disturbance at
the spinal/trigeminal level may be transient and reversible since
pain tolerances were normal outside of headache. The results are
thus in line pith the recent experimental studies by Hu et al. (Hu
et al. 1992). In these important studies deep craniofacial muscle
afferents were stimulated and prolonged facilitators effects in the
trigeminal nociceptive brain-stem neurons of anaesthetized rats
were induced. These findings were supported by the recent findings
that experimental myositis induces functional reorganization of the
rat dorsal horn (Hoheisel et al. 1994). A reversible expansion of
the cutaneous mechanoreceptive field was noted by Hu et al. and the
spontaneous activity in cutaneous afferents was increased (Hu et
al. 1992) in correspondence with previous studies (Coderre et al.
1993, Heppelmann et al. 1987). It is also known that input from
deep myofascial tissue is more effective in inducing central
sensitization than cutaneous input (Wall et al. 1984, Yu et al.
1993).
[0346] The decreased pain tolerance during headache in the present
study may indicate a central hyperalgesia. As pain tolerances were
normal outside of headache, the central changes are probably
reversibly linked to the headache pain in the episodic form,
whereas a more frequent activation may induce a permanent pain
condition, i.e. the chronic form. The cascade of increased
nociceptive activity from deep myofascial tissues may induce
secondary changes such as plasticity and sensitization in the
spinal dorsal horn/trigeminal nucleus (Hu et al. 1992, Hogeisel et
al. 1994, Coderre et al. 1993, Heppelmaan et al. 1987). The central
nociceptive modulation and perception are thereby disturbed
resulting in a prolonged hyperalgesia, which may persist despite
disappearance of the peripheral noxious stimulus. When the central
sensitization becomes sufficiently strong and widespread, the
headache becomes chronic due to self perpetuating disturbances in
the pain perception system.
[0347] Many of the abnormal findings in previous series of severely
affected patients with chronic tension-type headache (Schoenen et
al. 1991a, Langemark et al. 1989, Schoenen et al. 1991b) maybe a
function of the pain rather than the initial causative factor. It
can therefore be recommended to study mechanisms in patients with
episodic tension-type headache. Studies comparing the pain state to
the pain free state in these patients are likely to be the most
informative.
5TABLE IV Clinical characteristics of the subjects studied TH
patients Controls Number (n) 28 30 Males 11 12 Females 17 18
Age(years) 45(28-63) 42(23-67) Years with TH 23(1-45) -- Frequency
of TH 20(8-27) -- days/28 days Frequency of migr 8(2-11) --
days/year (n = 14) Mean values with range in brackets are given
[0348]
6TABLE V Pressure pain thresholds in 28 headache patients free of
headache and 30 healthy controls. Mean values of left and right
side are given in kPa with SD in brackets. Pressure pain Pressure
pain detection tolerance patients 384(161) 739(271) HANDS controls
358(168) 785(289) patients 225(97) 366(141) TEMPORAL REG. controls
203(103) 387(157) patients 339(172) 560(179) PARIETAL REG. controls
317(194) 571(201) No significant differences between patients and
controls.
[0349]
7TABLE VI Thermal thresholds in 28 headache patients free of
headache and 30 healthy controls. Mean values of left and right
side are given in .degree. C. with SD in brackets. Warm Detection
Pain threshold Pain tolerance patients 34.3 (3.1) 42.3 (3.1) 47.0
(2.2) HANDS controls 34.4 (1.2) 42.4 (2.7) 47.5 (2.2) patients
***34.7 (1.6) *40.1 (2.8) 44.1 (2.0) TEMP controls 33.8 (0.8) 39.1
(2.7) 43.9 (8.5) *p < 0.05 ***p < 0.001 (Mann-Whitney's
test)
[0350]
8TABLE VII EMG levels in 28 patients free of headache and in 30
healthy controls. REST indicate resting conditions and MVC indicate
maximal voluntary contraction. Mean values of left and right side
are given with SD in brackets. REST MVC RMS Mean F RMS Mean F (uV)
(Hz) (uV) (Hz) TEMPORAL MUSCLES patients **3.1 (2.4) 81 (25) 164
(66) 173 (28) controls 2.3 (0.9) 74 (17) 181 (101) 155 (30)
TRAPEZIUS MUSCLES patients *3.6 (1.2) 40 (10) 260 (141) 88 (18)
controls 3.1 (0.9) 41 (9) 259 (131) 88 (16) *p < 0.05 **p <
0.01 (Mann-Whitney's test)
EXAMPLE 3
[0351] Intiating Mechanisms of Experimentally Induced Tension-Type
Headache
[0352] To elucidate possible myofascial mechanisms of tension-tape
headache, the effect of 30 minutes of sustained tooth clenching
(10% of maximal EMG-signal) was studied in 58 patients with
tension-type headache and in 30 age and sex matched controls.
Pericranial tenderness, mechanical and thermal pain detection and
tolerance thresholds and EMG levels were recorded before and after
the clenching procedure. Within 24 hours 69% of patients and 17% of
controls developed a tension-tape headache. Shortly after
clenching, tenderness was increased in the group who subsequently
developed headache, whereas tenderness was stable in the group of
patients who remained headache free. Mechanical pain thresholds
evaluated by pressure algometry remained unchanged in the group
which developed headache, whereas thresholds increased in the group
which did not develop headache. Thermal pain detection and
tolerance thresholds remained unchanged in both groups. These
findings indicate that, although there may be several different
mechanisms of tension-type headache, one of them is sustained
muscle contraction. A peripheral mechanism of tension-type headache
is therefore possible, whereas a secondary segmental central
sensitization seems to be involved in subjects with frequent
tension-type headache. Finally, the increase in pressure pain
thresholds in patients who did not develop headache suggest that
clenching activated their antinociceptive system whereas those
developing headache were unable to do so.
[0353] Introduction
[0354] Tension-type headache is extremely prevalent (Rasmussen et
al. 1991) and represents a major health problem (Rasmussen et al.
1992). Nevertheless, its pathogenic mechanisms are largely unknown
(Pikoff et al. 1984, Olesen et al. 1991). Sustained involuntary
muscle contraction has been suggested as an important source of
pain in tension-type headache (Travell et al. 1983). In recent
years, central mechanisms have however, been favoured (Schoenen et
al. 1991a). Substantial evidence for any of the suggested
pathogenetic mechanisms has not yet been available. To study the
initiating mechanisms of headache it is valuable to induce it. The
time necessary to reach the laboratory males it impossible to study
the initial phase of spontaneous attacks. Furthermore, using a
known stimulus to induce headache makes it easier to analyze its
mechanisms. Experimental tooth clenching has previously induced
mild headaches in migraineurs (Jensen et al. 1985) but has never
been studied in subjects with tension-type headache. In the present
study tension-type headache was induced by sustained muscle
contraction in patients and controls and studied the pre- and
post-contraction phase by means of EMG, thermal and pressure pain
thresholds as well as headache and tenderness scoring.
[0355] Subjects and Methods
[0356] Subjects
[0357] Fifty-eight patients with frequent episodic or chronic
tension-type headache fulfilling the IHS-criteria (HCCIHS 1988)
were included (Table VIII). Twenty eight patients had frequent
episodic tension-type headache 38 days with headache per month and
30 patients had chronic, but not daily, tension-type headache
(HCCIHS 1988). The reason for this selection was that patients had
to have frequent headaches as well as days without headache in
order to be studied in the latter state. Further inclusion criteria
were duration of frequent tension-type headache in at least one
year and age between 18 and 70 years. The exclusion criteria were:
daily headache, migraine more than 1 day per month, cluster
headache, trigeminal neuralgia, other neurological, systemic or
psychiatric disorders, ingestion of major medications including
migraine prophylactics, any form of drug abuse or dependency as
daily ergotamine or large amounts of plain analgesics. The patients
were recruited from the out-patient headache clinic at Gentoftc
Hospital and complete physical and neurological examinations were
done before entry. Thirty healthy age- and sex matched subjects
(headache <14 days/year) were used as controls (Table VIII).
Informed consent was obtained and the study was approved by the
local ethical committee.
[0358] Procedure
[0359] All patients had to fill in a diagnostic headache diary
during a 4 week run-in period to ensure that patients fulfilled the
inclusion criteria. All subjects, patients and controls, were told
to fill out a special diary for at least 24 hours after the study.
Patients were examined when free of headache and were not allowed
to have taken any analgesics on the day of examination. The
EMG-parameters and pain characteristics were recorded twice on the
day of examination, immediately before and after the clenching
procedure. A 100 mm Visual Analogue Scale (VAS), where 0 mm was no
pain at all and 100 mm was the worst imaginable pain was used.
Recordings of pain intensity were made before, 30, 60 and 90
minutes after the clenching procedure in the laboratory, as well as
after 4, 6, and 24 hours after the clenching in the diary. All
subjects were informed that the purpose of the study was to measure
variations in muscle tension and pain characteristics during tooth
clenching. They were not informed of the risk of developing
headache in order to avoid bias.
[0360] Examination
[0361] The examination was performed in a standardized way by the
same person, a trained technician, throughout the whole study. The
study was blinded as the technician was unaware of the subjects
headache history. Before recordings of pain thresholds each
individual was carefully instructed to apply the same
interpretation of `painfiul` throughout the study. Initial test
sessions were applied to all subjects in order to familiarize them
with the test conditions.
[0362] Palpation
[0363] Pericranial tenderness was evaluated by palpation of 9 pairs
of muscles and tendon insertions by the technician and the
physician in a standardized, randomized procedure. Tenderness was
scored in each location according to an ordinal scale from 0 to 3,
and scores from all sites were summated. The maximum possible score
was thus 54 points. This Total Tenderness Score system (TTS) has
previous proved to be reliable (Bendtsen et al. 1995).
[0364] Pressure Pain Thresholds
[0365] The pressure pain thresholds were evaluated bilaterally on
the distal dorsal part of the second finger, and in two cranial
locations, one with interposed temporal muscle (Temp) and one
without interposed muscle, the parietal region (Par). A
standardized and previously evaluated method vas applied using an
electronic pressure algometer (Somedic AB, Sweden) with an 0.79
cm.sup.2 circular stimulation probe (Petersen et al. 1992, Jensen
et al. 1986, Brennum et al. 1989). Two pain qualities were
recorded, the Pressure Pain Detection Threshold (PPDT) defined as
the threshold, where the pressure sensation became painful, and the
Pressure Pain Tolerance (PPTO) defined as the threshold where the
patient would no longer tolerate the pain (Petersen et al. 1992).
By pressing a hand held button the subjects indicated that the
threshold was reached, and the pressure was released immediately.
