U.S. patent application number 10/871847 was filed with the patent office on 2005-12-22 for methods and composition for treatment of migraine and symptoms thereof.
Invention is credited to Salehani, Foad.
Application Number | 20050282879 10/871847 |
Document ID | / |
Family ID | 35481479 |
Filed Date | 2005-12-22 |
United States Patent
Application |
20050282879 |
Kind Code |
A1 |
Salehani, Foad |
December 22, 2005 |
Methods and composition for treatment of migraine and symptoms
thereof
Abstract
Compositions, methods and kits are provided for the treatment of
migraines. The compositions, methods and kits include an effective
dose of trimethobenzamide and an ethanolamine antihistamine that,
when administered to an individual suffering from migraine
headaches, will alleviate symptoms associated with the migraine
headaches. Compositions, methods, and kits for the treatment of
migraines include pharmaceutical compositions of trimethobenzamide
and diphenhydramine.
Inventors: |
Salehani, Foad; (Beverly
Hills, CA) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
755 PAGE MILL RD
PALO ALTO
CA
94304-1018
US
|
Family ID: |
35481479 |
Appl. No.: |
10/871847 |
Filed: |
June 17, 2004 |
Current U.S.
Class: |
514/400 ;
514/649 |
Current CPC
Class: |
A61K 31/137 20130101;
A61P 25/06 20180101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/4172 20130101; A61K 31/4172 20130101; A61K 31/137
20130101 |
Class at
Publication: |
514/400 ;
514/649 |
International
Class: |
A61K 031/4172; A61K
031/137 |
Claims
What is claimed as new and desired to be protected by Letters
Patent of the United States is:
1. A composition consisting essentially of a therapeutically
effective amount of trimethobenzamide and an ethanolamine
antihistamine.
2. The composition of claim 1, wherein the antihistamine is
doxylamine, diphenhydramine, bromodiphenhydramine, dimenhydrinate,
clemastine, bietanautine, carbinoxamine, diphenylpyraline,
embramine, medrylamine, moxastine, p-methyldiphenhydramine,
orphenadrine, phenyltoloxamine, or setastine.
3. The composition of claim 2, wherein the antihistamine is
doxylamine, diphenhydramine, bromodiphenhydramine, dimenhydrinate,
bietanautine, carbinoxamine, embramine, medrylamine, moxastine,
p-methyldiphenhydramine- , orphenadrine, phenyltoloxamine, or
setastine.
4. The composition of claim 3, wherein the antihistamine is
doxylamine, diphenhydramine, bromodiphenhydramine, or
dimenhydrinate.
5. The composition of claim 4, wherein the antihistamine is
diphenhydramine.
6. The composition of claim 1, wherein the composition is
formulated for non-parenteral delivery.
7. The composition of claim 6, wherein the composition is
formulated for oral delivery.
8. The composition of claim 1, wherein the composition is
formulated for parenteral delivery.
9. The composition of claim 8, wherein parenteral delivery is via
intra venous delivery or injection.
10. The composition of claim 9, wherein the parenteral delivery is
via injection.
11. The composition of claim 5, wherein the composition is
formulated for injection or oral delivery.
12. A pharmaceutical composition consisting essentially of a
therapeutically effective amount of trimethobenzamide and an
ethanolamine antihistamine, wherein the pharmaceutical composition
further comprises one or more pharmaceutically acceptable
excipients, adjuvants, diluents or stabilizers.
13. The pharmaceutical composition of claim 12, wherein the
antihistamine is doxylamine, diphenhydramine, bromodiphenhydramine,
dimenhydrinate, clemastine, bietanautine, carbinoxamine,
diphenylpyraline, embramine, medrylamine, moxastine,
p-methyldiphenhydramine, orphenadrine, phenyltoloxamine, or
setastine.
14. The pharmaceutical composition of claim 13, wherein the
antihistamine is doxylamine, diphenhydramine, bromodiphenhydramine,
dimenhydrinate, bietanautine, carbinoxamine, embramine,
medrylamine, moxastine, p-methyldiphenhydramine, orphenadrine,
phenyltoloxamine, or setastine.
15. The pharmaceutical composition of claim 14, wherein the
antihistamine is doxylamine, diphenhydramine, bromodiphenhydramine,
or dimenhydrinate.
16. The pharmaceutical composition of claim 15, wherein the
antihistamine is diphenhydramine.
17. The pharmaceutical composition of claim 12, wherein the
composition is formulated for non-parenteral delivery.
18. The composition of claim 17, wherein the composition is
formulated for oral delivery.
19. The pharmaceutical composition of claim 12, wherein the
composition is formulated for parenteral delivery.
20. The pharmaceutical composition of claim 19, wherein parenteral
delivery is via intra venous delivery or injection.
21. The pharmaceutical composition of claim 20, wherein the
parenteral delivery is via injection.
22. The pharmaceutical composition of claim 16, wherein the
composition is formulated for injection or oral delivery.
23. A composition comprising a therapeutically effective amount of
trimethobenzamide and diphenhydramine.
24. The composition of claim 23, wherein the composition is
formulated for non-parenteral delivery.
25. The composition of claim 24, wherein the composition is
formulated for oral delivery.
26. The composition of claim 23, wherein the composition is
formulated for parenteral delivery.
27. The composition of claim 26, wherein parenteral delivery is via
intra venous delivery or injection.
28. The composition of claim 27, wherein the parenteral delivery is
via injection.
29. A pharmaceutical composition comprising a therapeutically
effective amount of trimethobenzamide and diphenhydramine, wherein
the pharmaceutical composition further comprises one or more
pharmaceutically acceptable excipients, adjuvants, diluents or
stabilizers.
30. The pharmaceutical composition of claim 29, wherein the
composition is formulated for non-parenteral delivery.
31. The pharmaceutical composition of claim 30, wherein the
composition is formulated for oral delivery.
32. The pharmaceutical composition of claim 29, wherein the
composition is formulated for parenteral delivery.
33. The pharmaceutical composition of claim 32, wherein parenteral
delivery is via intra venous delivery or injection.
34. The pharmaceutical composition of claim 33, wherein the
parenteral delivery is via injection.
35. A method for the treatment of migraines comprising
administering to an individual in need thereof a unit dose of a
composition consisting essentially of trimethobenzamide and an
ethanolamine antihistamine.
36. The method of claim 35, wherein the method further comprises
the administration of an additional unit dose after a period of
time.
37. The method of claim 36, wherein the period of time is at least
one month.
38. The method of claim 35, wherein treatment is prophylactic and
wherein the unit dose is administered about one time per month.
39. The method of claim 35, wherein the antihistamine is
doxylamine, diphenhydramine, bromodiphenhydramine, dimenhydrinate,
clemastine, bietanautine, carbinoxamine, diphenylpyraline,
embramine, medrylamine, moxastine, p-methyldiphenhydramine,
orphenadrine, phenyltoloxamine, or setastine.
40. The method of claim 39, wherein the antihistamine is
doxylamine, diphenhydramine, bromodiphenhydramine, dimenhydrinate,
bietanautine, carbinoxamine, embramine, medrylamine, moxastine,
p-methyldiphenhydramine- , orphenadrine, phenyltoloxamine, or
setastine.
41. The method of claim 40, wherein the antihistamine is
doxylamine, diphenhydramine, bromodiphenhydramine, or
dimenhydrinate.
42. The method of claim 41, wherein the antihistamine is
diphenhydramine.
43. The method of claim 35, wherein the composition is formulated
for non-parenteral delivery.
44. The method of claim 43, wherein the composition is formulated
for oral delivery.
45. The method of claim 35, wherein the composition is formulated
for parenteral delivery.
46. The method of claim 45 wherein parenteral delivery is via intra
venous delivery or injection.
47. The method of claim 46, wherein the parenteral delivery is via
injection.
48. The method of claim 42, wherein the composition is formulated
for injection or oral delivery.
49. The method of any one of claims 35, 42, 43 or 45, wherein the
composition is a pharmaceutical composition further comprising one
or more pharmaceutically acceptable excipients, adjuvants, diluents
or stabilizers.
50. A method for the treatment of migraines comprising
administering to an individual in need thereof a unit dose of a
composition comprising trimethobenzamide and diphenhydramine.
51. The method of claim 50, wherein the method further comprises
the administration of an additional unit dose after a period of
time.
52. The method of claim 51, wherein the period of time is at least
one month.
53. The method of claim 50, wherein treatment is prophylactic and
wherein the unit dose is administered about one time per month.
54. The method of claim 50, wherein the composition is formulated
for non-parenteral delivery.
55. The method of claim 54, wherein the composition is formulated
for oral delivery.
56. The method of claim 50, wherein the composition is formulated
for parenteral delivery.
57. The method of claim 56 wherein parenteral delivery is via intra
venous delivery or injection.
58. The method of claim 57, wherein the parenteral delivery is via
injection.
59. The method of any one of claims 50, 54 or 56, wherein the
composition is a pharmaceutical composition further comprising one
or more pharmaceutically acceptable excipients, adjuvants, diluents
or stabilizers.
60. A kit for the treatment of migraines comprising a
pharmaceutical composition consisting essentially of a unit dose of
trimethobenzamide and an ethanolamine antihistamine, wherein the
pharmaceutical composition further comprises one or more
pharmaceutically acceptable excipients, adjuvants, diluents or
stabilizers.
61. The kit of claim 60, wherein the kit further comprises
instructions for use.
62. The kit of claim 61, wherein the pharmaceutical composition is
formulated for parenteral delivery.
63. The kit of claim 62, wherein the pharmaceutical composition is
formulated for injection and the kit further comprises a
syringe.
