U.S. patent application number 16/984094 was filed with the patent office on 2020-11-19 for injection paradigm for administration of botulinum toxins.
The applicant listed for this patent is Allergan, Inc.. Invention is credited to Andrew M. Blumenfeld, Mitchell F. Brin.
Application Number | 20200360492 16/984094 |
Document ID | / |
Family ID | 1000004993665 |
Filed Date | 2020-11-19 |
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United States Patent
Application |
20200360492 |
Kind Code |
A1 |
Blumenfeld; Andrew M. ; et
al. |
November 19, 2020 |
INJECTION PARADIGM FOR ADMINISTRATION OF BOTULINUM TOXINS
Abstract
Disorders such as headaches can be treated by administration of
a botulinum toxin to a patient suffering therefrom, such as a
migraine headache. A combined a fixed site/fixed dose and an
optional follow the pain variable dosage and injection site
paradigm is disclosed for optimizing clinical effectiveness of
botulinum toxin administration for patients suffering headache,
particularly chronic migraine.
Inventors: |
Blumenfeld; Andrew M.; (Del
Mar, CA) ; Brin; Mitchell F.; (Newport Beach,
CA) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
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|
Family ID: |
1000004993665 |
Appl. No.: |
16/984094 |
Filed: |
August 3, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16173664 |
Oct 29, 2018 |
10729751 |
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16984094 |
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15067515 |
Mar 11, 2016 |
10111938 |
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16173664 |
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62132689 |
Mar 13, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C12Y 304/24069 20130101;
A61K 9/0019 20130101; A61K 38/4893 20130101 |
International
Class: |
A61K 38/48 20060101
A61K038/48; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method for treating or reducing the occurrence of a headache
in a patient in need thereof, the method comprising: local
administration of a botulinum neurotoxin to 31 fixed injection
sites across seven head and neck muscles, and optionally up to 8
additional injection sites into three specific muscles, wherein
these three muscles are subset of the seven head and neck muscles,
wherein the 31 fixed injection sites comprise the frontalis,
corrugator, procerus, occipitalis, temporalis, trapezius and
cervical paraspinal muscles; and wherein the administration is by
injection and comprises injecting superficially at a 90.degree.
angle into the corrugator muscles; thereby alleviating or reducing
the occurrence of the headache in the patient; to thereby treat or
reduce the occurrence of headache in the patient.
2. The method of claim 1, wherein the headache is a migraine
headache.
3. The method of claim 1, wherein the headache is a chronic
migraine headache.
4. The method of claim 1, wherein the headache is a medication
overuse (MOU) headache.
5. The method of claim 1, wherein the botulinum neurotoxin is
serotype A.
6. The method of claim 5, wherein the botulinum neurotoxin type A
is onabotulinumtoxinA,
7. The method of claim 1, wherein the total amount of botulinum
toxin administered is from about 155 units to about 195 units of
onabotulinumtoxinA.
8. The method of claim 5, wherein the botulinum neurotoxin type A
is abobotulinumtoxinA.
9. The method of claim 1, wherein the botulinum neurotoxin is a
pure botulinum toxin.
10. The method of claim 9, wherein the pure botulinum neurotoxin is
incobotulinumtoxinA.
11. The method of claim 1, wherein the botulinum neurotoxin is
serotype B.
12. The method of claim 11, wherein the botulinum neurotoxin is
type E.
13. A method for alleviating or reducing the occurrence of a
headache in a patient in need thereof, the method comprises:
localizing one or more administration targets; isolating the one or
more administration targets; wherein the isolating step isolates
the one or more administration targets from an adjacent area;
administering a therapeutically effective amount of a clostridial
toxin to the one or more isolated administration targets; wherein
the one or more administration targets comprises the frontalis,
corrugator, procerus, occipitalis, temporalis, trapezius and
cervical paraspinal muscles; wherein the administrating step is by
injection and wherein the administering step comprises injecting
superficially at a 90.degree. angle into the corrugator muscles;
thereby alleviating or reducing the occurrence of the headache in
the patient.
14. The method of claim 13, wherein the headache is a migraine
headache.
15. The method of claim 13, wherein the headache is a chronic
migraine headache.
16. The method of claim 13, wherein the headache is a medication
overuse (MOU) headache.
17. The method of claim 13, wherein the clostridial toxin is a
botulinum toxin.
18. The method of claim 17, wherein the botulinum toxin is type
A.