If patients did not activate the button, the experiment was
terminated when reaching 800 kPa in the cranial region and 1500 kPa
in the fingers. Each threshold was calculated as the median value
of 3 determinations performed with intervals of 10-15 seconds.
[0366] Thermal Pain Thresholds
[0367] Thermal thresholds were evaluated with a computerized
version of the Thermotest (Somedic AB, Sweden) (Fruhstorfer et al.
1976). The thermode consisted of series-coupled Peltier elements
and measured 25.times.50 mm. The thenar region of the hand and the
anterior part of the temporal region were examined bilaterally.
Three stimulation qualities were recorded: the Warm Detection limit
(WD) defined as the lowest temperature detected as warm, the Heat
Pain Detection (HPD) defined as the temperature where the heat
sensation became painful, and the Heat Pain Tolerance (HPTO)
defined as the highest temperature tolerated (Jamal et al. 1985). A
baseline temperature of 32.degree. C. and a 1.0.degree. C./sec rate
of temperature change was used. Heat stimulation was terminated
when reaching 52.degree. C., if the patients had not responded
before. By pressing a hand-held button the subjects indicated when
the actual threshold vas reached. This value was recorded
automatically and the stimulator returned to baseline. Each
threshold was calculated as the average of 5 determinations
performed with intervals of 10-15 seconds.
[0368] Electromyography
[0369] EMG signals from the temporal and trapezius muscles were
recorded bilaterally by a 4-channels electromyograph (Counterpoint,
Dantec, Copenhagen) (Jensen et al. 1993a). A standardized,
previously described method where the temporal and frontal muscles
were investigated were applied (Jensen et al. 1993a). Data were
collected during rest in the supine position and during maximal
voluntary contractions (MVC) (Jensen et al. 1993a). The RMS voltage
was measured. Power spectrum was calculated for the frequency range
0 to 1 kHz and Mean Frequencies (Mean F) were extracted (Jensen et
al. 1993a).
[0370] Provocation
[0371] After the initial recording series the subjects were
instructed to clench their molar teeth and the EMG activity from
the temporal muscles was recorded. The subjects were instructed to
clench their teeth at 10% of their individual MVC value and to keep
this value constant for 30 minutes. The subjects received visual
feed back from the EMG-monitor, and were allowed 3 short (<60
sec) rests during the session. Force was not measured.
[0372] Statistics
[0373] The chi square test was used to test differences in headache
characteristics between patients and controls. The sign test was
used to compare the frequency of provoked headache with the
expected frequency. Wilcoxon's rank sum test (Wilc.) was used for
comparing paired data within subjects, and Mann-Whitney's test
(M-W.) was used for comparing unpaired data between patients and
controls. Five percent level of significance was used.
[0374] Results
[0375] All the included patients and healthy controls completed the
study. No significant variation in age- and sex distribution
between patients and controls appeared (Table VIII). Only two left
handed subjects (1 patient, 1 control) were included. Therefore no
correction for hand dominance was made.
[0376] Development of Headache
[0377] In total, 69% (40/58) of the patients and 17% (5/30) of the
healthy controls developed headache within 24 hours after tooth
clenching. The frequency of headache among patients was
significantly higher than expected from their usual headache
frequency (p=0.016) and higher than in healthy controls
(p<0.0001). Twenty-eight percent of patients (16/58) and 7% of
controls (2/30) developed headache within the first hour after
tooth clenching. The median duration from clenching to development
of headache was 1.5 hours in patients (range 0.5-20 hours) and 1.5
hours (range 0.5-6 hours) in controls. All headaches, in patients
as well as in controls, fulfilled the diagnostic criteria for
tension-type headache (n=7). The headaches were bilaterally located
in 85% (34/40) of the patients and in all controls. It was of
pressing quality in all subjects. It was not aggravated by physical
activity in 85% (34/40) of the patients and in all the controls. No
associated symptoms such as nausea, photophobia or phonophobia were
reported. Initially, the headache was cry mild in both groups, but
the intensity increased during the following hours in patients
(FIG. 9). Four and 24 hours after clenching those patients who bad
developed headache had significantly higher mean VAS-scores than
those few healthy controls who had developed headache (M-W. p=0.02)
(FIG. 9). In patients, the median headache duration was 8 hours
(range 1-24 hours) but not significantly different from 3 hours
(range 2-24 hours) (M-W. p=0.10) in the small number of controls
(n=5) with headache.
[0378] Variation between Observers
[0379] The Total Tenderness Scores (TTS) recorded by the 2
observers at the initial examination did not differ significantly
within patients (Wilc. p=0.24) nor in healthy controls (Wilc.
p=0.27).
[0380] Variation between Left and Right Sided Observations
[0381] The side to side variations were tested in patients as well
as in controls, and results corresponded to previous methodological
studies (Petersen et al. 1992, Fruhstorfer et al. 1976, Jensen et
al. 1993a, Jensen et al. 1993b). For simplicity mean values of left
and right sided observations are presented in the following.
[0382] Relation between Measurements in Patients and Controls
before Clenching
[0383] Tenderness
[0384] Initial median TTS in patients was 12 (range 0-29) and
significantly higher than the median score of 4 (range 0-10) in
healthy controls (M-W.p<10.sup.-7).
[0385] Pressure Pain Thresholds
[0386] Pressure Pain Detection Thresholds were increased in the
temporal regions of headache patients compared with healthy
controls (M-kV.p=0.03) (Table IX). No significant variations or
tendencies were found in the other locations (M-W.fingers p=0.98;
parietal p=0.21) (Table IX).
[0387] Pressure Pain Tolerances in patients were not significantly
different from those in healthy controls in any of the examined
regions (M-W.fingers p=0.87, temp. p=0.45; parietal p=0.69) (Table
IX).
[0388] Thermal Thresholds
[0389] The warn detection threshold was higher in the temporal
regions in patients than in healthy controls (M-W. p=0.02), while
the warm detection in the hands was normal (M-W. p=0.26) (Table X).
The heat pain detection and tolerance thresholds were normal in
both locations (Table X).
[0390] EMG
[0391] During rest the EMG-amplitude was significantly increased in
the trapezius muscle of patients compared to controls (M-W.
[0392] Trap p=0.04). A similar but not quite significant increase
was seen in the temporal muscles (M-W.Temp p=0.10) (Table XI).
Frequency values during rest as well as all EMG values during MVC
were not different from those of controls (Table XI).
[0393] Effect of Clenching on the Measured Tests
[0394] Tenderness
[0395] The median initial TTS was 12 (range 0-28) in patients who
developed headache and was increased significantly to 14 (range
0-33) at the recording 90 minutes after clenching (Wilc.p<0.001)
(FIG. 10). The median TTS in patients who remained headache free
was also 12 (range 0-24) and remained 12 (range 033) after
clenching (Wilc.p=0.33). A marked, but not quite significant
increase in TTS from 6 to 10 was seen in the few control subjects
who developed headache (Wilc.p=0.06), whereas TTS only increased
from 4 to 5 in controls who remained headache free (Wilc.p=0.0015)
(FIG. 10).
[0396] Pressure Pain Thresholds
[0397] Pressure Pain Detection Thresholds in fingers and in the
temporal regions remained constant in those subjects (patients as
well as controls) who developed headache, whereas a significant
increase of pain detection thresholds was seen in subjects who did
not develop headache (Wilc. Patients fingers p=0.01; temp p=0.024;
Controls fingers p=0.04; temp p=0.01) (FIG. 11A).
[0398] Pressure Pain Tolerance decreased in the parietal region in
patients who developed headache after clenching (Wilc.p=0.009),
whereas the tolerances remained stable in patients who remained
headache free. Pressure Pain Tolerances in the same region
increased in controls who remained headache free after stimulation
(Wilc.p=0.003) (FIG. 11B). Pressure Pain Tolerance was stable in
the hand and the temporal region in all subjects without regard to
headache development (FIG. 11B).
[0399] Thermal Thresholds
[0400] In patients as well as in controls, no significant
differences in thermal thresholds were seen between those who
developed headache and those who did not (FIG. 12).
[0401] EMG
[0402] During resting condition a significant decrease in amplitude
value was seen the temporal and the trapezius muscles after
clenching both in patients (Wilc.Temp. p<0.001, Trap. p<0.01)
and in controls (Wilc. Temp.p<0.001, Trap. p<0.01). This
decrease was similar in those who developed headache and in those
who did not (FIG. 13A). In contrast, only the group of patients who
developed headache showed decreased amplitude values in the
temporal muscle during MVC (Wilc. p=0.011) (FIG. 13B).
[0403] Discussion
[0404] Studies in a general population and in specialized headache
clinics have revealed that increased muscle tenderness and frequent
tooth clenching are consistent findings in subjects with
tension-type headache (Jensen et al. 1993b, Jensen et al. in prep.,
Wanmann et al. 1986, Langemark et al. 1987, Lous et al. 1982).
Whether these relations are causal or secondary to the pain has not
yet been clarified. However, if there is a causal connection it
should be possible to create an experimental headache model by
interfering smith these systems. Although several attempts to make
experimental pain in the chewing muscles have been made
(Christensen et a. 1981, Clark et al. 1991, Bakke et al. 1989),
only few studies have focused specifically on headache (Jensen et
al. 1985, Magnusson et al. 1984). Jensen et al. reported that 54%
of 48 migraineurs developed a muscle-contraction like headache
after shortlasting sustained clenching (Jensen et al. 1985). These
findings indicate that headache subjects in general are more
susceptible to develop headache after sustained muscle
contraction.
[0405] Relation between Measurements in Patients and Controls
before Clenching
[0406] Tenderness
[0407] The finding of increased muscle tenderness by manual
palpation as the most significant difference between headache
patients and healthy controls supports previous findings in a
general population (Jensen et al. 1993b). When selecting
psycho-physiological measures it is important to consider the
information carried by the particular measure. Local tenderness as
recorded by manual palpation is assumed to indicate increased
nociception from the free nerve endings in the connective tissue of
muscles, fascia and tendons (Jensen et al. 1990, Torebjork et al.
1984). Such increased nociception is probably due to a
sensitization of nociceptors by bradykinin, prostaglandines,
substance P, 5-HT, histamine and potassiu (Mense et al. 1992,
Jensen et al. 1992). Reduced muscle blood flow leading to ischemia
has been suggested as the cause of tenderness (Myers et al. 1983),
but recently normal blood flow in the temporal muscles of patients
with chronic tension-type headache has been demonstrated (Langemark
et al. 1990).