64. The kit of claim 62, wherein the pharmaceutical composition is
formulated for intra venous delivery.
65. The kit of claim 61, wherein the pharmaceutical composition is
formulated for non-parenteral delivery.
66. The kit of claim 65, wherein the pharmaceutical composition is
formulated for oral delivery.
67. The kit of any one of claims 60-66, wherein the unit dose of
trimethobenzamide and an ethanolamine antihistamine may be
formulated as a mixture or may be provided in separate dosage
forms, and wherein the kit may comprise one or more unit doses.
68. The kit of claim 67, wherein the unit dose of trimethobenzamide
and an ethanolamine antihistamine is formulated as a mixture.
69. A kit for the treatment of migraines comprising a
pharmaceutical composition comprising a unit dose of
trimethobenzamide and diphenhydramine, wherein the pharmaceutical
composition further comprises one or more pharmaceutically
acceptable excipients, adjuvants, diluents or stabilizers.
70. The kit of claim 69, wherein the kit further comprises
instructions for use.
71. The kit of claim 70, wherein the pharmaceutical composition is
formulated for parenteral delivery.
72. The kit of claim 71, wherein the pharmaceutical composition is
formulated for injection and the kit further comprises a
syringe.
73. The kit of claim 71, wherein the pharmaceutical composition is
formulated for intra venous delivery.
74. The kit of claim 70, wherein the pharmaceutical composition is
formulated for non-parenteral delivery.
75. The kit of claim 74, wherein the pharmaceutical composition is
formulated for oral delivery.
76. The kit of any one of claims 69-75, wherein the unit dose of
trimethobenzamide and dephenhydramine may be formulated as a
mixture or may be provided in separate dosage forms, and wherein
the kit may comprise one or more unit doses.
77. The kit of claim 76, wherein the unit dose of trimethobenzamide
and dephenhydramine is formulated as a mixture.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
REFERENCE TO A COMPACT DISK APPENDIX
[0003] Not applicable.
TECHNICAL FIELD
[0004] This invention relates to compositions for the treatment of
migraines, and also relates to methods for treatment of migraines.
This invention also relates to the compositions and methods for the
treatment of symptoms associated with migraines, including
headache, nausea, dizziness, etc.
BACKGROUND OF THE INVENTION
[0005] Approximately 28 million Americans are estimated to suffer
from migraine attacks, the majority of them women (20 million;
Lipton et al. 2001 Headache 41(7): 646-657), making this one of the
most prevalent disorders today, yet it has been reported that only
a minority of sufferers are diagnosed and receive appropriate
treatment (Silberstein et al., 2002 "Monograph: The State of
Migraine: Prevention and Treatment" ACCESS Medical Group,
Department of Continuing Medical Education, 3395 North Arlington
Heights Road, Suit A, Arlington Heights, Ill. 600004-1566; Diamond
2001 Postgraduate Medicine 109(1): 49-60: "A fresh look at migraine
therapy"; Morgan et al. "Migraine Headaches", 1998, University of
Wisconsin Hospitals and Clinics Authority, Madison, Wis.,
Department of Nursing UWH
#5355<www.texaschildneurology.com/migraine%2-
0Headaches.htm>).
[0006] Characterization of the Migraine Disorder
[0007] The disorder characterized as "migraine" is generally
considered a form of headache. However, migraine is a neurological
multifactorial syndrome, of which headache is only one of the many
ways the disease manifests itself. Migraines are characterized by
recurrent attacks of severe, pulsating and disabling headache,
vomiting, photo- and phonofobia and malaise, all of which generally
worsens with movement. In 20% of the patients additional transient
focal neurological (aura) symptoms may occur. The attacks occur in
two forms, migraine without aura (common migraine), which occurs in
75% of the patients and with aura (classic migraine), occur in
about 30% of the migraineurs. Both types however are experienced in
one third of the subjects (<http://en.wikipedia.org/wik-
i/Migraine>; U.S. Pat. No. 6,465,517).
[0008] While it is apparent that migraine and the disability
associated with severe migraine symptoms are a public health
problem, the exact causes and mechanisms are still widely debated,
which hampers treatment and diagnosis of the disorder. However,
generic factors might be involved in the disease. It has also been
suggested that patients may suffer from a defect in ion channels
and have a disturbed energy metabolism in brain and skeletal
muscle. These above described features are not observed with
ordinary headache such as for example tension headache (U.S. Pat.
No. 6,465,517). Empirical evidence has also suggested links between
hormone levels and migraine. Hormonal levels in menstruating women
are also implicated in the incidence of migraine.
[0009] In addition, certain comorbidities have also been observed
in migraine sufferers, where "comorbidity" refers to a
greater-than-coincidental association of two or more conditions in
the same person. Migraine has been associated with several
neurologic and psychological disorders, including epilepsy,
depression, anxiety disorders, stroke, bipolar disorder and
impaired cognition. Other comorbidities include irritable bowel
syndrome, asthma, and mitral valve prolapse (Diamond 2002).
Migraine associate with auras seem to be particularly linked to a
higher incidence of stroke.
[0010] The symptoms and their timing vary considerably among
migraine suffers, and to a lesser extent from one migraine attack
to the next. Symptoms may vary in severity and regularity of
occurrence as well as duration. Migraine can accompany, in some
cases, other types of headaches, for example, tension headaches.
Migraine often runs in families and can start in adolescence,
although some research indicates that it can start in early
childhood or even in utero. Silberstein et al., 2002 "Monograph:
The State of Migraine: Prevention and Treatment" ACCESS Medical
Group, Department of Continuing Medical Education, 3395 North
Arlington Heights Road, Suit A, Arlington Heights, Ill.
600004-1566; Diamond 2001 Postgraduate Medicine 109(1): 49-60: "A
fresh look at migraine therapy"; Morgan et al. "Migraine
Headaches", 1998, University of Wisconsin Hospitals and Clinics
Authority, Madison, Wis., Department of Nursing UWH
#5355<www.texaschildneurology.com/migraine%2-
0Headaches.htm>; <http://en.wikipedia.org/wiki/Migraine>;
U.S. Pat. No. 6,465,517).
[0011] Current Treatments
[0012] There are numerous regimens of suggested treatment for
migraine and the symptoms which are part of the migraine disorder.
However, to date, there does not appear to be a single treatment
(including prevention or prophylaxis) that is successful for the
majority of migraine sufferers. Additionally, treatment that has
proven effective in a particular migraine sufferer may not continue
to be successful, or may only be intermitently effective. The
current standard of care for migraines focuses on three major
areas: preventive drugs; avoidance of migraine triggers (e.g.,
particular foods, alcohol or other substances (e.g., paints,
perfumes, etc.), exposure to certain environmental factors, and
changes in sleep or lifestyle patterns, etc.); and/or drugs which
treat migraine or the symptoms thereof once a migraine has
developed (e.g., sumitriptan, analgesics, narcotic medications,
antipsychotic drugs, anti-emetics (e.g., compazine). Treatment
during migraine is often either ineffective, only partially
effective or the therapeutica agents are associated with
significant undesirable side effects, including one or more of:
hypotension, tiredness, increased weight, breathlessness,
dizziness, heaviness or pressure on the chest and arms, shortness
of breath, chest pain, nausea, muscle cramps, or peripheral
vasoconstriction; depending on the therapy of choice.
[0013] Imitrex.RTM. (sumitriptan) and related 5-hydroxytryptamine
(serotonin) receptor agonists are now available and are often
considered the therapy of choice for severe migraine that is
relatively infrequent. These serotonin receptor agonists are
effective and generally have few side effects when used
occasionally. Side effects usually consist of dizziness, heaviness
or pressure on the chest and arms, shortness of breath, and
sometimes chest pain. Triptans are contra-indicated for patients
with coronary artery disease. Some members of this family of drugs
are: sumatriptan, zolmitriptan, naratriptan, rizatriptan,
elitriptan. (http://en.wikipedia.org/wiki/Migraine>; U.S. Pat.
Nos. 6,465,517; 6,255,334; 5,872,145; 5,721,252.)
[0014] As described above and known to those of skill in the art, a
number of different therapies are available which may prevent or
alleviate migraine some of the time for some individuals, but
complete avoidance of the disease seems to be impossible and most
of the prescribed drugs are known for their undesired side-effects.
Certain beta-adrenoreceptor antagonists (propranolol, metoprolol,
atenolol) have been described as efficacious for prevention or
prophylaxis. However, beta-blockers have multiple side effects,
like hypotension, tiredness, increased weight and breathlessness.
For a number of years ergotamine or other ergot alkaloids were the
only drugs for the treatment of migraine. (See for example U.S.
Pat. No. 6,685,951.) However, they have low oral and rectal
bioavailablity and may cause nausea, muscle cramps, or peripheral
vasoconstriction. Further, calcium channel blockers, hormonal
manipulators, analgesics, and non-steroidal anti-inflammatory drugs
(NSAID's) are sometimes prescribed, but evidence for preventive
efficacy is rare. Numerous patents and references are available
detailing the current standard of care for migraine. See for
example: U.S. Pat. Nos. 6,479,551; 6,716,837; 6,635,639, 6,476,042;
6,402,678; 6,077,539; 6,380,242, 6,255,334; 6,503,884; 6,251,935;
4,443,464; 5,744,4872; 5,036,078, 5,538,959; U.S. Pat. App. No.
2003/0008892 A1 and references cited therein.