19. The method of claim 18, wherein the botulinum neurotoxin type A
is onabotulinumtoxinA,
20. The method of claim 17, wherein the total amount of botulinum
toxin administered is from about 155 units to about 195 units of
onabotulinumtoxinA.
21. The method of claim 18, wherein the botulinum neurotoxin type A
is abobotulinumtoxinA.
22. The method of claim 5, wherein the botulinum neurotoxin is a
pure botulinum toxin.
23. The method of claim 17, wherein the pure botulinum neurotoxin
is incobotulinumtoxinA.
24. The method of claim 17, wherein the botulinum neurotoxin is
serotype B.
25. The method of claim 17, wherein the botulinum neurotoxin is
type E.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 16/173,664, filed Oct. 29, 2018, now U.S. Pat.
No. 10,729,751, which is a continuation application of U.S.
application Ser. No. 15/067,515, filed Mar. 11, 2016, now U.S. Pat.
No. 10,111,938, which claims the benefit of U.S. Provisional patent
application No. 62/132,689 filed Mar. 13, 2015 and may be related
to U.S. patent application Ser. No. 13/075,485 filed Mar. 30, 2011,
now U.S. Pat. No. 8,501,195, incorporated entirely by
reference.
FIELD
[0002] Embodiments of the present invention relate to the treatment
of various disorders, specifically to injection administration
protocols utilizing botulinum neurotoxins. In particular, the
present disclosure is directed to methods for improving
administration protocols for treatment of chronic migraine.
BACKGROUND
[0003] It is known that botulinum toxins can be utilized to treat a
variety of disorders. Examples include U.S. Pat. No. 5,714,468
(migraine) issued Feb. 3, 1998; Published U.S. Patent Application
No. 2005019132 (headache), Ser. No. 11/039,506, filed Jan. 18,
2005; Published U.S. Patent Application No. 20050191320 (medication
overuse headache), Ser. No. 10/789,180, filed Feb. 26, 2004; and
U.S. Pat. No. 7,811,587 (neuropsychiatric disorders), issued Oct.
12, 2010; all incorporated entirely by reference.
[0004] An example of a disorder treatable with botulinum toxins is
chronic migraine (CM), a disabling headache disorder, affecting
1.3% to 2.4% of the general population and considered the most
common type of primary chronic daily headache in the United States.
CM is linked with suffering, disability, and medication overuse,
and only one third of CM patients use headache prophylactic
medication. Few headache preventive treatments have been
investigated for patients with CM. Thus there remains a need for
optimized and targeted methodologies to treat this malady in
particular, specific and useful injection and dosage paradigms for
utilizing botulinum toxins to treating CM.
SUMMARY
[0005] In one embodiment, the present invention teaches a method
for prophylactically treating a headache in a patient suffering
from chronic migraine headaches, the method comprises of local
administration of a clostridial neurotoxin, such as a botulinum
neurotoxin, to the frontalis, corrugator, procerus, occipitalis,
temporalis, trapezius and cervical paraspinal muscles of the
patient that suffers from the migraine headache, where the
botulinum neurotoxin is administered, to the frontalis at about
twenty units divided among four sites of injection, to the
corrugator at about ten units divided among two sites of injection;
to the procerus at about five units to one site of injection; to
the occipitalis at about thirty units divided among six sites of
injection to about forty units divided among eight sites of
injection; to the temporalis at about forty units divided among
eight sites of injection up to fifty units divided among ten sites
of injection; to the trapezius at about thirty units divided among
six sites of injection up to about fifty units divided among ten
sites of injection and to the cervical paraspinal muscles at about
twenty units divided among four sites of injection, and where the
botulinum neurotoxin is injected at 31 to 39 injection sites.
[0006] In some aspects, the present disclosure is directed to a
method for reducing the occurrence or alleviating a headache in a
patient suffering from chronic migraine headaches in a patient with
chronic migraine headaches, the method comprises: localizing one or
more administration target; isolating the one or more
administration target; administering a therapeutically effective
amount of a clostridial toxin to the isolated one or more
administration target; wherein the one or more administration
target comprises the frontalis, corrugator, procerus, occipitalis,
temporalis, trapezius and cervical paraspinal muscles; wherein the
administrating step is by injection and wherein the administering
step comprises limiting the injection to a defined tissue depth and
injection angle.