[0408] Pressure Pain Thresholds
[0409] A decreased pressure pain detection threshold indicates a
state of allodynia, i.e. pain elicited by stimuli which normally
are non-noxious. A decrease in pressure pain tolerance threshold
indicates a state of hyperalgesia, i.e. increased sensitivity for
supra threshold noxious stimuli, which may and ray not coexist with
allodynia (Jensen et al. 1990). Identification of allodynia and
hyperalgesia may therefore be of special interest in the study of
central and peripheral mechanisms of nociception. In addition, we
have studied responses from the hands and the cranial regions in
order to determine a possible anatomical variation in the response
to pain stimulation. We also waited to study the muscular
contribution and recorded thresholds from two neighboring cranial
regions one with and one without interposed muscle. The fact that
pressure pain detection thresholds and tolerances were lower in the
temporal region than in the nearby parietal region indicates that
myofascial nociception contributes considerably to the recorded
responses. However, the finding of largely normal thresholds and
tolerances in headache free patients indicates that the general
pain sensitivity in the cranial region is not permanently disturbed
as previously suggested (Schoen et al. 1991a, Langemark et al.
1989).
[0410] Thermal Thresholds
[0411] Thermal warm detection represents the activity in
unmyelinated C-fibers (Campbell et al. 1989) whereas the heat pain
detection represents activation of cutaneous C-fibers responsive to
mechanical and heat stimuli and their central modulation (Campbell
et al. 1909). In addition, the myelinated A mechano beat fibers
type I may be activated when the heat pain tolerance is tested. If
central pain perception is increased, decreased warmth and heat
pain thresholds are expected. However, thermal pain detection and
tolerances were normal in the headache patients suggesting normal
pain sensitivity as discussed above. The present findings differ
from a previous finding of decreased heat pain detection thresholds
in patients with chronic tension-type headache (Langemark et al.
1989). In the prior study patients were, however, more severely
affected and most of them had daily headaches and long lasting drug
overuse (Langemark et al. 1989). It is likely that chronic pain may
induce central sensitization to incoming nociceptive signals, and
the previously described decrease in noxious thresholds in severely
affected headache patients may, therefore, be an effect of chronic
pain rather than its cause.
[0412] EMG
[0413] It has been a widely held view that tension-type headache is
caused by involuntary contraction of cranial muscles. The slightly
increased amplitude values during rest indicate that the
pericranial muscles arc insufficiently relaxed (Jensen et al.
1994). However, this increase in EMG level was unaffected by the
presence or absence of headache, and is therefore not likely to be
a primary cause of pain (Jensen et al. 1994). The decreased
amplitude values during maximal voluntary contraction in patients
developing headache and not in controls indicate that in some other
way a muscular factor may be involved (Jensen et al. 1994).
[0414] Effect of Clenching on Headache and the Measured Tests
[0415] The present results indicate that sustained muscle
contraction can induce headache although the recordings have not
been repeated during a similar placebo provocation. An important
finding is the increased tenderness in subjects who developed
headache. Headache had not developed in the majority of subjects at
90 minutes after provocation, when the increased tenderness was
recorded. This suggests that clenching causes tenderness, that
tenderness precedes headache and that tenderness may be one of the
causes of the subsequent headache. A similar increase in tenderness
scores during spontaneous attacks of tension-type headache has
recently been shown (Jensen et al. in press). Muscle tenderness
usually requires several hours to develop (Christensen et al.
1981). A further increase in tenderness would therefore probably
have been detected if we had continued to record tenderness several
hours after clenching. In the present study, the experimental
headache occurred swish a lag time of one to several hours. In
addition, the pain was mild initially and gradually, in the course
of hours, reached its peak. In contrast, the intensity of headache
in control subjects did not increase after onset. The very low
VAS-score in controls may represent discomfort rather than clinical
relevant pain as reported by the patients. This indicates that the
antinociceptive system may be deficient in headache patients. The
exact degree of clenching seems to be of minor importance.
Approximately the same percentage of subjects developed headache
with 10% of mammal contraction in the present study and with 5% or
30% of maximal contraction in the previous migraine study (Jensen
et al. 1985).
[0416] Mechanisms of Tension-Type Headache Suggested by the Present
Results
[0417] The pressure pain detection thresholds remained stable in
patients who developed headache but increased in subjects who did
not develop headache. We also found decreased pain tolerances in
patients who developed headache, unchanged values in the remaining
patients and increased values in controls, suggesting that headache
patients do not activate their antinociceptive system or that it is
less effective in these patients (Le Bars et al. 1979). On the
other hand, their central antinociceptive suppression is not so
permanently and severely affected that it is reflected in permanent
hyperalgesia, since the noxious thresholds and tolerances were
normal outside of a headache episode. In addition, as the thermal
thresholds remained unaffected of the headache state, no evidence
for a general hypersensitivity to pain was found. The similar
decreases in EMG-levels in both groups after clenching indicate
that the increased EMG-levels in patients free of headache may be a
secondary characteristic. This is supported by similar findings in
a recent study of patients during and outside of spontaneous
tension-type headache attacks (Jensen et al. in press). Based on
the present findings, results from previous studies (Jensen et al.
1993b, Jensen et al. 1994, Jensen et al. in press) mid results from
recent animal studies (Mense et al. 1993, Le Bars et al. 1919) on
peripheral and central pain mechanisms we suggest the following
mechanism of tension-type headache: involuntary contraction of
muscles, due to mechanical or psychological stress, causes
activation and chemical sensitization of the myofascial mechano
receptors and their afferent fibres. This increased peripheral
input may result in sensitization and functional reorganization of
second order sensory neurons in the dorsal horn (Hoheisel et al.
1994) as stimuli in the deep myofascial tissues are much more
effective, in this respect than stimuli in the cutaneous tissues
(Wall et al. 1984, Yu et al. 1993). Normally, increased peripheral
nociceptive input is counteracted by increased activity in the
antinociceptive system and no headache arises. However, in some
individuals and under certain circumstances this homeostatic
mechanism does not function. An abnormal sensitization arises and
combined with an impaired central antinociceptive mechanism, an
episode of tension-type headache may develop. However, the relative
importance of peripheral and central sensitization and of the
antinociceptive system remain further clucidation. In conclusion,
the results obtained be the present inventors suggest that muscular
factors play an important role in the initiation of a headache
episode. However, the further development and transition into the
chronic pain state is probably due to a central sensitization with
or without impairment of the central antinociceptive system.
9TABLE VIII Clinical characteristics of the subjects studied TH
patients Controls Number (n) 58 30 Males 22 12 Females 36 18
Age(years) 45(21-63) 42(23-67) Years with TH 23(1-45) -- Frequency
of TH 17(8-27) -- days/28 days Frequency of migraine 7(2-12) --
days/year (n = 28) Mean values with range in brackets are given. TH
indicates tension-type headache
[0418]
10TABLE IX Pressure pain detection thresholds (PPDT) and tolerances
(PPTO) in 58 headache patients free of headache and 30 healthy
controls. Mean values of left and right side with SD in brackets
are given in kPa. PPDT PPTO FINGER patients 353(137) 779(294)
controls 358(168) 785(289) TEMPORAL REGION patients *220(76)
399(146) controls 203(103) 387(157) PARIETAL REGION patients
323(146) 600(190) controls 317(195) 571(201) *p < 0.05
[0419]
11TABLE X Thermal thresholds in 58 headache patients free of
headache and in 30 healthy controls. Mean values of left and right
side with SD in brackets are given in .degree. C. Warm Pain Pain
detection threshold tolerance HANDS patients 34.5(1.2) 42.3(3.0)
47.2(2.3) controls 34.4(1.2) 42.4(2.7) 47.5(2.2) TEMPORAL REGION
patients *34.2(1.7) 39.6(2.7) 44.0(2.0) controls 33.8(0.8)
39.1(2.7) 43.9(2.9) *p < 0.05
[0420]
12TABLE XI EMG levels in 58 patients free of headache and in 30
healthy controls during rest and maximal voluntary
contraction(MVC). Mean values of left and right side with SD in
brackets are given; RMS indicate root mean square values of
amplitudes (uV) and Mean F indicate mean frequency (Hz). REST MVC
RMS Mean F RMS Mean F TEMPORAL MUSCLES patients 2.7 (1.9) 78 (22)
164 (81) 164 (32) controls 2.3 (0.9) 74 (17) 181 (101) 155 (30)
TRAPEZIUS MUSCLES patients *3.5 (1.2) 39 (9) 246 (124) 88 (16)
controls 3.1 (0.9) 40 (9) 259 (131) 88 (16) *p < 0.05
EXAMPLE 4
[0421] A Nitric Oxide Synthase Inhibitor is Effective in Chronic
Tension-Type Headache and is Counteracting Central
Sensitization
[0422] Introduction
[0423] Nitric oxide (NO) is an almost ubiquitous molecule that
probably plans an important role in the modulation and transmission
of pain (Meller and Gebhart 1993). NO is assumed to be of
particular importance for the development of central sensitization,
i.e. increased excitability of neurons in the central nervous
system (McMahon et al. 1993; Meller and Gebhart 1993). In this way
NO may contribute to the development of chronic pain The synthesis
of NO is catalyzed by the enzyme NO synthase (NOS) (Moncada et al.
1991), Recent animal studies have shown that NOS inhibitors reduce
central sensitization in persistent pain models (Haley et al. 1992;
Hao and Xu 1996; Mao et al. 1997). Chronic tension-type headache
responds poorly to analgesics and new treatments are badly needed
(Rasmussen et al. 1991). The aim of the present study was to
evaluate whether intravenous infusion of the NOS inhibitor,
L-N.sup.0 methyl arginine hydrochloride (L-NMMA), is effective in
the treatment of this disorder.
[0424] Materials and Methods
[0425] Subjects
[0426] Sixteen patients with a diagnosis of chronic tension-type
headache according to the criteria of the International Headache
Society (Headache Classification Committee 1988) were recruited
from the out-patient headache clinic at Glostrup Hospital. There
were 12 women and 4 men with a mean age (range) of 38.5 (23-52)
years. Five patients with coexisting infrequent migraine (.English
Pound. one day/month) were accepted. All patients completed a
diagnostic headache diary during a 4-week run-in period (Russell et
al. 1992). At screening, a full physical and neurological
examination, including 12-lead ECG were carried out. Blood samples
for routine haematological and biochemical testing, and urine
sample for urine analysis were taken. The patients were not allowed
to take analgesics 12 hours prior to the treatment. Exclusion
criteria were: daily medication (including prophylactic headache
therapy but not oral contraceptives); pregnant or breast feeding
women; abuse of analgesics (corresponding to >2 gm of
aspirin/day) or alcohol; serious somatic or psychiatric diseases
including depression (Hamilton Depression Score .sup.317 (Hamilton
1960)); ischemic heart disease; a supine diastolic blood pressure
>90 mmHg or heart rate <50 beats per minute at study entry.