[0015] Given the prevalence of the disorder and the related adverse
effects on quality of life, productivity and medical costs,
migraine has been characterized as a public health crisis
(Silberstein et al., 2002, and references cited therein). In the
American Migraine Study II (Lipton et al. 2001 Headache 41(7):
646-657), results were reported indicating that the highest
incidence of migraine in women, the majority of sufferers, occurs
between the ages of 25 and 55, the most productive years for the
average working adult. Further, an increase in both severity and
frequency of attacks was observed for women in their 30s. These
statistics, along with the characteristics of migraine as a
disorder--painful, debilitating and resulting in the loss of
productivity in the workplace and participation with friends and
family--highlights the need for effective therapies for a broad
range of individuals. To date, there does not appear to be a drug
or regimen which can effectively treat a broad range of those
suffering from the pain and unpredictability associated with
migraine. As is apparent from the studies quoted above, and any of
the publicly available materials regarding migraines, e.g., public
health (e.g., <www.headaches.org>), university, "self-help"
websites, medical journals and continuing medical education
monographs, there is an urgent need for effective drugs and
treatment regimes to manage this disorder. (Silberstein et al.,
2002 "Monograph: The State of Migraine: Prevention and Treatment"
ACCESS Medical Group, Department of Continuing Medical Education,
3395 North Arlington Heights Road, Suit A, Arlington Heights, Ill.
600004-1566; Diamond 2001 Postgraduate Medicine 109(1): 49-60: "A
fresh look at migraine therapy"; Morgan et al. "Migraine
Headaches", 1998, University of Wisconsin Hospitals and Clinics
Authority, Madison, Wis., Department of Nursing UWH
#5355<www.texaschildneurology.com/migraine%20Headaches.htm>;
<http://en.wikipedia.org/wiki/Migraine>; U.S. Pat. Nos.
6,465,517; 6,479,551; 6,716,837; 6,635,639, 6,476,042; 6,402,678;
6,077,539; 6,380,242, 6,255,334; 6,503,884; 6,251,935;
4,443,464).
[0016] All references, patent, and patent applications cited herein
are hereby incorporated by reference in their entirety.
BRIEF SUMMARY OF THE INVENTION
[0017] The present invention relates to compositions, methods, and
kits for the treatment of migraine headaches. In one embodiment,
the invention provides a composition consisting essentially of a
therapeutically effective amount of trimethobenzamide and an
ethanolamine antihistamine. In certain embodiments, the
antihistamine is doxylamine, diphenhydramine, bromodiphenhydramine,
dimenhydrinate, clemastine, bietanautine, carbinoxamine,
diphenylpyraline, embramine, medrylamine, moxastine,
p-methyldiphenhydramine, orphenadrine, phenyltoloxamine, or
setastine. In certain embodiments, the antihistamine is doxylamine,
diphenhydramine, bromodiphenhydramine, dimenhydrinate,
bietanautine, carbinoxamine, embramine, medrylamine, moxastine,
p-methyldiphenhydramine, orphenadrine, phenyltoloxamine, or
setastine. In certain embodiments, the antihistamine is doxylamine,
diphenhydramine, bromodiphenhydramine, or dimenhydrinate. In
certain embodiments, the antihistamine is diphenhydramine. In
certain embodiments, the composition is formulated for
non-parenteral delivery, such as for oral delivery, or the
composition is formulated for parenteral delivery, such as via
intra venous delivery or via injection. In certain embodiments, the
composition is formulated for injection or oral delivery.
[0018] In one embodiment, the invention provides a pharmaceutical
composition consisting essentially of a therapeutically effective
amount of trimethobenzamide and an ethanolamine antihistamine,
wherein the pharmaceutical composition further comprises one or
more pharmaceutically acceptable excipients, adjuvants, diluents or
stabilizers. In certain embodiments, the antihistamine is
doxylamine, diphenhydramine, bromodiphenhydramine, dimenhydrinate,
clemastine, bietanautine, carbinoxamine, diphenylpyraline,
embramine, medrylamine, moxastine, p-methyldiphenhydramine,
orphenadrine, phenyltoloxamine, or setastine. In certain
embodiments, the antihistamine is doxylamine, diphenhydramine,
bromodiphenhydramine, dimenhydrinate, bietanautine, carbinoxamine,
embramine, medrylamine, moxastine, p-methyldiphenhydramine,
orphenadrine, phenyltoloxamine, or setastine. In certain
embodiments, the antihistamine is doxylamine, diphenhydramine,
bromodiphenhydramine, or dimenhydrinate. In certain embodiments,
the antihistamine is diphenhydramine. In certain embodiments, the
composition is formulated for non-parenteral delivery, such as for
oral delivery, or the composition is formulated for parenteral
delivery, such as via intra venous delivery or via injection. In
certain embodiments, the composition is formulated for injection or
oral delivery.
[0019] In one embodiment, the invention provides a composition
comprising a therapeutically effective amount of trimethobenzamide
and diphenhydramine. In certain embodiments, the composition is
formulated for non-parenteral delivery. In certain embodiments, the
composition is formulated for oral delivery. In certain
embodiments, the composition is formulated for parenteral delivery,
such as via intra venous delivery or via injection. In certain
embodiments, the composition is formulated for injection.
[0020] In one embodiment, the invention provides a pharmaceutical
composition comprising a therapeutically effective amount of
trimethobenzamide and diphenhydramine, wherein the pharmaceutical
composition further comprises one or more pharmaceutically
acceptable excipients, adjuvants, diluents or stabilizers. In
certain embodiments, the composition is formulated for
non-parenteral delivery. In certain embodiments, the composition is
formulated for oral delivery. In certain embodiments, the
composition is formulated for parenteral delivery, such as via
intra venous delivery or via injection. In certain embodiments, the
composition is formulated for injection.
[0021] In one embodiment, the invention provides a method for the
treatment of migraines comprising administering to an individual in
need thereof a unit dose of a composition consisting essentially of
trimethobenzamide and an ethanolamine antihistamine. In certain
embodiments, the method further comprises the administration of an
additional unit dose after a period of time, such as after at least
one month. In certain embodiments, the method comprises a
prophylactic treatment, wherein the unit dose is administered about
one time per month. In certain embodiments of the method, the
antihistamine is doxylamine, diphenhydramine, bromodiphenhydramine,
dimenhydrinate, clemastine, bietanautine, carbinoxamine,
diphenylpyraline, embramine, medrylamine, moxastine,
p-methyldiphenhydramine, orphenadrine, phenyltoloxamine, or
setastine. In certain embodiments of the method, the antihistamine
is doxylamine, diphenhydramine, bromodiphenhydramine,
dimenhydrinate, bietanautine, carbinoxamine, embramine,
medrylamine, moxastine, p-methyldiphenhydramine, orphenadrine,
phenyltoloxamine, or setastine. In certain embodiments fo the
method, the antihistamine is doxylamine, diphenhydramine,
bromodiphenhydramine, or dimenhydrinate. In certain embodiments of
the method, the antihistamine is diphenhydramine. In certain
embodiments of the method, the composition is formulated for
non-parenteral delivery, such as oral delivery. In certain
embodiments of the method, the composition is formulated for
parenteral delivery, such as via intra venous delivery or via
injection. In certain embodiments of the method, the composition is
formulated for injection or oral delivery. In certain embodiments
of the invention, the composition is a pharmaceutical composition
further comprising one or more pharmaceutically acceptable
excipients, adjuvants, diluents or stabilizers.
[0022] In one embodiment, the invention provides a method for the
treatment of migraines comprising administering to an individual in
need thereof a unit dose of a composition comprising
trimethobenzamide and diphenhydramine. In certain embodiments, the
method further comprises the administration of an additional unit
dose after a period of time, such as after at least one month. In
certain embodiments, the method comprises a prophylactic treatment,
wherein the unit dose is administered about one time per month. In
certain embodiments of the method, the composition is formulated
for non-parenteral delivery. In certain embodiments of the method,
the composition is formulated for oral delivery. In certain
embodiments of the method, the composition is formulated for
parenteral delivery, such as via intra venous delivery or via
injection. In certain embodiments of the method, the composition is
formulated for injection. In certain embodiments of the method, the
composition is a pharmaceutical composition further comprising one
or more pharmaceutically acceptable excipients, adjuvants, diluents
or stabilizers.
[0023] In one embodiment, the invention provides a kit for the
treatment of migraines comprising a pharmaceutical composition
consisting essentially of a unit dose of trimethobenzamide and an
ethanolamine antihistamine, wherein the pharmaceutical composition
further comprises one or more pharmaceutically acceptable
excipients, adjuvants, diluents or stabilizers. In certain
embodiments, the kit further comprises instructions for use. In
certain embodiments of the kit, the pharmaceutical composition is
formulated for parenteral delivery. In certain embodiments of the
kit, the pharmaceutical composition is formulated for injection and
the kit further comprises a syringe.
[0024] In certain embodiments of the kit, the pharmaceutical
composition is formulated for intra venous delivery. In certain
embodiments of the kit, the pharmaceutical composition is
formulated for non-parenteral delivery, such as for oral delivery.
In certain embodiments of the kit, the unit dose of
trimethobenzamide and an ethanolamine antihistamine may be
formulated as a mixture or may be provided in separate dosage
forms, and wherein the kit may comprise one or more unit doses. In
certain embodiments of the kit, the unit dose of trimethobenzamide
and an ethanolamine antihistamine is formulated as a mixture.
[0025] In one embodiment, the invention provides a kit for the
treatment of migraines comprising a pharmaceutical composition
comprising a unit dose of trimethobenzamide and diphenhydramine,
wherein the pharmaceutical composition further comprises one or
more pharmaceutically acceptable excipients, adjuvants, diluents or
stabilizers. In certain embodiments, the kit further comprises
instructions for use. In certain embodiments of the kit, the
pharmaceutical composition is formulated for parenteral delivery.