[0007] In some aspects, the present disclosure is directed to a
method for improving efficacy of headache treatment by a
clostridial toxin, such as a botulinum toxin, in a patient in need
thereof by minimizing adverse effects associated with clostridial
toxin administration, comprising localizing one or more
administration target, isolating the one or more administration
target, administering a therapeutically effective amount of the
clostridial toxin to the isolated one or more administration
target, wherein the administrating step is by injection and wherein
the administering step comprises limiting the injection to a
defined tissue depth and injection angle. In some embodiments, the
adverse effects include ptosis, neck pain/weakness, headache, or
combinations thereof. In some embodiments, the method further
comprises evaluating the patient for manifestations of adverse
effects prior to the locating, isolating and administrating steps.
In some embodiments, the method further comprises informing the
patient of the manifestation of adverse effects.
[0008] In some aspects, the present disclosure provides a method
for minimizing adverse effects associated with the administration
of a clostridial toxin, such as a botulinum toxin, for treating or
alleviating a headache in a patient with chronic migraine, the
method comprises locating one or more administration target,
isolating the one or more administration target, administering a
therapeutically effective amount of a clostridial toxin to the
isolated one or more administration target; wherein the
administrating step is by injection and wherein the administering
step comprises limiting the injection to a defined tissue depth and
injection angle. In some embodiments, the adverse effects comprise
ptosis, neck pain and/or weakness, headache, or combinations
thereof. In some embodiments, the present method further increases
patient compliance in timely getting re-treatment.
[0009] The present method also comprises assessing a patient for
pre-existing conditions prior to clostridial toxin treatment for
expectation management, selecting a suitable injection protocol to
minimize aggravating the pre-existing conditions or delaying the
clostridial toxin administration until the pre-existing conditions
improve. In some embodiments, the pre-existing conditions include
ptosis, neck pain or weakness, headache, or combinations
thereof.
[0010] The present method further comprises identifying a patient
who may be prone to having clostridial toxin administration
associated adverse effects, informing the patient of the risk of
adverse effects and selecting a suitable injection protocol to
prevent or minimize the risk of adverse effects. In some
embodiments, the adverse effects include ptosis, neck pain or
weakness, headache, or combinations thereof.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0011] The following drawings are presented to illustrate aspects
and features of embodiments of the present invention.
[0012] FIGS. 1A and 1B show the forehead anatomy, identifying one
or more administration target sites thereof in accordance with one
embodiment of the present injection paradigm;
[0013] FIGS. 2A-2D detail the anatomy, the administration sites,
and injection technique for administrating a botulinum toxin into
the corrugator muscle in accordance with aspects of the present
method;
[0014] FIGS. 3A-3D detail the anatomy, the administration site, and
injection technique for administrating a botulinum toxin into the
procerus muscle in accordance with aspects of the present
method;
[0015] FIGS. 4A-4D detail the anatomy, the administration sites,
and injection technique for administrating a botulinum toxin into
the frontalis muscle in accordance with aspects of the present
method;
[0016] FIGS. 5 A-5D show some examples of ptosis;
[0017] FIGS. 6A-6D detail the anatomy, the administration sites,
and injection technique for administrating a botulinum toxin into
the temporalis muscle in accordance with aspects of the present
method;
[0018] FIGS. 7A and 7B show the back-of-head and neck anatomy,
identifying one or more administration target sites thereof in
accordance with aspects of the present injection paradigm;
[0019] FIGS. 8A-8B show the administration sites and injection
technique for administrating a botulinum toxin into the occipitalis
muscle in accordance aspects of the present method;
[0020] FIGS. 9A-9B show the administration sites and injection
technique for administrating a botulinum toxin into the cervical
paraspinal muscle group in accordance aspects of the present
method;
[0021] FIGS. 10A-10B show the administration sites and injection
technique for administrating a botulinum toxin into the trapezius
muscle in accordance aspects of the present method; and
[0022] FIG. 11 is a diagram for assessing a patient's neck
pain/weakness in accordance with aspects of the present method.
DESCRIPTION
[0023] In certain embodiments, the dose of a botulinum toxin used
according to embodiments of the present invention is less than the
amount of botulinum toxin that would be used to paralyze a muscle,
because an intent of a method according to embodiments of the
present invention is not to paralyze a muscle but to reduce a pain
sensory output from sensory neurons located in or on a muscle, or
in or under the skin.