All patients gave written informed consent to participate in the
study, which was approved by the local ethics committee and
conducted in accordance with the Declaration of Helsinki.
[0427] Procedures
[0428] Using a double-blind crossover design, the patients were
randomized to receive 6 mg/kg L-NMMA (Clinalfa, Switzerland) or
placebo (isotone glucose) on two days with a typical episode of
tension-type headache separated by at least one week. Randomization
(Med.Stat) and drug preparation were performed by staff not
involved in the study. The medication was given over 15 minutes
into an antecubital vein (Braun Perfusor). The following parameters
were measured at baseline and 15, 30, 60 and 120 minutes post
administration: headache intensity on a 100-mm Visual Analog Scale
(VAS) (0--no headache and 100--worst imaginable headache) and on a
Verbal Rating Scale (VRS) from 0-10 (0--no headache; 5--moderate
headache; 10--worst imaginable headache). Blood pressure and pulse
rate were measured 5 minutes prior to administration of treatment
and at 5, 10, 15, 20, 25, 30, 60, 90 and 120 minutes post
administration. Twelve-lead ECG was monitored continuously. Any
adverse events were recorded. Patients trial unrelieved headache at
120 minutes post treatment were allowed to take rescue medication.
All patients were asked to record details of the following on a
diary card at 4, 8, 12, 16, 20 and 24 hours post administration:
headache intensity on VRS, any medication taken and adverse events.
Between 4-7 days after each treatment, the patients returned to the
clinic, the diary cards were collected and any adverse events were
noted.
[0429] Data Analysis and Statistics
[0430] Primary endpoint was the reduction of pain intensity over
time on active treatment compared to placebo. The secondary
endpoints were reduction of pain intensity at 30, 60, 90 and 120
minutes post dosing on VAS and VRS compared to pre-treatment pain
score within each treatment. Comparison of pain intensity on VAS,
blood pressure and pulse rate over time between treatments were
performed with ANOVA. Paired-Samples T Test was used to compare
pre-treatment pain score on VAS with pain score at 30, 60, 90, 120
minutes post dosing within each treatment. The sum of differences
between the pre-treatment VRS score and the VRS score at 30, 60,
90, 120 minutes post dosing was calculated in order to obtained a
summary measure of pain score for each treatment (Matthews et al.
1990). These sums of differences for each treatment were compared
by Wilcoxon Signed Rank test Five percent was accepted as level of
significance.
[0431] Results
[0432] Treatment Efficacy
[0433] L-NMMA reduced pain intensity (VAS) over time significantly
more than placebo (p=0.007). Relative percent changes in pain
intensity from baseline are shovel in FIG. 14. Pain score was
significantly reduced after 30, 60, 90 and 120 minutes post
treatment with L-NMMA (Table XII). There was no significant
reduction in pain intensity following treatment with placebo at any
time points. The pain intensity on VRS was significantly lover
after treatment with L-NMMA than after treatment with placebo
(p=0.02).
[0434] Adverse Events and Rescue Medication
[0435] The mean arterial blood pressure (MAP) and pulse rate
changed significantly over time during treatment with L-NMMA
compared with placebo p=0.0001 and p=0.0001). The maximum increase
in MAP was 12.+-.2% and occurred 15 minutes post dosing. The
maximum decrease in pulse rate was 16.+-.2% and occurred 10 minutes
post dosing. The increase in MAP and decrease in pulse rate are
consistent with known pharmacological properties of L-NMMA.
Patients were unaffected by these changes. Seven patients reported
subjective symptoms in relation to the L-NMMA infusion These were:
tiredness (2), dryness of the mouth (3), drowsiness (1), exhaustion
(1), nausea (1) and a feeling of tingling in arm (1). Four patients
reported subjective symptoms in relation to placebo treatment.
These were: a feeling of tingling in arm (2) and shoulder (2),
dryness of the mouth (1), warm sensation in the body (1) and
drowsiness (1). No patients withdrew from the study because of side
effects, Three patients treated with L-NMMA and 7 patients treated
with placebo used simple analgesics as rescue medication.
[0436] Discussion
[0437] There is ample experimental evidence showing that persistent
activity in peripheral nociceptors may lead to sensitization of
spinal dorsal horn neurons partly via activation of
N-methyl-D-aspartate (NMDA) receptors (Coderre et al. 1993). Since
many of the effects of the NOVA receptor activation are mediated
through production of NO, it seems probable that NO plays an
important role in the hyperalgesia ill the spinal cord (Meller and
Gebhart 1993). In support for this, animal models have shown that
NOS inhibitors reduce spinal dorsal horn sensitization induced by
continues painful input from the periphery Haley et al. 1992; Hao
and Xu 1996; Roche et al. 1996). However, the efficacy NOS
inhibitors have not previously been examined in patients.
[0438] Recently, it has been demonstrated that spinal dorsal horn
sensitization due to prolonged nociceptive input from pericranial
myofascial tissues probably plays an important role in the
pathophysiology of chronic tension-type headache (Bendtsen et al.
1996a, 1996b; Jensen et al. 1997). Thus, it is likely that the
analgesic effect of L-NMMA in chronic tension-type headache is due
to reduction of central sensitization at the level of the spinal
dorsal horn.
[0439] In conclusion, the present study provides the first evidence
of an effect of NOS inhibitors in human chronic pain, and indicates
that the effect of NO is via reduction of central sensitization
probably at the level of the dorsal horn/trigeminal nucleus.
13TABLE XII Pain scores on VAS before treatment and at 30, 60, 90
and 120 minutes post dosing. Mean values (SD) are given. 30 60 90
120 Baseline minutes minutes minutes minutes L-NMMA 49 .+-. 16 38
.+-. 18* 35 .+-. 18* 34 .+-. 21* 33 .+-. 21* Placebo 44 .+-. 14 41
.+-. 17.sup.NS 40 .+-. 17.sup.NS 42 .+-. 16.sup.NS 40 .+-.
17.sup.NS *= p < 0.05 and .sup.NS= not significant compared with
pretreatment values (Paired-Samples T Test).
EXAMPLE 5
[0440] Muscular Factores are of Importance in Tension-Type
Headache
[0441] Introduction
[0442] A recent study from by the present inventors demonstrated
for the first time that chronic tension-type headache has a
physiological basis and is caused at least partly by qualitative
changes in the central processing of sensory information (Bendtsen
et al. 1996b). It was suggested that muscular disorders are of
primary importance for the development of central sensitization. To
test this hypothesis, the present study of the psychophysical tests
suggested in the IHS classification (Headache Classification 1988)
as well as thermal pain sensitivity was conducted. The primary aim
was to compare the mechanical and the thermal pain sensitivity in
tension-type headache patients with and without disorders or
pericranial muscles. The secondary aim was to study the clinical
characteristics of these patients.
[0443] Patients and Methods
[0444] Patients
[0445] Fifty-eight patients with tension-type headache fulfilling
the IHS-criteria (Headache Classification 1988) were included
(Table XIII). Twenty-nine patients had frequent episodic
tension-type headache (ETH) and 29 patients had chronic
tension-type headache (CTH). The patients were recruited from the
out-patient headache clinic at Gentofte Hospital and complete
physical and neurological examinations were done before entry.
According to the primary aim patients with restricted tenderness in
the pericranial muscles were favoured, since the percentage of
patients associated with muscular disorders is 80-90% in
consecutive populations (Jensen et al., 1996, Langemark et al.,
1988). Further inclusion criteria were duration of tension-type
headache for at least one year and age between 18 and 70 years. The
exclusion criteria were: migraine more than 1 day per month,
cluster headache, trigeminal neuralgia, other neurological,
systemic or psychiatric disorders, ingestion of major medications
including prophylactics for migraine or other headaches, any form
of drug abuse or dependency as daily ergotamine or large amounts of
plain analgesics.
[0446] Thirty healthy subjects (12 males and 18 females) with a
mean age of 42 years (range 23-67 years) and without tension-type
headache (<14 days tension-type headache/year) were used as
controls. Informed consent was obtained and the study was approved
by the local ethical committee. The present study was a part of a
multifaceted study of tension-type headache, of which other parts
have been published previously (Jensen, 1996, Jensen and Olesen,
1996).
[0447] Procedure
[0448] All patients had to fill in a diagnostic headache diary
during a 4 week run-in period to ensure that they fulfilled the
inclusion criteria. Patients were instructed to fulfil the diary at
the end of each day with headache and to record the mean intensity
on a 0-3 scale, where 0 was no pain and 3 was severe incapacitating
pain that requires bed rest Mussel et al. 1992). The approximate
start and disappearance of headache and the total intake of
analgesics or other medications should also be recorded. A standard
dose of analgesics was defined as a dose equivalent to 1000 mg of
aspirin. All patients were examined when free of headache and were
not allowed to have taken any analgesics on the day of
examination.
[0449] Examination
[0450] The examination was performed in a standardized way, which
has been described previously (Jensen, 1996, Jensen and Olesen,
1996). All recordings were performed by the same observer, the
technician, throughout the entire study and the observer was
blinded for the following subdivision of patients. Before
recordings of pain thresholds each individual was carefully
instructed to apply the sane interpretation of `painful` throughout
the study. Initial test sessions were applied to all subjects in
order to familiarize them with the test conditions.
[0451] Palpation
[0452] Pericranial tenderness was evaluated by palpation of 9 pairs
of pericranial muscles and tendon insertions by the technician in a
standardized, randomized procedure (Langemark and Olesen, 1989,
Jensen et al., 1993b, Bendtsen et al., 1995a). Tenderness vats
scored in each location according to an ordinal scale from 0 to 3,
and scores from all sites were summated. The maximum possible score
was thus 54 points. This Total Tenderness Score system (TTS)
(Langemark and Olesen, 1987) has previously proved to be reliable
Bendtsen et al., 1995). We have previously demonstrated that the
most ideal cut-off point for separating tension-tape headache
subjects from non-headache subjects with respect to muscle
tenderness was the 75% quartile of TTS obtained from a general
population, whereas pressure algometry and EMG provided no further
information (Jensen et al., 1996). In the following, TTS is used as
the only criteria for further subdivision patients with TTS above 9
(equal to the 75% quartile of TTS from healthy controls) was
classified as having an association with muscular disorder (MUS),
whereas those with TTS value at 9 or below were classified as
unassociated with such a disorder (non-MUS).