In certain embodiments of the kit, the pharmaceutical composition
is formulated for injection and the kit further comprises a
syringe. In certain embodiments of the kit, the pharmaceutical
composition is formulated for intra venous delivery.
[0026] In certain embodiments of the kit, the pharmaceutical
composition is formulated for non-parenteral delivery, such as for
oral delivery. In certain embodiments of the kit, the unit dose of
trimethobenzamide and diphenhydramine may be formulated as a
mixture or may be provided in separate dosage forms, and wherein
the kit may comprise one or more unit doses. In certain embodiments
of the kit, the unit dose of trimethobenzamide and diphenhydramine
is formulated as a mixture.
DETAILED DESCRIPTION OF THE INVENTION
[0027] Provided herein are compositions and methods for the
treatment of migraine which are broadly and consistently effective
in relieving symptoms during a migraine attack and preventing
recurrence in habitual, longterm migraneurs. As described herein,
co-administration of trimethobenzamide and an ethanolamine
antihistamine, including the compositions described herein, is
therapeutically effective in reducing or eliminating the symptoms
of migraine within a short period of time following administration
and a single dosing is often effective for weeks, months or longer
in preventing the recurrence of migraine. In particular embodiments
of the invention are provided compositions comprising
trimethobenzamide and diphenhydramine and methods of use for
treating migraine therewith.
[0028] Migraine Treatment
[0029] As described above, "migraine" is a term used to describe a
multifactorial disorder whose exact cause is unknown and which, to
date, there has been little success in developing effective
therapuetics which are consistently efficacious for a wide range of
individuals in need thereof.
[0030] As used herein, the term "migraine" refers to all
classifications of migraines, and treatment of this disorder refers
to the treatment of the headache and/or other associated symptoms
of the disorder, including, but not limited to both "classical"
(with aura) and other migraines. These include all types of
migraines, including those referred to as menstrual migraines,
cluster headaches, hemiplegic migraines, basilar migraines, etc.
The compositions and methods described herein may also be used in
the treatment of pediatric migraine.
[0031] Additionally the compositions and their uses as described
herein are not limited by the triggering event which may proceed a
migraine. Examples of triggering events include, but are not
limited to, particular environmental factors (e.g., light, glare,
noise, odors (including perfume or other volatile compounds or
mixtures thereof (e.g., paint, household or industrial cleaners,
deodorizers, etc.), altitude changes, weather changes, weather
conditions, insecticides, second hand smoke, flickering light
(e.g., fluorescent, computer or video monitors, etc)), "allergic"
or other reactions to substances (e.g., foods (e.g., chocolate,
cheese, nuts, coffee, preserved meats, tomatoes, citrus fruits,
etc.), alcohol (e.g., red wine, spirits, etc.), chemicals (e.g.,
sulfites, etc.)), sweeteners (e.g., aspartame, etc.) preservatives,
flavor enhancers (e.g., MSG, etc.) drug interactions, etc.) or
physiological factors.
[0032] Physiological factors which may act as migraine triggers
include, but are not limited to, stress, exercise, hormonal
changes, birth control pills, too much or too little sleep, or a
change in sleep pattern, medicines (e.g., antibiotics (such as,
tetracycline, griseofulvin, etc.), antihypertensives (such as,
nifedipine, captopril, etc.), hormones (such as, oral
contraceptives, estrogens, etc.), histamine-2 blockers (such as,
cimetidine, ranitidine, etc.), vasodilators (such as,
nitroglycerin, isosorbide dinitrate, etc.) antihistamines (e.g.,
anticholinergics, aspirin or diuretics), hypoglycemia and missing
meals. Migraines may also be triggered by any other type of
headache. The methods and compositions herein are not intended for
use in the treatment of headaches or earaches associated with
sinusitis or earaches not associated with migraine.
[0033] The compositions and uses thereof described herein are
intended to treat migraine at any stage, including, but not limited
to, before occurrence (prevention, prophylaxis), after experience
of a triggering event but prior to occurrence of headache,
concomitant with or after the occurrence of a signalling symptom
associated with impending migraine (e.g., an aura) and during the
migraine attack.
[0034] The term "treatment" as used herein, and as well understood
in the art, is an approach for obtaining beneficial or desired
results, including clinical results. For purposes of this
invention, beneficial or desired clinical results can include one
or more, but are not limited to, alleviation or amelioration of one
or more symptoms, diminishment of extent of the disorder,
stabilized (i.e., not worsening) state of disorder, including
amelioration or palliation of the symptoms of the disorder, and
prevention or diminishment (whether partial or total) of
occurrences of migraine attacks. For each of the foregoing, the
amelioration or alleviation may pertain to a lessening in one or
more of the frequency, severity, duration or number of symptoms
experienced by an individual who suffers from migraines.
[0035] Migraine attacks are known to last from hours to days. It
has been reported that the typical migraine may last from hours to
up to 3 or 4 days. The actual migraine "attack" can be considered
to be that period during which the migraneur may be suffering the
pain associated with a migraine headache or any of the other
symptoms associated with a migraine (with or without concomitantly
experiencing the headache). The administration of the compositions
described herein may be at any point during the migraine attack, or
may be prior to the onset of the migraine attack, but after
experiencing a known or suspected triggering event (e.g., exposure
to known or suspected environmental factor, chemical, during
particular portions of the menstrual cycle, changes in altitude,
weather, etc.). The administration of the compositions described
herein may be prophylactic, i.e. prior to onset of migraine or
experiencing a known triggering event, and taken routinely, such as
monthly, to prevent recurring migraine attacks.
[0036] Symptoms associated with the migraine disorder and
experienced during some portion of the migraine attack may include,
but are not limited to, one or more of headache, naseau, aura
(e.g., visual changes such as bright flashing lights; flickering,
colored zigzag lines; blind spots; loss of vision off to one side,
a tingling sensation or numbness in the arms or legs, dizziness,
etc.), photophobia, phonophobia, or vomiting. Other symptoms
experienced may also include abdominal pain, particularly in
children.
[0037] Compositions
[0038] Trimethobenzamide
[0039] Trimethobenzamide (also referred to as
"trimethoxybenazamide") belongs to the class of anti-emetics known
as "substituted benzamides." The classification is based on the
similarity of the basic chemical structure. Other substituted
benzamides include metoclopramide, cisapride, sulpiride, tiapride,
and sultopride. However, while most substituted benzamides have
anti-emetic activity, the pharmacological profile, including side
effects and indication for use, across this structurally related
family differs significantly. For instance, cisapride was found to
be ineffective for migraine prevention, while Metoclopramide
exerted an antimigraine effect (Fanciullacci et al., "Dopamine
involvement in the migraine attack", Funct Neurol. 2000; 15 Suppl
3:171-81, Dept. of Internal Medicine, Headache Center, University
of Florence, Italy). Trimethobenzamide is further classified as an
anti-cholinergic therapeutic.
[0040] Trimethoxybenzamide is shown below in its hydrochloride salt
form, also referred to as
N-[p-[2-(dimethylamino)ethoxy]benzyl]-3,4,5-trimethox- ybenzamide
monohydrochloride. It is a commercially available pharmaceutical
known as Tigan.RTM.. Tigan.RTM. is generally administered via
injection for treatment of uncontrollable vomiting. When
administered alone, adverse reactions may include hypersensitivity,
Parkinson-like symptoms, hypotension, blood dyscrasias, diskinesia,
blurring of vision, coma, convulsions, depression, diarrhea,
disorientation, dizziness, drowsiness, headache, jaundice, muscle
cramps, and opisthotonos. Use of Tigan.RTM. is contraindicated in
children and individuals with known hypersensitivity to
trimethobenzamide. As used herein, the term "trimethoxybenzamide"
is taken to refer to the compound as shown below, including free
acid or any salt forms, solvates, or steroisomers thereof,
including mixtures of the foregoing. 1
[0041] Antihistamines
[0042] Antihistamines are compounds (drugs) which block the action
of histamine, and thus prevent or alleviate symptoms of an allergic
response. Most antihistamines selectively bind to, but do not
activate, either the H1 or H2 histamine receptors, or a combination
of both receptors. Compounds which bind to, but do not activate the
histamine receptors are also referred to as blocking or
antagonizing the histamine receptor, or, as histamine antagonists
or histamine inhibitors.
[0043] Some antihistamines are selective for either the H1 or H2
receptor. Antihistamines generally referred to as "classical
antihistamines" are generally attributed to block the H1 receptor.
H1 receptor antagonists block the H1 receptors in, for example,
bronchi, capillaries and certain other smooth muscles, and are used
to prevent or allay, for example, motion sickness, seasonal
rhinitis, allergic dermitis and, sometimes to induce somnolence.
Some H1 antihistamines also block H 1 receptors of the central
nervous system and are not as well understood.
[0044] Antihistamines are also broadly classed as central nervous
system (CNS) depressants, and certain antihistamines are
differentiated based upon their CNS side effect of being either
sedating (e.g., most H1 antagonists, chlopheniramine, etc.) or
non-sedating (e.g., loratadine).
[0045] Antihistamines are also classified according to the chemical
structure. For examples, classes of antihistamines include
piperazines (e.g., compazine, meclozine, hydroxyzine, etc.);
piperadines (e.g., azatadine, triprolidine, etc.); phenothiazines
(e.g., thorazine, temaril, etc.); tricyclic antidepressants (e.g.,
imipramine, doxopin, amitryptoline, etc.); ethylenediamines (e.g.,
PBZ, etc.); alkylamines (e.g., brompheniramine, chloropheniramine,
etc.); and others (e.g., terfenadine, astemizole, loratadine,
acrivastine, etc.). Ethanolamine antihistamines are another class
of antihistamines.