[0024] The following definitions apply herein:
[0025] "About" or "approximately" as used herein means within an
acceptable error range for the particular value as determined by
one of ordinary skill in the art, which will depend in part on how
the value is measured or determined, (i.e., the limitations of the
measurement system). For example, "about" can mean within 1 or more
than 1 standard deviations, per practice in the art. Where
particular values are described in the application and claims,
unless otherwise stated, the term "about" means within an
acceptable error range for the particular value.
[0026] "Administration", or "to administer" means the step of
giving (i.e. administering) a botulinum toxin to a subject, or
alternatively a subject receiving a pharmaceutical composition. The
present method can be performed via administration routes including
intramuscular, non-intramuscular, intra-articular, extra-articular,
peri-articular, intradermal, subcutaneous administration, topical
administration (using liquid, cream, gel or tablet formulation),
intrathecal administration, intraperitoneal administration,
intravenous infusion, implantation (for example, of a slow-release
device such as polymeric implant or miniosmotic pump), or
combinations thereof.
[0027] "Alleviating" means a reduction of an undesirable condition
or its symptoms, for example headache intensity or
headache-associated symptoms. Thus, alleviating includes some
reduction, significant reduction, near total reduction, and total
reduction. An alleviating effect may not appear clinically for
between 1 to 7 days after administration of a clostridial
derivative to a patient or sometime thereafter.
[0028] "Botulinum toxin" means a neurotoxin produced by Clostridium
botulinum, as well as a botulinum toxin (or the light chain or the
heavy chain thereof) made recombinantly by a non-Clostridial
species. The term "botulinum toxin", as used herein, encompasses
the botulinum toxin serotypes A, B, C.sub.1, D, E, F and G, and
their subtypes and any other types of subtypes thereof, or any
re-engineered proteins, analogs, derivatives, homologs, parts,
sub-parts, variants, or versions, in each case, of any of the
foregoing. "Botulinum toxin", as used herein, also encompasses a
"modified botulinum toxin". Further "botulinum toxin" as used
herein also encompasses a botulinum toxin complex, (for example,
the 300, 600 and 900 kDa complexes), as well as the neurotoxic
component of the botulinum toxin (150 kDa) that is unassociated
with the complex proteins.
[0029] "Clostridial derivative" refers to a molecule which contains
any part of a clostridial toxin. As used herein, the term
"clostridial derivative" encompasses native or recombinant
neurotoxins, recombinant modified toxins, fragments thereof, a
Targeted vesicular Exocytosis Modulator (TEM), or combinations
thereof.
[0030] "Clostridial toxin" refers to any toxin produced by a
Clostridial toxin strain that can execute the overall cellular
mechanism whereby a Clostridial toxin intoxicates a cell and
encompasses the binding of a Clostridial toxin to a low or high
affinity Clostridial toxin receptor, the internalization of the
toxin/receptor complex, the translocation of the Clostridial toxin
light chain into the cytoplasm and the enzymatic modification of a
Clostridial toxin substrate.
[0031] "Effective amount" as applied to the biologically active
ingredient means that amount of the ingredient which is generally
sufficient to induce a desired change in the subject.
[0032] "Implant" means a controlled release (e.g., pulsatile or
continuous) composition or drug delivery system. The implant can
be, for example, injected, inserted or implanted into a human
body.
[0033] "Local administration" means administration of a clostridial
derivative to or to the vicinity of a symptomatic site in a patient
by a non-systemic route. Thus, local administration excludes
systemic routes of administration, such as intravenous or oral
administration.
[0034] "Peripheral administration" means administration to a
location away from a symptomatic location, as opposed to a local
administration.
[0035] "TEMs", abbreviated for Targeted Exocytosis Modulators are
retargeted endopeptidases that direct the catalytic activity of the
light chain to specific types of neuronal cells or to target cells
that were not affected by botulinum toxins expanding the beneficial
clinical effect of inhibition of exocytosis in several human
diseases.
[0036] "Treating" or "treatment" means to prevent, reduce the
occurrence, alleviate, or to eliminate an undesirable condition,
for example headache, either temporarily or permanently.
[0037] "Therapeutically effective amount" refers to an amount
sufficient to achieve a desired therapeutic effect. The
therapeutically effective amount usually refers to the amount
administered per injection site per patient treatment session,
unless indicated otherwise.