[0453] Pressure Pain Thresholds
[0454] The pressure pain thresholds were evaluated bilaterally on
the distal dorsal part of the second finger, and in two cranial
locations, one with interposed temporal muscle (Temp) and one
without interposed muscle in the parietal region (Par). A
standardized and previously evaluated method was applied using an
electronic pressure algometer (Somedic AB, Sweden) with an 0.79
cm.sup.2 circular stimulation probe (Petersen et al., 1992, Jensen
et al., 1986, Brennum et al., 1989). Two pain qualities were
recorded, the Pressure Pain Detection Threshold (PPDT) defined as
the threshold, where the pressure sensation became painful, and the
Pressure Pain Tolerance (PPTO) defined as the threshold where the
patient would no longer tolerate the pain (Petersen et al., 1992).
By pressing a hand held button the subjects indicated that the
threshold was reached, and the pressure was released immediately.
If patients did not activate the button, the experiment was
terminated when reaching 800 kPa in the cranial region and 1500 kPa
in the fingers. Each threshold was calculated as the median value
of 3 determinations performed with intervals of 10-15 seconds, and
mean values of left and right sided recordings are presented in the
following.
[0455] Thermal Pain Thresholds
[0456] Thermal thresholds were evaluated with a computerized
version of the Thermotest (Somedic AB, Sweden) (Fruhstorfer et al.,
1976, Yanmitsky et al., 1995). The thermode consisted of
series-coupled Peltier elements and measured 25.times.50 mm. The
thenar region of the hand and the anterior part of the temporal
region were examined bilaterally. Three stimulation qualities were
recorded; the Warm Detection limit (WD) defined as the lowest
temperature detected as warm, the Heat Pain Detection (HPD) defined
as the temperature where the heat sensation became painful, aid the
Heat Pain Tolerance (HPTO) defined as the highest temperature
tolerated (Jensen et al., 1996, Jensen and Olesen, 1996). A
baseline temperature of 32.degree. C. and a 1.0.degree. C./sec rate
of temperature change was used. Heat stimulation was terminated
when reaching 52.degree. C., if the patients had not responded
before. By pressing a hand-held button the subjects indicated when
the actual threshold was reached. This value was recorded
automatically and the stimulator returned to baseline. Each
threshold was calculated as the average of S determinations
performed with intervals of 10-15 seconds, and mean values of left
and right sided recordings are presented in the following.
[0457] Electromyography
[0458] EMG signals from the temporal and trapezius muscles were
recorded bilaterally by a 4-channels electromyograph (Counterpoint,
Dantec, Copenhagen). A standardized, previously described method
was applied (Jensen et al., 1993). Data were collected during rest
in the supine position and during maximal voluntary contractions
(MVC) (Jensen et al. 1996). The root mean square (RMS) voltage was
measured. Power spectrum was calculated for the frequency range 0
to 1 kHz and Mean Frequencies (Mean F) were extracted (Jensen et
al., 1996).
[0459] Statistics
[0460] Clinical data are presented as mean values with range (Table
XIII and XIV) and the psychophysical data as mean values .+-.SE.
Mann-Whitncy's U test was used for testing unpaired observations in
patients with and without association with muscular disorders.
Analysis of variance was used to control for the variations in sex
distribution among the groups. Spearnan's test was used for
calculation of coefficients of correlation. Five percent was
accepted as level of significance.
[0461] Results
[0462] Two patients (a male with the episodic and a male with the
chronic subform.) were excluded from the present study due to
deficient diaries. The remaining 56 patients, 28 with CTH and 28
with ETH completed the studs and detailed clinical data with
respect to their association with muscular disorder are presented
in Table XIII and Table XIV. Fourteen patients with chronic
tension-type headache had a history of coexisting migraine with a
mean value of 7.3 days with migraine per year, not significantly
different from the 15 ETH patients, who had a history of 7.7 days
with migraine per year. Similarly, there was no significant
difference between the prevalence of migraine in patients with
muscular disorders compared to those without such disorder. No
significant variations in the clinical characteristics between
patients with and without disorders of pericranial muscles could be
detected (Table XIII, XIV)
[0463] Tenderness Recorded by Manual Palpation.
[0464] According to the prior definition of association with
muscular disorders, CTH patients associated with muscular disorder
(MUS) had, as expected, significantly higher TTS at 18.5 compared
to 6.2 in those without such an association (non-MUS)
(p<0.0001). Similarly, ETH patents with MUS had significantly
higher TTS at 15.3 compared to 4.3 in those without such an
association (p<0.0001).
[0465] Pressure Pain Thresholds
[0466] Pressure pain detection and tolerance thresholds were
significantly lower in CH patients associated with MUS compared to
non-MUS patients in all the examined locations (PPDT p<0.001;
PPTO p<-0.05) (Table XV) (FIG. 15).
[0467] In patients with ETH, there were no significant differences
in the pressure pain thresholds and tolerances between subjects
with or without association with muscular disorders in any of the
examined locations (Table XVI) (FIG. 16).
[0468] Thermal Pain Thresholds
[0469] There were no significant differences in heat detection,
heat pain and heat pain tolerance thresholds from the hands and the
temporal regions between CTH patients with and without a muscular
disorder. Similarly, no significant variations in thermal
thresholds could be detected in ETH patients with and without a
muscular disorder.
[0470] Relation between Tenderness and Pain Thresholds
[0471] In CTH patients, the Total Tenderness Score (TTS) was highly
correlated to the mechanical pain thresholds at the temporal region
(Temp: ITS vs PPDT:r=-0.61, p<0.001; TTS vs PPTO:r=-0.65,
p<0.001), and a similar tendency was seen at the parietal region
(TTS vs PPDT r=4.59, p=0.003; TTS vs PPTO r=-0.24, p=0.27) and at
the extracephalic region (Hands: TTS vs PPDT r=-0.36, p=0.06, TTS
vs PPTO, r=0.48, p=0.02). No such relations could be detected in
ETH patients in any of the examined locations. When TTS was
correlated to thermal thresholds no significant relations appeared
either in the chronic or the episodic form.
[0472] EMG
[0473] When EMG levels were recorded from the temporal and the
trapezius muscles under resting conditions and during maximal
voluntary contraction, CTH patients with association to muscular
factors had significantly higher RMS values in their trapezius
muscles during resting condition compared to non-MUS patients
(p=0.02). No other significant differences between the 2 subgroups
in neither CTH nor ETH patients appeared.
[0474] Relation to Healthy Controls
[0475] Tenderness by Manual Palpation
[0476] The mean Total Tenderness Score (TTS) in the 30 healthy
controls was 4.7 (quartiles 0-9) and was significantly lower than
9.8 (quartiles 4-15) in those 28 patients with ETH (p=0.002). In
CTH patients TTS was 14.1 (quartiles 4-15) and significantly higher
than in ETH patients (p=0.03) and in healthy controls
(p<0.0001).
[0477] Pressure Pain Thresholds
[0478] Compared to healthy controls, CTH patients with non-MUS had
significantly higher pressure pain thresholds and tolerance
thresholds in all the examined locations (p<0.01), whereas the
mechanical tolerances tended to be significant lower in CTH
patients with MUS (Fingers PPTO, p=0.07; Temp PPTO p=0.05). No
significant differences could be detected in the parietal regions
or in pressure pain detection thresholds from the other locations.
When pressure pain detection and tolerance thresholds from the 2
subgroups of ETH patients were compared to those from healthy
controls no significant differences appeared.
[0479] Thermal Pain Thresholds
[0480] When the thermal thresholds were compared to healthy
controls, significantly higher values of all the tested qualities
were noted in cephalic locations in those 10 CTH patients without
association with muscular disorders, whereas only warm detection
values were higher on the hands of these patients (Temporal:WD
p=0.02, WPDT p=0.04, WPTO p=0.028; Hands: WD p=0.02). No
significant variations in thermal thresholds could otherwise be
detected in relation to healthy controls.
[0481] EMG
[0482] Only CTH patients associated with muscular factors had
significantly higher RMS values in the temporal (p=0.008) and the
trapezius muscles during rest (p=0.004) than healthy controls. No
other differences between patients and controls were noted.
[0483] Discussion
[0484] Relation between Tenderness and Pain Thresholds
[0485] In the present study highly significant inverse correlations
between TTS, pressure pain detection and tolerance thresholds were
found in patients with CTH corresponding with our recent study
(Bendtsen et al.: 1996). Others have reported relatively small and
clinically insignificant relations (Schoenen et al. 1991a, Jensen
et al., 1996, Sandrini et al., 1994)) and the pressure pain
thresholds provided only limited diagnostic value (Jensen et al.,
1996). This discrepancy may be due to the fact that the pressure
pain threshold represents the lower end, and the pressure pain
tolerance the upper end of a pain stimulus response curve.
Tenderness obtained by manual palpation elicit pain intensities
between these extremes where the difference between patients and
controls is largest as discussed recently by Bendtsen et al
(Bendtsen et al., 1996b, Bendtsen et al, 1996c). The diagnostic
tests given in the IHS classification were previously assessed in a
study from a highly specialized headache clinic (Snadrini et al.,
1994) and in subjects from a general population (Jensen et al.,
1996). In the latter study, 87% of subjects with chronic, and 66%
of subjects with episodic tension-type headache had a disorder of
the pericranial muscles (Jensen et al., 1996). In the former,
Sandrini et al reported that 61% of patients with episodic, and 66%
of patients with chronic tension-type headache had disorder of
pericranial muscles. An earlier study, where only EMG and pressure
algometry were assessed, 72% were found to be associated with
disorders of pericranial muscles (Schoenen et al., 1991).
Tenderness determined by manual palpation was previously found to
be the most sensitive and specific test for disorder of pericranial
muscles (Jensen et al., 1996) and was therefore applied as the only
test to separate the 2 subforms in the present study.
[0486] Pathophysiological Mechanisms of the Disorderly of
Pericranial Muscles
[0487] It has been uncertain whether the increased, pericranial
myofascial tenderness was the cause or the effect of the pain. A
recent, experimental study indicated, however, that tenderness
precedes the induced headache by several hours when tension-type
headache is induced by tooth clenching (Jensen et al., 1996).
Possible mechanisms for the tenderness include 1) sensitization of
peripheral myofascial nociceptors; 2) sensitization of second order
neurons at the spinal/trigeminal level; 3) impaired central
modulation of the nociceptive activity. As tension-type headache is
a disease in man and not known in animals, experimental animal
models are of limited value for evaluation of these mechanisms.