[0046] Ethanolamine Antihistamines
[0047] The ethanolamine antihistamines include, for example,
doxylamine (3475,
N,N-Dimethyl-2-[1-phenyl-1-(2-pyridinyl)ethoxy]ethanamine (Merck),
Dimethyl-[2-(1-phenyl-1-pyridin-2-yl-ethoxy)-ethyl]-amine
(Autonom)), diphenhydramine (3341,
2-Diphenylmethoxy-N,N-dimethylethanamine (Merck)
(2-Benzhydryloxy-ethyl)-dimethyl-amine (Autonom)),
bromodiphenhydramine (1402,
2-[(4-Bromophenyl)phenylmethoxy]-N,N-dimethylethaneamine (Merck),
{2-[(4-Bromo-phenyl)-phenyl-methoxy]-ethyl}-dimethyl-amine
(Autonom)), dimenhydrinate (3231,
2-(benzhydryloxy)-N,N-dimethylethylamine 8-chlorotheophyllinate or
diphenhydramine 8-chlorotheophyllinate (Merck)), bietanautine
(1210, 2-(benzhydryloxy)-N,N-dimethylethylamine bis(theophylline
7-acetate) (Merck)), carbinoxamine (1808,
2-[(4-Chlorophenyl)-2-pyridinylmethoxy]-N,N-dimethylethanamine
(Merck),
{2-[(4-Chloro-phenyl)-pyridin-2-yl-methoxy]-ethyl}-dimethyl-amine
(Autonom)), embramine (3588,
2-[1-(4-Bromophenyl)-1-phenylethoxy]-N,N-dim- ethylethanamine
(Merck), {2-[1-(4-Bromo-phenyl)-1-phenyl-ethoxy]-ethyl}-di-
methyl-amine (Autonom)), medrylamine, moxastine (6312,
2-(1,1-Diphenylethoxy)-N,N-dimethylethanamine (Merck),
[2-(1,1-Diphenyl-ethoxy)-ethyl]-dimethyl-amine (Autonom)),
p-methyldiphenhydramine (6078,
N,N-Dimethyl-2-[(4-methylphenyl)phenylmeth- oxy]ethanamine (Merck),
Dimethyl-[2-(phenyl-p-tolyl-methoxy)-ethyl]-amine (Autonom)),
orphenadrine (6945, N,N-Dimethyl-2-[(2-methylphenyl)phenylmet-
hoxy]ethanamine (Merck),
Dimethyl-[2-(phenyl-o-tolyl-methoxy)-ethyl]-amine (Autonom)),
phenyltoloxamine (7400, N,N-Dimethyl-2-[2-phenylmethyl)phenox-
y]ethanamine (Merck), [2-(2-Benzyl-phenoxy)-ethyl]-dimethyl-amine
(Autonom)), and setastine (8548,
1-[2-[1-(4-Chlorophenyl)-1-phenylethoxy]-
ethyl]hexahydro-1H-azepine (Merck),
1-{2-[1-(4-Chloro-phenyl)-1-phenyl-eth- oxy]-ethyl}-azepane
(Autonom)). Clemastine (2367, (2R)-2-[2-[(1R)-1-(4-Chl-
orophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine (Merck)) and
diphenylpyraline (3363, 4-(Diphenylmethoxy)-1-methylpiperidine
(Merck), 4-Benzhydryloxy-1-methyl-piperidine (Autonom)), are
closely related in activity to these ethanolamine antihistamines,
and while they are not strictly ethanolamines, are included in this
class of antihistamines. The numbers after each compound indicate
the monograph number from the thirteenth edition of the Merck
Index. The names are either from Autonom version 2.1 (Beilstein
Informationssysteme GmbH) module in ChemDraw Ultra version 6.0.2
(CambridgeSoft.com, Cambridge, Mass.), or the Merck Index. Most of
these ethanolamine antihistamines are commercially available
pharmaceutical compositons, for example diphenydramine is available
as Benadryl.RTM., dimenhydrinate is available as
Dramamine.RTM..
[0048] Like certain other antihistamines, many ethanolamine
antihistamines are known to also possess anticholinergic effects
which may contribute to drug interactions and/or side effects. For
example, possible side effects of diphenhydramine include
hypotension, headache, palpitations, tachycardia, extrasystoles,
sedation, sleepiness, dizziness, epigastric distress, and diarrhea.
It is contraindicated for use in neonates, premature infants, and
nursing mothers. Diphenhydramine may also be administered to
individuals who have adverse diskinesia side effects following
treatment with trimethobenzamide for uncontrolled vomiting (occurs
in approximately <2% of individuals treated). The
co-administration of diphenhydramine for treatment of migraine does
not appear to have been previously known. The structures of
exemplary ethanolamine antihistamines are shown below, and include
any salt forms, solvates, or stereoisomers thereof. 234
[0049] Anti-Migraine Composition
[0050] The present invention encompasses compositions consisting
essentially of a therapeutically effective amount of a substituted
benzamide antiemetic and an ethanolamine antihistamine. A
therapeutically effective amount is one that provides effective
treatment of migraines. For example, upon administration of a
therapeutically effective amount to an individual suffering from
migraines, the symptoms disappear within less than about 1 hour,
less than about 30 minutes, less than about 20 minutes, less than
about 15 minutes, less than about 10 minutes, or less than about 5
minutes following the administration of the therapeutically
effective amount.
[0051] In one embodiment of the invention, the substituted
benzamide antiemetic is trimethobenzamide and the ethanolamine
antihistamine is doxylamine, diphenhydramine, bromodiphenhydramine,
dimenhydrinate, clemastine, bietanautine, carbinoxamine,
diphenylpyraline, embramine, medrylamine, moxastine,
p-methyldiphenhydramine, orphenadrine, phenyltoloxamine, or
setastine. In another embodiment of the invention, the substituted
benzamide antiemetic is trimethobenzamide and the ethanolamine
antihistamine is doxylamine, diphenhydramine, bromodiphenhydramine,
dimenhydrinate, bietanautine, carbinoxamine, embramine,
medrylamine, moxastine, p-methyldiphenhydramine, orphenadrine,
phenyltoloxamine, or setastine. In another embodiment of the
invention, the substituted benzamide antiemetic is
trimethobenzamide and the ethanolamine antihistamine is doxylamine,
diphenhydramine, bromodiphenhydramine, or dimenhydrinate. In
another embodiment of the invention, the compositions consist
essentially of a therapeutically effective amount of
trimethobenzamide and diphenhydramine.
[0052] The invention also encompasses a composition comprising a
therapeutically effective amount of trimethobenzamide and
diphenhydramine, including any salt forms, solvates, or
steroisomers thereof.
[0053] All compositions discussed herein encompass pharmaceutical
compositions of the two compounds, whether formulated separately or
as a mixture. For example, a pharmaceutical composition of
trimethobenzamide and diphenydramine would include separate
formulations, e.g. separate capsules, tablets, gels, etc. for oral
delivery or separate solutions for parenteral delivery, such as
separate vials for injection. A pharmaceutical composition, for
example, of trimethobenzamide and diphenhydramine would also
include a mixture of the two in the same formulation, e.g. in one
capsule, tablet, gel, etc. for oral delivery or one solution for
parenteral delivery, such as one vial for injection. A mixture of
the compounds is any pharmaceutical composition comprising an
effective amount of the compounds, wherein the compounds may be
mixed at any point in the process of making the compounds and
formulating the pharmaceutical composition.
[0054] In another aspect of the invention, the therapeutically
active anti-migraine composition, and methods of using the
composition, encompass where the moieties of the trimethobenzamide
and ethanolamine antihistamine are combined in a single
therapeutically active anti-migraine compound.
[0055] Such therapeutically active compounds include where the
trimethobenzamide and ethanolamine antihistamine are linked via a
frangible linker or a non-frangible linker, as known to those of
skill in the art. In certain embodiments, the anti-migraine
compound comprises the trimethobenzamide and diphenhydramine
moieties. The moieties so incorporated into the anti-migraine
compound may include the entire trimethobenzamide or ethanolamine
antihistamine molecule (absent atoms as necessary at the linking
site), or the portion of the trimethobenzamide or ethanolamine
antihistamine necessary for therapeutic activity.
[0056] Methods of Migraine Treatment
[0057] Migraines are effectively treated by the co-administration
of trimethobenzamide and an ethanolamine antihistamine. A
therapeutically effective amount of trimethobenzamide and an
ethanolamine antihistamine may be co-administered via parenteral or
non-parenteral delivery. Co-administration is defined as
administration of the therapeutically effective amount of each
compound simultaneously, or within a certain period of time. For
example, the compounds may be formulated as a mixture that is
administered, as separate formulations administered simultaneously,
or as separate formulations administered within a time period, such
as within less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or
30 minutes of each other, wherein either compound can be
administered first.
[0058] The compounds can be formulated for parenteral delivery,
such as intra venous (IV), intra muscular (IM) injection, or intra
peritoneal (IP) injection, or for non-parenteral delivery, such as
oral (e.g. tablet, capsule, gel, etc.), topical (e.g., transdermal,
etc.), nasal, inhaler, or suppository. The term "injection" can
refer to both IM and IP delivery. When administered separately, the
trimethobenzamide can be formulated for parenteral delivery or
non-parenteral delivery and the ethanolamine antihistamine can be
formulated independently for parenteral delivery or non-parenteral
delivery. Any combination of delivery of a therapeutically
effective amount may be co-administered, such as parenteral
delivery of both compounds, non-parenteral delivery of both
compounds, parenteral delivery of trimethobenzamide with
non-parenteral delivery of the ethanolamine antihistamine, or
non-parenteral delivery of trimethobenzamide with parenteral
delivery of the ethanolamine antihistamine. In certain embodiments,
the therapeutically effective amounts of trimethobenzamide and the
ethanolamine antihistamine are formulated as a mixture for
parenteral (e.g., injection, etc.) or non-parenteral (e.g., oral,
etc.) delivery. In particular embodiments the trimethobenzamide and
ethanolamine antihistamine are administered orally, either with a
single tablet or capsule, or simultaneously with separate tablets
or capsules. In other embodiments, the trimethobenzamide and
ethanolamine antihistamine are administered via injection (e.g.,
IM, IP), ether as a mixture or via separate injections.
[0059] In certain embodiments of the above described methods, the
ethanolamine antihistamine is doxylamine, diphenhydramine,
bromodiphenhydramine, dimenhydrinate, clemastine, bietanautine,
carbinoxamine, diphenylpyraline, embramine, medrylamine, moxastine,
p-methyldiphenhydramine, orphenadrine, phenyltoloxamine, or
setastine. In certain embodiments of the above described methods,
the ethanolamine antihistamine is doxylamine, diphenhydramine,
bromodiphenhydramine, dimenhydrinate, bietanautine, carbinoxamine,
embramine, medrylamine, moxastine, p-methyldiphenhydramine,
orphenadrine, phenyltoloxamine, or setastine. In certain
embodiments of the above described methods, the ethanolamine
antihistamine is doxylamine, diphenhydramine, bromodiphenhydramine,
or dimenhydrinate. In certain embodiments of the above described
methods, the ethanolamine antihistamine is diphenhydramine.
[0060] The therapeutically effective amount of trimethobenzamide is
one that, in combination with a therapeutically effective amount of
an ethanolamine antihistamine, provides effective treatment of
migraines, for example where upon administration to an individual
suffering from migraines, the symptoms disappear within less than
about 1 hour, less than about 30 minutes, less than about 20
minutes, less than about 15 minutes, less than about 10 minutes, or
less than about 5 minutes after the administration of the
therapeutically effective amount. Similarly, the therapeutically
effective amount of an ethanolamine antihistamine is one that, in
combination with a therapeutically effective amount of
trimethobenzamide, provides effective treatment of migraines, for
example where upon administration to an individual suffering from
migraines, the symptoms disappear within less than about 1 hour,
less than about 30 minutes, less than about 20 minutes, less than
about 15 minutes, less than about 10 minutes, or less than about 5
minutes after the administration of the therapeutically effective
amount.
[0061] A unit dose for the treatment of migraines is the combined
therapeutically effective amounts of trimethobenzamide and an
ethanolamine antihistamine, whether formulated as a mixture or
separately. When a therapeutically effective amount of
trimethobenzamide and an ethanolamine antihistamine is formulated
as a mixture, the therapeutically effective amount of the mixture
is a unit dose of the composition comprising trimethobenzamide and
an ethanolamine antihistamine. When the unit dose is not a
formulated mixture of the trimethobenzamide and the ethanolamine
antihistamine, i.e. when the therapeutically effective amounts of
trimethobenzamide and an ethanolamine antihistamine are formulated
and administered independently (including simultaneously), a unit
dose is the therapeutically effective amounts of each compound
co-administered (simultaneously or within a certain time period of
each other). When co-administration is not simultaneous, the
symptoms disappear within less than about 1 hour, less than about
30 minutes, less than about 20 minutes, less than about 15 minutes,
less than about 10 minutes, or less than about 5 minutes after the
administration of the last compound administered.
[0062] In one embodiment, the method for treatment of migraines
comprises co-administering to an individual in need thereof a unit
dose of trimethobenzamide and an ethanolamine antihistamine, or
administering a unit dose of a composition consisting essentially
of trimethobenzamide and an ethanolamine antihistamine. The method
may further comprise co-administering one or more additional unit
doses of trimethobenzamide and an ethanolamine antihistamine, or
administering one or more additional unit doses of a composition
consisting essentially of trimethobenzamide and an ethanolamine
antihistamine, after a period of time from the initial dose, such
as after at least a month. The method of treatment may be
prophylactic, wherein an individual who suffers from recurring
migraines may be administered unit doses of trimethobenzamide and
an ethanolamine antihistamine, or unit doses of a composition
consisting essentially of trimethobenzamide and an ethanolamine
antihistamine routinely, for example about once a month.
[0063] In certain embodiments of the methods described herein, the
ethanolamine antihistamine is doxylamine, diphenhydramine,
bromodiphenhydramine, dimenhydrinate, clemastine, bietanautine,
carbinoxamine, diphenylpyraline, embramine, medrylamine, moxastine,
p-methyldiphenhydramine, orphenadrine, phenyltoloxamine, or
setastine. In certain embodiments of the methods described herein,
the ethanolamine antihistamine is doxylamine, diphenhydramine,
bromodiphenhydramine, dimenhydrinate, bietanautine, carbinoxamine,
embramine, medrylamine, moxastine, p-methyldiphenhydramine,
orphenadrine, phenyltoloxamine, or setastine. In certain
embodiments of the methods described herein, the ethanolamine
antihistamine is doxylamine, diphenhydramine, bromodiphenhydramine,
or dimenhydrinate. In certain embodiments of the methods described
herein, the ethanolamine antihistamine is diphenhydramine.
[0064] The methods described herein are for the treatment of
migraines specifically, and are not intended to treat non-migraine
headaches. Non-migraine headaches include tension (i.e. stress)
headaches and secondary headaches, i.e. headaches that are caused
by other conditions, such as sinusitis, tooth ache, ear infections,
etc. For example, compositions and methods described herein have
been used on individuals suffering from sinusitis or ear infections
with no effect on the pain associated with these conditions. While
not limiting the compositions or methods of the invention to any
particular mechanism, it is possible that the combination of
trimethobenzamide and ethanolamine antihistamine acts to block the
sympathetic nerve, which alleviates migraine headaches and all
symptoms associated with migraines.
[0065] Kits
[0066] The invention also provides kits for the treatment of
migraines comprising a pharmaceutical composition consisting
essentially of at least one unit dose of a substituted benzamide
antiemetic and an ethanolamine antihistamine, wherein the
pharmaceutical composition further comprises acceptable excipients,
adjuvants, diluents, or stabilizers, wherein a kit includes
instructions for use in the treatment of migraines. The unit dose
of the substituted benzamide antiemetic and the ethanolamine
antihistamine may be formulated separately or as a mixture. These
can be formulated with suitable excipients, adjuvants, diluents or
stabilizers for either parenteral (e.g. IV, injection (IM or IP))
or non-parenteral (e.g., oral, topical, nasal, inhaler, or
suppository) delivery. For example, a unit dose may comprise a
formulated mixture of the substituted benzamide antiemetic and the
ethanolamine antihistamine. Alternatively, the unit dose may
comprise the substituted benzamide antiemetic formulation separate
from the ethanolamine antihistamine formulation.
[0067] The co-administration of these formulations in accordance
with the instructions for use provides the desired therapeutic
treatment of migraines. When the unit dose consists essentially of
separate formulations, these may be independently formulated for
parenteral or non-parenteral delivery. For example, the substituted
benzamide antiemetic may be formulated for parenteral delivery
while the ethanolamine antihistamine may be formulated for
non-parenteral delivery. For ease of administration, both compounds
may be formulated for the same type of delivery, including where
the substituted benzamide antiemetic and the ethanolamine
antihistamine are formulated as a mixture.
[0068] In one embodiment of the invention, the substituted
benzamide antiemetic and the ethanolamine antihistamine are
formulated for parenteral delivery, in some cases as a mixture. In
such embodiments, the kit further comprises at least one syringe
for delivery of the dose. The formulation for parenteral delivery
may comprise a multi-dose formulation, wherein a new syringe is
used to remove a unit dose from the multi-dose formulation. In one
embodiment, the substituted benzamide antiemetic and the
ethanolamine antihistamine are formulated for non-parenteral
delivery, such as oral delivery. In certain embodiments, a unit
dose is formulated as a mixture of the substituted benzamide
antiemetic and the ethanolamine antihistamine for oral delivery,
such as a capsule or pill.
[0069] In certain embodiments, the substituted benzamide antiemetic
is trimethobenzamide and the ethanolamine antihistamine is
doxylamine, diphenhydramine, bromodiphenhydramine, dimenhydrinate,
clemastine, bietanautine, carbinoxamine, diphenylpyraline,
embramine, medrylamine, moxastine, p-methyldiphenhydramine,
orphenadrine, phenyltoloxamine, or setastine. In another
embodiment, the substituted benzamide antiemetic is
trimethobenzamide and the ethanolamine antihistamine is doxylamine,
diphenhydramine, bromodiphenhydramine, dimenhydrinate,
bietanautine, carbinoxamine, embramine, medrylamine, moxastine,
p-methyldiphenhydramine- , orphenadrine, phenyltoloxamine, or
setastine. In another embodiment, the substituted benzamide
antiemetic is trimethobenzamide and the ethanolamine antihistamine
is doxylamine, diphenhydramine, bromodiphenhydramine, or
dimenhydrinate. In certain embodiments, the substituted benzamide
antiemetic is trimethobenzamide and the ethanolamine antihistamine
is diphenhydramine.