Fortunately, quantitative analyses of mechanical and thermal pain
thresholds in humans can be used for this purpose. Thermal pain-
and tolerance thresholds are normal in most of these patients,
which indicates that pain mediated by C-fibers is registered and
modulated normally. The present finding of markedly increased
tenderness, slightly decreased mechanical but normal thermal
thresholds at cephalic and extracephalic locations in CTH patients
associated with muscular disorder, strongly indicates a
hyperalgesic response to mechanical stimulation in these patients
in line with previous studies (Bendtsen et al., 1196c, Schoenen et
al., 1991b, Langemark et al., 1989). This is also supported by our
findings of a highly significant inverse relation between
tenderness and mechanical threshold. It has recently been
demonstrated that due to central sensitization, pain in CTH and in
fibromyalgia may be mediated via low-threshold mechanosensitive
afferents projecting to dorsal horn neurons (Bendtsen et al.,
1996c, Bendtsen et al. in press). This is supported by prior
observations by Bendtsen et al., where an abnormal qualitative
stimulus response function was found only in those 20 CTH patients
with the most pronounced tenderness whereas 20 patients without
abnormal tenderness exhibited a fairly normal stimulus response
curve (Bendtsen et al., 1996c). A further support for myofascial
involvement is the finding of increased EMG amplitude levels only
from the pericranial muscles of CTH patients associated with
muscular disorders, whereas EMG levels otherwise were similar to
those in controls. The mechanisms of pain in tension-type headache
without association with a muscular disorder cannot be explained by
simple allodynia and/or hyperalgesia as both mechanical and thermal
pain thresholds from these patients were significantly increased
compared to healthy controls, indicating a higher pain
tolerability. Therefore, other mechanisms, probably in the central
modulation of pain, must be considered. As the clinical features
examined in the present study were fairly similar between the 2
subgroups in both the episodic and the chronic form it is very
likely, however, that several pathophysiological mechanisms are
shared and further documentation about the fairly rare patients
with tension-type headache without association with muscular
disorders are highly needed. Taken together our data strongly
suggest that central sensitization is of key importance in chronic
tension-type headache with disorders of pericranial muscles,
whereas other mechanisms must be considered in patients without
such disorders.
[0488] Relationship between Episodic and Chronic Tension-Type
Headache
[0489] The present study is the first study which have examined
this wide variety of clinical characteristics and psychophysical
tests in both episodic and chronic tension-type headache. A marked
difference in nociceptive mechanical thresholds between the 2
subgroups in the chronic, but not in the episodic form was
demonstrated, whereas tenderness recorded by manual palpation was
highly increased in both the episodic and the chronic tension-type
headache. A hypothesis of the pathophysiological evolution of
tension-type headache can therefore be created. In ETH patients
with disorder of pericranial muscles, the most likely mechanism is
a slightly increased input from myofascial nociceptors projecting
to a widely normal central paw perception system. As chronic
tension-type usually evolves from the episodic form (Langemark et
al., 1989) it is suggested that prolonged painful input from the
periphery may sensitize the central nervous system and that the
pain in CTH associated with muscular disorder thus may be due to a
central misinterpretation of the incoming signals at the dorsal
horn or trigeminal level. Such mechanisms have been demonstrated in
animal models (Coderre et al., 1993, Mense et al., 1993, Hu et al.,
1992, Hoheisel et al.: 1994), and irritative stimuli from
myofascial, deep tissues are found to be much more effective for
induction of central sensitization than cutaneous stimuli (Yu et
al., 1993). Muscular disorders may therefore be of major importance
for the conversion of episodic into chronic tension-type headache.
As the most frequently reported precipitating factors leading to
tension-type headache are stress, mental tension and tiredness
(Rasmussen et al., 1993, Clark et al., 1995, Ulrich et al., 1996),
central supraspinal involvement is undoubtedly also involved,
although precipitating factors may be different from causative
factors. Whether the precipitating factors and the evolution of
pain vary between the patients with and with disorders of
pericranial muscles remains to be elucidated.
[0490] In conclusion, the present data indicate that the fine
balance between periphery nociceptive input and their central
modulation sterns to be disturbed in the majority of patients with
tension-tape headache, namely those associated with muscular
disorders. An a central misinterpretation of the incoming
peripheral stimuli may be the result, a vicious circle is started
and is probably maintained long time after the primary eliciting
stimuli/stressor had stopped. Disorders of pericranial muscles may
therefore be of major importance for the conversion of episodic
into chronic tension-type headache, whereas other mechanisms should
be considered for those patients without such disorders. The
present study supplements the understanding of the interaction
between peripheral and central changes in tension-type headache,
and thereby, hopefully, will lead to a better understanding,
prevention and treatment of the most prevalent tape of
headache.
14TABLE XIII Clinical characteristics of patients with chronic
tension-type headache (N = 28) Patients Patients with MUS without
MUS Number (n) 18 10 Males/females 7/11 7/3 Age (years) 48.1
(34-64) 49.4 (37-59) Years-with TH 24.8 (1-45) 26.2 (2-50)
Frequency of TH 22.6 (15-28) 23.7 (15-28) (days/28 days) Intensity
1.7 (1-2.5) 1.4 (1-2) (0-3 scale) Duration 11.3 (4.2-24) 9.5
(2.9-24) (hours) Medication 1.6 (0-3.1) 1.8 (0-4.1) (doses/day)
Mean values with range in brackets are given. MUS indicate
association with muscular disorder as defined in the text, and
without MUS indicate no such association. TH indicates tension-type
headache.
[0491]
15TABLE XIV Clinical characteristics of patients with episodic
tension-type headache(N = 28) Patients Patients with MUS without
MUS Number (n) 14 14 Males/females 1/13 5/9 Age (years) 39.8
(20-56) 42.6 (21-59) Years with TH 20.2 (2-40) 19.6 (8-30)
Frequency 9.6 (5-14) 10.0 (6-14) (days/28 days) Intensity 1.7
(1.0-2.1) 1.8 (1.4-2.2) (0-3 scale) Duration 9.7 (4.7-18) 8.6
(3.3-24) (hours) Medication 1.0 (0-2) 0.8 (0-1.4) (doses/day) Mean
values with range in brackets are given. MUS indicate association
with muscular disorder as defined in the text, and without MUS
indicate no such association. TH indicates tension-type
headache.
[0492]
16TABLE XV Pressure pain detection and tolerance thresholds in
patients with chronic tension-type headache (N = 28). Mean values
are given in kPa with SE in brackets. Patients Patients with MUS
without MUS (n = 18) (n = 10) p-value Pain detection thresholds
Fingers 262 (17) 374 (23) p < 0.001 Temporal region 143 (9) 241
(18) p < 0.0001 Parietal region 217 (18) 368 (28) p < 0.001
Pain tolerance thresholds Fingers 535 (32) 776 (50) p < 0.001
Temporal region 252 (17) 394 (23) p < 0.0001 Parietal region 471
(38) 521 (27) p = 0.04
[0493]
17TABLE XVI Pressure pain detection and tolerance thresholds in
patients with episodic tension-type headache (N = 28). Mean values
are given in kPa with SE in brackets. Patients Patients with MUS
without MUS (n = 14) (n = 14) p-value Pain detection thresholds
Fingers 247 (12) 269 (18) p = 0.14 Temporal region 162 (10) 169
(10) p = 0.72 Parietal region 223 (16) 221 (16) p = 0.89 Pain
tolerance thresholds Fingers 610 (34) 595 (50) p = 0.47 Temporal
region 317 (18) 327 (23) p = 0.98 Parietal region 453 (23) 449 (30)
p = 0.85
EXAMPLE 6
[0494] Gabapentin has a Prophylactic Effect in Chronic Tension-Type
Headache
[0495] Introduction
[0496] GABA is an important inhibitory transmitter in the central
nervous system and it has been suggested that the encoding of
low-threshold mechanical threshold stimuli depends upon the
presence of a tonic activation of intrinsic glycine and/or
GABAergic neurons (Yaksh and Malmberg 1994). Gabapentin was
synthesized to be a systemically active GABA analogue and was found
to have anticonvulsant effect. Although initially employed in
humans to control seizures, recent clinical cases indicated that
the agent showed efficacy in treating human neuropathic pain states
(Rosner et al 1996), and a considerably effect in several
experimental pain models (Hwang and Yaksh 1996, Xiao and Bennett
1996). The exact mechanism is not fully understood, but several
mechanisms have been suggested. Binding studies fail to show
affinity for either GABA A or GABA B, although Gabapentin can
increase the rate of GABA synthesis and release. Furthermore,
Gabapentin showed binding affinity to the alpha-2-subunit of a
calcium channel (Gee et al. 1996), and these calcium channels are
recently reported to play a very exciting role in the genetic
studies of migraine disorders. As the side effect profile of
Gabapentin is favorable, the prophylactic effect of Gabapentin in a
small open labeled pilot stud in patients with chronic tension-tape
headache was evaluated
[0497] Materials and Methods
[0498] Three patients with a diagnosis of chronic tension-type
headache according to the International Headache Society (Headache
Classification Committee 1958) were recruited from the outpatient
headache clinic at Glostrup Hospital. The patients were males with
a mean age of 42 years (range 35-49). The mean life time duration
of chronic tension-type headache was 16 years (range 7-21). Two
patients had a coexisting but infrequent migraine. Exclusion
criteria were: daily major medication (including prophylactic
headache therapy); abuse of analgesics or alcohol; serious somatic
or psychiatric diseases including depression.
[0499] Procedures
[0500] Using an open libeled design, patients fulfilled a
diagnostic headache diary during at least 4 weeks run-in period to
ensure the diagnostic criteria Thereafter, the patients received
Gabapentin (Neurontin.RTM.) tablets, initially 300 mg (one tablet)
per day on day one, increasing with 300 mg (1 tablet) per day to
900 mg (3 tablets) on day 3. The treatment period lasted 4 weeks,
and during this period patients were asked to continue with
headache diaries, and record headache intensity, frequency,
duration, any medication taken and any possible adverse events. At
a follow up visit at day 29-32, diaries were collected and any
adverse events and evaluation of the treatment were recorded. Due
to the low number of patients, no statistical analysis were done.
The primary efficacy parameters were headache intensity, frequency
and duration, and the mean values from the run-in period were
compared to those obtained during the treatment period.
[0501] Results
[0502] All patients completed the study. Headache intensity
decreased 35%, namely from 5.5 on a 0-10 VAS intensity scale during
run-in period to 3.6 during active treatment. Duration of the
individual headache episode was reduced by 8%, and frequent, of
headache decreased by 45%, namely from 23.5 days per 4 weeks during
run-in period to 13 days per 4 weeks during the active treatment
period. The mean daily intake of analgesics decreased by 72% from
1.1 dose per day to 0.3 dose per day. One patient had excellent
effect of Gabapentin with complete relief of the headache after 2
days treatment, another patient had a moderate effect on headache
intensity and frequency, and the third patient had no significant
effect on any of efficacy parameters. Those two subjects with good
or excellent effect reported no side effects, whereas the third
patient who had no beneficial effect of Gabapentin complained of
sedation, vertigo and slight nausea. These side effects disappeared
completely after cessation of the drug intake.