[0070] In another embodiment, the invention provides kits for the
treatment of migraines comprising a pharmaceutical composition
consisting essentially of at least one unit dose of
trimethobenzamide and an ethanolamine antihistamine, wherein the
pharmaceutical composition further comprises acceptable excipients,
adjuvants, diluents, or stabilizers, and wherein the kit includes
instructions for use for treatment of migraine. The unit dose of
the trimethobenzamide and the ethanolamine antihistamine may be
formulated separately or as a mixture. These can be formulated with
suitable excipients, adjuvants, diluents or stabilizers for either
parenteral (e.g., IV, injection (IM or IP)) or non-parenteral
(e.g., oral, topical, nasal, inhaler, or suppository) delivery. In
another embodiment, the ethanolamine antihistamine is doxylamine,
diphenhydramine, bromodiphenhydramine, dimenhydrinate, clemastine,
bietanautine, carbinoxamine, diphenylpyraline, embramine,
medrylamine, moxastine, p-methyldiphenhydramine, orphenadrine,
phenyltoloxamine, or setastine. In another embodiment, the
ethanolamine antihistamine is doxylamine, diphenhydramine,
bromodiphenhydramine, dimenhydrinate, bietanautine, carbinoxamine,
embramine, medrylamine, moxastine, p-methyldiphenhydramine,
orphenadrine, phenyltoloxamine, or setastine. In another
embodiment, the ethanolamine antihistamine is doxylamine,
diphenhydramine, bromodiphenhydramine, or dimenhydrinate. In
certain embodiments, the ethanolamine antihistamine is
diphenhydramine.
[0071] In certain embodiments, the invention provides kits for the
treatment of migraines comprising a pharmaceutical composition
comprising at least one unit dose of trimethobenzamide and
diphenhydramine, wherein the pharmaceutical composition further
comprises acceptable excipients, adjuvants, diluents, or
stabilizers, wherein a kit includes instructions for use for the
treatment of migraines. The unit dose of trimethobenzamide and
diphenhydramine may be formulated separately or as a mixture. These
can be formulated with suitable excipients, adjuvants, diluents or
stabilizers for either parenteral (e.g., W, injection (IM or IP))
or non-parenteral (e.g., oral, topical, nasal, inhaler, or
suppository) delivery.
[0072] The unit dose may comprise a formulated mixture of
trimethobenzamide and diphenhydramine. Alternatively, the unit dose
may comprise a trimethobenzamide formulation separate from a
diphenhydramine formulation. The co-administration of these
formulations provides the desired therapeutic treatment of
migraines (i.e. unit dose). When the unit dose comprises separate
formulations, these may be independently formulated for parenteral
or non-parenteral delivery. For example, the trimethobenzamide may
be formulated for parenteral delivery while the diphenhydramine may
be formulated for non-parenteral delivery. For ease of
administration, both compounds may be formulated for the same type
of delivery, where the trimethobenzamide and the diphenhydramine
may be formulated as a mixture.
[0073] In one embodiment of the invention, the trimethobenzamide
and the diphenhydramine are formulated for parenteral delivery, and
may be formulated as a mixture. In such embodiments, the kit may
further comprise at least one syringe for delivery of a unit dose.
In certain embodiments, the mixture is formulated for IM delivery.
The formulation for parenteral delivery may comprise a multi-dose
formulation, wherein a new syringe is used to remove a unit dose
from the multi-dose formulation. In one embodiment, the
trimethobenzamide and the diphenhydramine are formulated for
non-parenteral delivery, such as oral delivery. In certain
embodiments, a unit dose is formulated as a mixture of
trimethoxybenzamide and diphenhydramine for oral delivery, such as
a capsule, gel or tablet.
[0074] Formulations and Dosage
[0075] The compositions discussed herein can be generally
administered as pharmaceutical compositions, wherein the
pharmaceutical compositions are formulated by methods well know to
those skilled in the art. The pharmaceutical compositions are
manufacture with acceptable excipients, adjuvants, diluents or
stabilizers to provide the appropriate formulation for the desired
administration, such as parenteral (e.g., Iv, injection (IM or IP))
or non-parenteral (e.g., oral, topical, nasal, inhaler or
suppository). As the compounds used in the methods and compositions
discussed herein are generally commercially available, the suitable
formulations are readily known to those skilled in the art. For
example, the compositions and methods discussed herein comprising
trimethobenzamide and diphenhydramine were prepared from
commercially available pharmaceutical compositions. A commercially
available composition of trimethobenzamide for oral delivery, such
as a capsule, may contain 250 mg to 300 mg of trimethobenzamide
hydrochloride as well as inactive ingredients such as D&C Red
No. 28, FD&C Blue No. 1, lactose, magnesium stearate, starch,
and titanium oxide. A commercially available composition of
trimethoxybenzamide in single dose ampules for injection may
contain 200 mg trimethobenzamide hydrochloride in 2 mL, along with
inactive ingredients such as 0.2% methyl and propyl parabens
(preservatives), 1 mg sodium citrate and 0.4 mg citric acid as
buffers, pH adjusted to approximately 5.0 with sodium hydroxide.
Similarly, multi-dose vials for injection may contain 100 mg/mL
trimethobenzamide hydrochloride, along with inactive ingredients
such as 0.45% phenol (preservative) 0.5 mg/mL sodium citrate and
0.2 mg/mL citric acid as buffers, pH adjusted to approximately 5.0
with sodium hydroxide. Similarly, diphenhydramine is commercially
available as a composition for injection containing 50 mg/mL
diphenhydramine hydrochloride, adjusted to pH 5.0 or 6.0 with
either sodium hydroxide or hydrochloric acid, where multi-dose
vials may contain additional inactive ingredients, such as 0.1
mg/mL benzethonium chloride as a germicidal agent. Capsules are
also commercially available, typically containing 25 mg or 50 mg of
diphenhydramine hydrochloride.
[0076] While the trimethobenzamide and ethanolamine antihistamines
discussed herein are generally commercially available, such that
appropriate doses can be readily prepared from existing
pharmaceutical compositions, the compositions, methods and kits
discussed herein encompass any suitable pharmaceutical formulation
of the desired dose of compounds, either formulated as a mixture or
separately. Such formulations are known to those skilled in the
art, and examples of suitable excipients, adjuvants, diluents or
stabilizers can be found, for example, in Gennaro, ed., Remington's
The Science and Practice of Pharmacy, 20.sup.th edition, Lippincott
Williams &Wilkins.
[0077] The unit dose required for the compositions, methods and
kits discussed herein can be adjusted as necessary to suit the
individual being treated, for example adjusted to the weight, age
or general health of the individual, as is within the skill of a
medical practitioner. For a unit dose of trimethobenzamide and an
ethanolamine antihistamine such as diphenhydramine, dosage
formulated for either parenteral or non-parenteral delivery as
discussed herein, comprises trimethobenzamide in the range of
approximately 10 mg to 1000 mg, also approximately 25 mg to 500 mg,
also approximately 50 mg to 500 mg, also approximately 250 mg to
300 mg and diphenhydramine in the range of approximately 1 mg to
200 mg, also approximately 5 mg to 150 mg, also approximately 10 mg
to 100 mg, also approximately 25 to 50 mg. In certain embodiments,
the dose is formulated for oral delivery to an adult with 250 mg of
trimethobenzamide and 25 mg diphenhydramine. In certain
embodiments, an adult dose is formulated for injection with 200 mg
trimethobenzamide and 50 mg diphenhydramine in 3 mL solution for
injection. Trimethobenzamide is contraindicated in children under 7
years of age via injection or oral delivery. Children under 7 years
of age may be treated instead with a 100 mg suppository via the
rectum, administered with the ethanolamine antihistamine according
to the methods described herein. For the ethanolamine
antihistamines, pediatric dosages are calculated according to the
known dosing regimens according to the weight and age of the
individual for the particular antihistamine. For example, the
diphenhydramine pediatric dose for the claimed mixtures is 5
mg/kg/24 hours, where the dose is delivered over 24 hours in 3-4
doses.
[0078] The invention discussed herein further encompasses methods
of manufacturing a medicament for the treatment of migraine
headaches. The methods of manufacturing such medicaments are well
known to those skilled in the art. Such medicaments are embodied by
the compositions, methods and kits discussed herein.
[0079] The invention is further illustrated by the following
non-limiting examples.
EXAMPLES
Example 1
Treatment of Migraine Headache with a Single Injection of
Trimethobenzamide and Diphenhydramine
[0080] Individuals with a history of recurrent migraine headaches
were selected for treatment. The individuals were queried to assess
the symptoms relating to the migraine headaches. These symptoms
include pulsating or throbbing headache, photophobia or visual
disturbances (e.g. bright flashing lights; flickering, colored
zigzag lines; blind spots; loss of vision off to one side), earache
or noise disturbances (e.g. phonophobia; buzzing or ringing in
ears), nausea or vomiting, abdominal discomfort, limpness or
numbness in extremities, tingling (e.g. pins and needles) in
extremities, strange tastes or smells, dizziness, and excessive
sweating or irritability. Dosages of trimethobenzamide and
diphenhydramine were prepared from commercially available
preparations of Tigan.RTM. and Benadryl.RTM., respectively. A
single dose for injection contained 200 mg of trimethobenzamide in
2 mL mixed with 50 mg of diphenydramine in 1 mL. Injections were
given by intramuscular injection (Gluteus muscle) to 113
individuals (two individuals were enlisted but not treated), where
the dose delivered was adjusted according to body weight of the
individual. A single dose for delivery by mouth (oral delivery) was
prepared from commercially available capsules, containing 250 mg of
trimethobenzamide and 25 mg diphenydramine. The appropriate amount
was prepared according to individual body weights and given orally
to 5 individuals (individuals 70, 74, 78, 79, and 84 in Table
1).