[0503] Discussion and Conclusion
[0504] The present results suggest a positive prophylactic effect
of Gabapentin in chronic tension-type headache, which is in
accordance with the predictions made from the model involving
central sensitization provided by the present invention. Although
the exact mechanism of action of gabapentin is not fully
elucidated, the preliminary experimental evidence are highly in
favor of a pathophysiological explanation of chronic tension-type
headache, as caused by central sensitization.
EXAMPLE 7
[0505] Dextromethorphan has a Prophylactic Effect in Chronic
Tension-Type Headache
[0506] Introduction
[0507] The common role played by NMDA antagonism in preclinical
models is consistent with the observation that systemic ketamine
reduces the allodynia, hyperalgesia and after sensation present in
patients with peripheral pain injury, and the magnitude of the
relief is, in general, proportional to dose. Dextromethorphan has
been shown to reduce the after sensation induced by repetitive
stimuli in human volunteers (Price et all 1994). Furthermore, the
NMDA receptors are shown to act on the neuronal excitability via
opening or closing of ion channels. The increase in intracellular
calcium by such opening of the ion channels is believed to initiate
a cascade of biochemical events, including pain. Effective blockade
of these events is possible by NMDA antagonists, which are also
highly effective in various human pain conditions related to
central sensitization (Persson et al 1995). The major problem in
this treatment strategy is, however, the central side effects of
most NMDA antagonists. Dextromethorphan has been known for decades
as a cough suppressant and has a very favorable side effect
profile. Therefore the prophylactic effect of Dextromethorphan was
evaluated in a small, open labeled pilot study in patients with
chronic tension-type headache.
[0508] Materials and Methods
[0509] Five patients with a diagnosis of chronic tension-type
headache according to the International Headache Society (Headache
Classification Committee 1988) were recruited from the outpatient
headache clinic at Glostrup Hospital. There were 2 males and 3
females, and the mean age was 45.4 yeas (range 39-48). The mean
life time duration of chronic tension-type headache was 12.2 years
(range 4-25). One patient had coexisting but infrequent migraine.
Exclusion criteria were: daily major medication (including
prophylactic headache therapy); abuse of analgesics or alcohol;
serious somatic or psychiatric diseases including depression
[0510] Procedures
[0511] Using an open labeled design, patients fulfilled a
diagnostic headache diary during at least 4 weeks run-in period to
ensure the diagnostic criteria. Thereafter, the patients received
Dextromethorphan (Dexofan.RTM.) tablets at 30 mg each, three times
per day. The treatment period lasted 4 weeks, and during this
period patients were asked to continue with headache diaries, and
record headache intensity, frequency, duration, any medication
taken and any possible adverse events. At a follow up visit at day
29-32, diaries were collected and possible adverse events and
evaluation of the treatment were recorded. Due to the restricted
number of patients, no statistical analysis were done. The efficacy
parameters were headache intensity, frequency and duration, and
intake of simple analgesics. Mean values from the run-in period
were compared to those obtained during the treatment period.
[0512] Results
[0513] All patients completed the study. The intensity of headache
was reduced 18% namely from 4.4 on a 0-10 VAS intensity scale
during the run-in period to 3.6 during active treatment. Duration
of the individual headache episode was reduced by 11%, and
frequency of headache decreased by 4%, namely from 28 days per 4
weeks period during run-in to 27 days per 4 weeks period during
active treatment. Intake of analgesics decreased by 72% from a mean
intake at 1.8 dose per day during run-in period to 0.5 dose per day
during active treatment. Two patients reported a marked effect with
considerable relief of headache intensity and duration within very
few days of treatment, one patient had a slight relief of headache
intensity and two patients reported no effect at all. Four patients
reported no side effects, and marked side effects with sedation was
reported in one patient, the patient with best clinical response.
These side effects diminished considerably after a dose reduction
to 40 mg per day.
[0514] Discussion and Conclusion
[0515] The present results suggest a positive prophylactic effect
of Dextromethorphan in chronic tension-type headache. The lack of
effect in some patients may be due to a relatively small dosage.
Although the exact mechanism of Dextromethorphane is not fully
elucidated, the preliminary evidence in experimental pain model is
in favor of an effect according to the present, pathophysiological
model of chronic tension-type headache, i.e. the central
sensitization model of the present invention,
EXAMPLE 8
[0516] Possible Mechanisms of Action of Action of Nitric Oxide
Synthase Inhibitors in Chronic Myofascial Pain
[0517] Pain from the musculoskeletal system is probably the most
common type of chronic pain (Magni et al. 1990). Progress in basic
pain research has increased our knowledge about the mechanisms
underlying chronic myofascial pain (sense 1993). Thus, substantial
experimental evidence indicates that central sensitization
generated by prolonged nociceptive input from the periphery plays
an important role in the pathophysiology of chronic pain
particularly from myofascial tissues (Woolf 1983, Hu et al. 1992;
Woolf and Doubell 1994; Bendtsen et al. 1996a). The freely
diffusible gas nitric oxide (NO) is assumed to be of importance for
the development of central sensitization (McMahon et al. 1993;
Meller and Gebhart 1993). Thus, nitric oxide synthase (NOS)
inhibitor reduce central sensitization in animal models of
persistent pain (Haley et al. 1992; Hao and Xu 1996; Mao et al.
1997). We recently demonstrated that NOS inhibition has an
analgesic effect in patients with chronic myofascial pain (Ashina
et al. 1998a). However, the mechanisms of this effect have so far
been unknown. The aim of the present study was to investigate
whether the NOS inhibitor, L-N.sup.G methyl arginine hydrochloride
(L-NMMA), modulates muscle hardness (Sakai et al. 1995) and
myofascial tenderness (Jensen et al. 1998) in patients with chronic
myofascial pain.
[0518] Materials and Methods
[0519] Subjects
[0520] Sixteen patients with a diagnosis of chronic tension-type
headache according to the criteria of the International Headache
Society (Headache Classification Committee 1988) were included
(Table XVII). Five of the patients had coexisting infrequent
migraine (<four days/year). The patients were recruited from the
out-patient headache clinic at Glostrup University Hospital without
respect to presence or absence of myofascial tenderness. All
patients underwent a general physical and a neurological
examination and completed a diagnostic headache diary during a
4-week run-in period (Russell et al. 1992). Exclusion criteria
were; daily medication (including prophylactic headache therapy but
not oral contraceptives); abuse of analgesics (corresponding to
>2 gm of aspirin/day); serious somatic or psychiatric diseases
including depression (Hamilton Depression Score #17 (Hamilton
1960)). Patients were examined and treated during a typical day of
tension-type headache. All patients gave written consent to
participate in the study, which was approved by the Danish Board of
Health and the local ethics committee. The study was conducted in
accordance with the Declaration of Helsinki.
[0521] Apparatus
[0522] Muscle hardness. The muscle hardness of the trapezius muscle
was measured with a hardness meter, which has previously been
described in detail (Horikawa et al. 1993). In brief, the hardness
meter consists of a laser distance sensor and a pressure terminal
with a surface area of 1 cm.sup.2. The muscle hardness is estimated
by recording the relation between the applied pressure and the
displacement of the skin over the muscle. All calculations are
performed by a software-program in order to avoid observer bias.
Hardness is expressed in kPa/cm. We have previously demonstrated
that the hardness meter can measure muscle hardness reliably if the
same observer is used throughout a study (Ashina et al. 1998b).
[0523] Pressure pain thresholds. An electronic pressure algometer
(Somedic AB, Stockholm, Sweden) was used to measure pressure pain
thresholds. The algometer has been described in detail elsewhere
(Jensen et al. 1986). A circular stimulation probe (0.50 cm.sup.2)
and a pressure loading rate of 22 kPa/s (1 kPa=10.sup.3 N/m.sup.2)
were used.
[0524] Methods
[0525] The recordings were performed in a standardized manner by
the sane observer, a trained technician (HA), throughout the study.
All parameters were recorded at baseline, 60 and 120 minutes after
start of infusion. The trial was designed as a double blind,
placebo controlled, crossover study. The first part of the study
examined the analgesic effect of L-NMMA and has previously been
described in detail (Ashina et al. 1998a). Briefly, patients were
randomized to receive 6 mg/kg L-NMMA (Clinalfa, Switzerland) or
placebo (isotonic glucose) over 15 minutes into an antecubital vein
on two days separated by at least one week. The patients mere not
allowed to take analgesics 12 hours prior to the examination.
Headache intensity as measured on a 100 mm Visual Analog Scale
(VAS) (0--no headache and 100--worst imaginable headache) before,
during and after start of infusion.
[0526] Muscle hardness. The muscle hardness was measured at a
standard anatomical point on the trapezius muscle on the
non-dominant side, as previously described (Ashina et al. 1998b).
Briefly, the point was located on the center of the descending part
of the trapezius muscle midway between the processus spinosus of
the seventh cervical vertebra and the acromion. The muscle hardness
was calculated as the mean of five consecutive determinations. All
recordings were stored in the computer, and they were not analyzed
before the study was completed.
[0527] Total tenderness. Tenderness of percranial myofascial
tissues was recorded according to the Total Tenderness Scoring
system (Langemark and Olesen 1987), which has previously proved to
be reliable (Bendtsen et al. 1995). Eight pairs of muscles and
tendon insertions (masseter, temporal, frontal, sternocleidomastoid
and trapezius muscles, coronoid and mastoid processes, and neck
muscle insertions) were palpated. Tenderness was scored on a
4-point (0-3) scale at each location (local tenderness score) and
values from left and right sides were summed to a Total Tenderness
Score (TTS) (maximum possible score=48).
[0528] Pressure pain thresholds. Pressure pain detection thresholds
(PPDTs) were measured at the dorsum of the second finger (middle
phalanx) and at a fixed point at the anterior part of the temporal
muscle as previously described (Bendtsen et al. 1996b).
Measurements were performed at the non-dominant side. The PPDT was
defined as the pressure at which the sensation changed from
pressure alone to pain. The subject indicated that the pain
threshold was reached by pressing a handheld button. The algometer
display was thereby Afrozen@ and the pressure was immediately
released. Each threshold was calculated as the mean of five
consecutive determinations performed with intervals of
approximately 30 seconds.