[0081] All individuals showed reduction in symptoms within
approximately 10 minutes of injection or ingestion for all
individuals. All but 11 of the treated individuals were monitored
over time. In 3 of these 11 individuals, mild headaches were
reported approximately 7-10 days after treatment. However, there
was evidence of possible sinusitis for these individuals at that
time and they were not available for later follow up. It was
determined in 5 individuals (unrelated to this study) having
sinusitis without migraines that similar treatment with
trimethobenzamide and diphenhydramine does not provide significant
reduction in the headaches due to the sinusitis. Table 1 indicates
the response to treatment for the remaining 107 individuals
(includes 19 and 80, enlisted but not treated).
[0082] In all individuals, the migraine headache subsided and all
symptoms were alleviated. These results, along with the lack of
efficacy for treating sinusitis headache, suggest that the
trimethobenzamide and diphenhydramine treatment is uniquely and
specifically effective for migraine treatment. This is further
supported in that headaches did not recur in other than these three
individuals for up to 9 months, including those individuals who
suffered migraines more than 10 times a month in the 3 months prior
to treatment.
[0083] In some individuals, approximately 30% or less, some
drowsiness was observed. However, the side effects normally
associated with administration of either trimethobenzamide or
diphenhydramine alone were not observed in any of the individuals.
No adverse effects with regard to general health, or blood
pressure, were noted by any of the treated individuals who suffered
from migraines. Repeated administration of trimethobenzamide and
diphenhydramine to non-migraine individuals caused no discernible
effects with regard to blood pressure or general health. Overall,
these results suggest that administering trimethobenzamide and
diphenhydramine, either orally or by intra muscular injection, is a
safe and effective treatment for migraines.
1TABLE 1 Occurrence of migraine headaches pre and post treatment in
individuals treated with trimethobenzamide and diphenhydramine. All
doses were IM injection with the exception of those with (O) in the
dose column (oral dose). Pre treatment condition Post treatment
Individual Headaches Average Headaches # of # Sex Age per month
Severity* Duration Symptoms** per month Months*** doses 1 F 24 1-2
3 24 1-2-3-4-6 0 9 1 2 F 48 15-18 2.5 24 1-2-4 0 9 1 3 F 43 1 3 24
1-2-4-6 <<1**** 6 1 4 F 79 8 3 24 1-2-3-6-7 0 9 1 5 F 35 10
2.5 24 1-2-4 0 9.5 1 6 M 31 6 3 24 1-2-3-4 0 8.5 1 7 M 37 6 3 24
1-2-4-6 0 8.5 1 8 F 24 1 3 24 1-2-3-6 0 8.5 1 9 F 19 11 2.5 24
1-3-4 0 8.5 1 10 F 47 12 3 24 1-2-3-4 0 8.5 1 11 M 49 8 2.5 24
1-2-4-7 0 8.5 1 12 F 43 1 2 24 1-2 0 8.5 1 13 F 32 9 2 24 1-2-4 0
8.5 1 14 M 24 10 2.5 24 1-2-5-6 0 8 1 15 M 29 10 3 24 1-2-4 0 8 1
16 M 33 2 2.5 24 1-2 0 8 1 17 F 10 10 2.5 24 1-2-3-4 0 8 1 18 F 34
10 2.5 24 1-2-3-4-6 0 8 1 19 N/A 20 F 34 5 3 24 1-2-4-7 0 8 1 21 M
32 1 2.5 24 1 0 8 1 22 M 39 1 3 24 1-2 0 8 1 23 F 35 9 3 24
1-2-3-4-6 0 8 1 24 F 34 10 3 24 1-2-3-5 0 8 1 25 F 10 5 2.5 24
1-2-4 0 8 1 26 F 10 8 2.5 24 1-2-3-4 0 8 1 27 F 47 9 2.5 24
1-2-3-4-7 0 8 1 28 M 21 4 2.5 24 1-2-4 0 8 1 29 F 22 10 2.5 24
1-2-3-4-6 0 8 1 30 F 65 4 2.5 24 1-2-3 0 8 1 31 F 45 6 3 24 1-2-4 0
8 1 32 F 27 1 2.5 24 1-2 0 7 1 33 M 69 8 2.5 24 1-2-4-7 0 7 1 34 F
22 5 3 24 1-2-3-6 0 7 1 35 F 43 1 3 24 1-3 0 7 1 36 F 49 6 3 24
1-2-3 0 7 1 37 F 30 2 3 24 1-2-3 0 7 1 38 M 31 8 3 24 1-2-3-6 0 7 1
39 F 25 10 2.5 24 1-2-3-6-7 0 7 1 40 F 35 9 3 24 1-2-3-4-6 0 7 1 41
F 34 4 2.5 24 1-2-6-7 0 7 1 42 F 34 8 2.5 24 1-2-3-4-7 0 7 1 43 F
35 8 2.5 24 1-2-3-5-6 0 7 1 44 F 26 1 N/A 48 N/A 0 N/A 1 45 F 39 7
2.5 24 1-2-3 0 7 1 46 F 27 8 2.5 24 1-2-3 0 7 1 47 M 20 1 2.5 24
1-5 0 7 1 48 M 48 9 2.5 24 1-2-3-4 0 7 1 49 F 38 9 3 24 1-2-3-7 0 7
1 50 M 46 8 2.5 24 1-2-3-4 0 7 1 51 M 15 6 2.5 24 1-2-4-6 0 6 1 52
M 26 2 2.5 24 1-2 0 6 1 53 F 9 1 2.5 24 1-5 0 6 1 54 F 23 2 2.5 24
1-2 0 5 1 55 M 14 8 2.5 24 1-2-4-6-7 0 5 1 56 M 16 First Time 1 3
24 1-2-4 0 5 1 57 M 15 First Time 1 3 24 1-2-3 0 5 1 58 M 26 2 2.5
24 1-2-3 0 5 1 59 M 38 9 2.5 24 1-2-3-5 0 5 1 60 F 28 9 2.5 24
1-2-3-4 0 5 1 61 F 46 7 2.5 24 1-2-3-4 0 5 1 62 F 40 8 2.5 24
1-2-3-4-6 0 5 1 63 F 40 8 2.5 24 1-2-3-4 0 5 1 64 F 30 8 3 24
1-2-3-4-6 0 5 1 65 F 51 2 3 24 1-2-3 0 5 1 66 F 38 8 3 24 1-2-3-4 0
5 1 67 M 15 8 3 24 1-2-3-4-5 0 5 1 68 M 45 8 3 24 1-2-3-4 0 5 1 69
F 24 8 3 24 1-2-3-4 0 5 1 70 F 29 1 2.5 24 1- 0 5 1(O) 71 F 13 4
2.5 24 1-2 0 5 1 72 F 46 7 3 24 1-2-3-4 0 5 1 73 F 47 8 3 24
1-2-3-4-7 0 5 1 74 F 33 4 2.5 24 1-2-3-4 0 5 1(O) 75 F 35 8 3 24
1-2-3-4-5 0 5 1 76 M 64 8 2.5 24 1-2-3-4 0 5 1 77 M 33 6 2.5 24
1-2-3-4 0 5 1 78 F 52 8 2.5 24 1-2-3-4-6 0 5 1(O) 79 F 44 8 2.5 24
1-2-3-4 0 5 1(O) 80 N/A 81 M 40 8 2.5 24 1-2-3-4 0 5 1 82 F 19 8
2.5 24 1-2-3-4 0 5 1 83 F 57 5 2.5 24 1-2-3-5 0 5 1 84 F 35 4 3 24
1-2-3-4 0 5 1(O) 85 M 29 8 3 24 1-2-3-4-7 0 5 1 86 F 55 8 2.5 24
1-2-3-4 0 5 1 87 M 35 8 2.5 24 1-2-3-4 0 5 1 88 F 32 11 2.5 24
1-2-3-4-6-7 0 4 1 89 Constant 1-2-3 24 1-2-3-4-5- 0 4 1 6-7 90 F 40
4 2.5 24 1-2-3 0 4 1 91 F 38 Every Day 1-2-3 24 1-2-3-4 0 4 1 92 F
53 8 2.5 24 1-2-3-4 0 4 1 93 M 58 8 2.5 24 1-2-3-4 0 4 1 94 F 9 8
2.5 24 1-2-3-4-6 0 4 1 95 F 65 6 2.5 24 1-2-3-4 0 2 1 96 M 19 8 2.5
24 1-2-3-4-5 0 2 1 97 M 26 1 2.5 24 1-2-3-4 0 2 1 98 F 10 2 2.5 24
1-2-3 0 2 1 99 F 56 8 1-2-3 24 1-2-3-4-7 0 2 1 100 F 37 4 2.5 24
1-2-3-4 0 2 1 101 F 33 2 3 24 1-2-3-4-5-6 0 2 1 102 F 14 1 3 24
1-2-3-4 0 2 1 103 F 13 7 2.5 24 1-2-3-4-5 0 2 1 104 F 13 8 2.5 24
1-2-3-4 0 2 1 105 F 27 8 2.5 24 1-2-3-4-5 0 1 1 106 F 19 8 2.5 24
1-2-3-4-5 0 1 1 107 M 31 6 2.5 24 1-2-3-4-6 0 1 1 108 M 41 8 2.5 24
1-2-3-4 0 1 1 109 F 23 4 2.5 24 1-2-3-4 0 2 wks 1 *Severity 1 =
mild, 2 = moderate, 3 = severe **Symptoms 1 = throbbing headache, 2
= photophobia or visual disturbance 3 = earache or noise
disturbance, 4 = nausea or vomiting, 5 = abdominal discomfort, 6 =
limpness in extremities, 7 = pins and needles in extremities.
***Months without a headache following a single treatment. ****This
individual had one headache in 9 months (at 6 months).
* * * * *
References