[0529] Data Analysis and Statistics
[0530] Results are presented as means SDs. For each of the
variables, the sum of the differences between the pre-treatment
value and each of the post-treatment values was calculated in order
to obtain a summary measure of effect for each treatment (Matthews
et al. 1990). The summary scores calculated for active treatment
and placebo were compared by use of the Wilcoxon Signed Ranks test
Within each treatment pretreatment values were compared with values
at 60 and 120 minutes post dosing by use of the Wilcoxon Signed
Ranks test Five percent was accepted as level of significance.
[0531] Results
[0532] Muscle hardness. The summary scores of muscle hardness of
the trapezius muscle was reduced significantly more following
treatment with 1 compared with placebo (p=0.04) (FIG. 17). Compared
to baseline, hardness was significantly reduced at 60 and 120
minutes after treatment with L-NMMA (p=0.04 and p<0.05,
respectively). There alas no significant reduction in muscle
hardness at any time after treatment with placebo (Table
XVIII).
[0533] Tenderness. The summary of tenderness score tended to be
reduced more following treatment with L-NMMA than with placebo, but
the difference was not statistically significant (p=0.11) (FIG.
18). However, compared to baseline TTS was significantly reduced at
60 and 120 minutes after treatment with L-NMMA compared with
pretreatment values (p=0.007 and p=0.008, respectively). There was
no significant reduction in TTS at any time after treatment pith
placebo (Table XVIII).
[0534] Pressure pain thresholds. There was no significant
difference between PPDTs recorded during treatment with L-NMMA and
placebo (finger: p=0.78 and temporal region: p=0.77). There were
also no changes in PPDTs at 60 and 120 minutes after treatment with
L-NMMA compared with pre-treatment values neither in the finger nor
in the temporal region (Table XVIII). Compared to baseline PPDT
decreased significantly in the finger (p=0.04), but not in the
temporal region following treatment with placebo (Table XVIII).
[0535] Pain intensity. Pain intensity was significantly more
reduced following treatment with L-NMMA than following treatment
with placebo (FIG. 19) as previously reported (Ashina et al.
1998a). Pain scores were significantly reduced at each time point
after treatment with L-NMMA, while there was no significant
reduction in pain intensity at any time point after treatment with
placebo (FIG. 19).
[0536] Discussion
[0537] In the present study, chronic tension-type headache was used
as a model for chronic myofascial pain, since nociception from
myofascial tissues probably plays an important role in the
pathophysiology of chronic tension-type headache. Thus, several
studies have consistently reported increased myofascial tenderness
as the most prominent abnormal finding in patients with chronic
tension-type headache (Langemark and Olesen 1987; Jensen et al.
1993; Jensen et al. 1998; Bendtsen et al. 1996b; Lipchik et al.
1997; Ashina et al. 1998b). A further support for myofascial
involvement is the recent findings of increased muscle hardness
(Sakai et al. 1995) and a positive correlation between muscle
hardness and tenderness in chronic tension-type headache (Ashina et
al. 1998b). The mechanisms contributing to the increased tenderness
and muscle hardness are unknown. Recently it has been suggested
that the increased tenderness in patients with chronic tension-type
headache and fibromyalgia may be due to central sensitization of
spinal dorsal horn neurons induced by prolonged nociceptive input
from myofascial tissues (Bendtsen et al. 1996a, 1997; Jensen et al.
1998). An investigation of myofascial tenderness and muscle
hardness in patients with chronic tension-type headache may
therefore contribute to our understanding of myofascial pain.
[0538] Animal experiments have suggested that NO is an important
transmitter in pain pathways of the spinal cord and that
sensitization of these pathways may be caused by or associated with
activation of NOS and the generation of NO (Haley, et al, 1992;
Meller et al. 1992; Meller and Gebhart 1993). In support for this,
it has recently been shown in animal models of persistent pain that
NOS inhibitors reduce spinal dorsal horn sensitization induced by
continues painful input from the periphery (Meller et al. 1994;
Roche et al. 1996; Mao et al. 1997). In addition, we have recently
demonstrated that NOS inhibition has an analgesic effect in
patients with chronic myofascial pain (Ashina et al. 1998a). In the
latter study we found that headache intensity was significantly
reduced during treatment with L-NMMA compared with placebo. The
present study provides important information about the mechanisms
of the antinociceptive action of NOS inhibition in chronic
myofascial pain. We found that both muscle hardness and tenderness
were significantly reduced at each time point after treatment with
L-NMMA, while there was no significant reduction in muscle hardness
or tenderness at any time after treatment with placebo. Although
the tenderness was significantly reduced, the reduction of
tenderness compared to placebo was not significant. This may be due
to lack of statistical power. The muscle hardness was significantly
reduced following treatment with L-NMMA compared to placebo.
Although statistically significant, the reduction of hardness was
very small. This is understandable because the increased hardness
is a rather stable feature (Ashina et al. 1998c) which is not easy
to change in an acute experiment. Similar arguments apply to
myofascial tenderness (Jensen et al. 1998). Long term treatment
could perhaps result in larger changes. The importance of the
present results lies in the proof of concept not in the magnitude
of the effect. The pressure pain detection thresholds in the finger
and temporal region were largely unchanged following treatment with
L-NMMA This indicates that L-NMMA did not significantly alter
general pain sensitivity. The questions are what mechanisms leading
to the increased muscle hardness and tenderness; how L-NMMA
modulates muscle hardness and tenderness; and whether the effects
of L-NMMA observed in the present study are due to an action in
muscle or in the CNS? It has been shown that the central
neuroplastic changes may increase the drive to motor neurons both
at the supraspinal and the segmental level (Woolf 1983). In this
way it is possible that sustained muscle contraction due to
increased hypersensitivity in CNS contributes to increased muscle
hardness and tenderness in chronic tension-type headache. This is
supported by recent findings of increased tenderness and muscle
activity in patients with chronic tension-type headache was found
not only on days with headache but also on days without headache
(Lipchik et al. 1997; Ashina et al. 1998b; Jensen et al. 1998).
Furthermore, muscle hardness recorded in patients on days with
headache did not differ from hardness recorded on days without
headache (Ashina et al. submitted 1998b). Collectively, these
results indicate that permanently altered muscle hardness,
tenderness and muscle activity may reflect an increased input from
myofascial nociceptors with subsequent sensitization of second
order neurons. L-NMMA inhibits all three types of NOS (endothelial
NOS, neuronal NOS and inducible NOS) (Southan and Szabo 1996) and
rich sources of nNOS are present not only in nervous tissue but
also in all striated muscles of mammals (Grozdanovic et al. 1995).
In addition to nNOS, skeletal muscles also contain eNOS. Recent
study has demonstrated that NO has important physiological
functions in skeletal muscles such as promoting relaxation and
modulating increases in contraction (Kobzik et al. 1994).
Interestingly, contractile function of muscles was enhanced by
blockers of NO synthase Kobzik et al. 1994). Because of this
inverse correlation between contractile function and nNOS activity,
one could expect that L-NMMA will induce the contraction of muscle
with subsequent increase of muscle hardness and tenderness.
However, in the present study we observed the reduction of muscle
hardness and tenderness following treatment with L-NMMA. Thus, the
effects of L-NMMA observed in the present study may be due to
reduction of sensitization of second order neurons receiving input
from myofascial tissues and locating at the level of the spinal
dorsal horn/trigeminal nucleus.
[0539] The increased muscle hardness and tenderness may reflect a
tissue oedema or metabolic alterations due to microcirculatory
disturbance (Henriksson et al. 1993). It is possible that L-NMMA
acts directly in myofascial tissues or nociceptors located in such
tissues. Thus, the ability of NOS inhibitors to cause
vasoconstriction (Rees et al. 1990) may prevent inflammatory
mediators and algogenic substances involved in hardness and
tenderness from reaching their site of action (Haley et al. 1992).
In addition, it has been demonstrated that NOS inhibitors have
antinociceptive effect after peripheral administration (Haley et
al. 1992; Kindgren-Milles and Arndt 1996; Nakamura et al. 1996).
However, the exact role of NO in the periphery is still far from
understood, and additional research is needed to clarify whether NO
may activate or sensitize peripheral nociceptors. The
antinociceptive effect of NOS inhibition might also result from
non-specific effects elicited by L-NMMA, such as changes in blood
pressure and pulse rate. Mean arterial blood pressure and pulse
rate were continuously monitored in the present study. We found
that the peak increase in mean arterial blood pressure (12%) and
maximum decrease in pulse rate (16%) occurred 15 and 10 minutes
respectively after treatment with L-NMMA. The difference in the
mean arterial blood pressure and pulse rate between L-NMMA and
placebo disappeared 60 minutes after start of infusion (Ashina et
al. 1998a). In contrast, the antinociceptive effect on headache
intensity and the reduction of muscle hardness and tenderness
lasted at least 120 minutes after start of infusion. It therefore
seems unlikely that the observed effects of L-NMMA were caused by
hypertensive effects of the agent. In conclusion, the present study
indicates that the NOS inhibitor L-NMMA elicits its antinociceptive
effect in myofascial pain by modulation of nociceptive information
from myofascial tissues. This antinociceptive effect is probably
caused by reduction of central sensitization at the level of the
spinal dorsal horn/trigeminal nucleus.
18TABLE XVII Clinical data on patients. Patients Number 16
Females/males 12/4 Age, years 39 (23-52) Headache frequency, days/4
weeks 22 (15-28) Mean values with range within parentheses.
[0540]
19TABLE XVIII Muscle hardness, Total Tenderness Score (TTS) and
pressure pain detection thresholds (PPDT) in the finger and the
temporal region (TR) recorded before and 60 and 120 minutes after
start of the infusion of L-NMMA or placebo. Baseline 60 minutes 120
minutes Muscle hardness L-NMMA 107" 17 101" 17* 101" 17* Placebo
106" 18 104" 17.sup.NS 105" 22.sup.NS TTS L-NMMA 18" 11 15" 11**
14" 11** Placebo 17" 12 16" 13.sup.NS 15" 13.sup.NS PPDT/finger
L-NMMA 455" 155 436" 129.sup.NS 449" 144.sup.NS Placebo 457" 141
435" 143.sup.NS 420" 130* PPDT/TR L-NMMA 279" 108 264" 86.sup.NS
277" 95.sup.NS Placebo 274" 104 271" 109.sup.NS 262" 95.sup.NS Mean
values (" SDs) are given. Post treatment values compared with
pre-treatment values (Wilcoxon Signed Ranks test). **= p <
0.0009, *= p < 0.05 and .sup.NS= not significant
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