[0038] Disclosed herein are embodiments of an administration
paradigm for botulinum neurotoxins. In some embodiments, the method
can include specific administration locations and dosage amounts of
a botulinum toxin to treat various disorders, including, for
example, chronic migraine (CM), Medication overuse (MOU),
neuropsychiatric (ND) disorders, and the like. In certain
embodiments of the invention, the disorder can be treated by
intramuscular administration of the toxin in specific amounts or
ranges of amounts to specific sites within the upper torso of the
patient. In certain embodiments, such sites can include, for
example, the head, the neck, one or both shoulders, in both the
anterior or posterior positions.
[0039] In some embodiments, the clostridial derivative of the
present method includes a native, recombinant clostridial toxin,
recombinant modified toxin, fragments thereof, targeted exocytosis
modulators (TEMs), or combinations thereof. In some embodiments,
the clostridial derivative is a botulinum toxin. In alternative
embodiments, the clostridial derivative is a TEM.
[0040] In some embodiments, the botulinum neurotoxin can be a
modified neurotoxin, that is a botulinum neurotoxin which has at
least one of its amino acids deleted, modified or replaced, as
compared to a native toxin, or the modified botulinum neurotoxin
can be a recombinant produced botulinum neurotoxin or a derivative
or fragment thereof. In certain embodiments, the modified toxin has
an altered cell targeting capability for a neuronal or non-neuronal
cell of interest. This altered capability is achieved by replacing
the naturally-occurring targeting domain of a botulinum toxin with
a targeting domain showing a selective binding activity for a
non-botulinum toxin receptor present in a non-botulinum toxin
target cell. Such modifications to a targeting domain result in a
modified toxin that is able to selectively bind to a non-botulinum
toxin receptor (target receptor) present on a non-botulinum toxin
target cell (re-targeted). A modified botulinum toxin with a
targeting activity for a non-botulinum toxin target cell can bind
to a receptor present on the non-botulinum toxin target cell,
translocate into the cytoplasm, and exert its proteolytic effect on
the SNARE complex of the target cell. In essence, a botulinum toxin
light chain comprising an enzymatic domain is intracellularly
delivered to any desired cell by selecting the appropriate
targeting domain.
[0041] In some embodiments, the clostridial derivative is a
botulinum toxin, which is selected from the group consisting of
botulinum toxin types A, B, C.sub.1, D, E, F and G. In one
embodiment, the clostridial derivative of the present method is a
botulinum toxin type A. The botulinum toxin can be a recombinant
botulinum neurotoxin, such as botulinum toxins produced by E.
coli.
[0042] The clostridial derivative, such as a botulinum toxin, for
use according to the present invention can be stored in
lyophilized, vacuum dried form in containers under vacuum pressure
or as stable liquids. Prior to lyophilization the botulinum toxin
can be combined with pharmaceutically acceptable excipients,
stabilizers and/or carriers, such as, for example, albumin, or the
like. Acceptable excipients or stabilizers include protein
excipients, such as albumin or gelatin, or the like, or non-protein
excipients, including poloxamers, saccharides, polyethylene glycol,
or the like. In embodiments containing albumin, the albumin can be,
for example, human serum albumin or recombinant human albumin, or
the like. The lyophilized material can be reconstituted with a
suitable liquid such as, for example, saline, water, or the like to
create a solution or composition containing the botulinum toxin to
be administered to the patient.
[0043] In some embodiments, to increase the resident time of the
clostridial derivative in the joint, the clostridial derivative is
provided in a controlled release system comprising a polymeric
matrix encapsulating the clostridial derivative, wherein fractional
amount of the clostridial derivative is released from the polymeric
matrix over a prolonged period of time in a controlled manner.
Controlled release neurotoxin systems have been disclosed for
example in U.S. Pat. Nos. 6,585,993; 6,585,993; 6,306,423 and
6,312,708, each of which is hereby incorporated by reference in its
entirety.
[0044] The therapeutically effective amount of the clostridial
derivative, for example a botulinum toxin, administered according
to the present method can vary according to the potency of the
toxin and particular characteristics of the condition being
treated, including its severity and other various patient variables
including size, weight, age, and responsiveness to therapy. The
potency of the toxin is expressed as a multiple of the LD.sub.50
value for the mouse, one unit (U) of toxin being defined as being
the equivalent amount of toxin that kills 50% of a group of 18 to
20 female Swiss-Webster mice, weighing about 20 grams each.
[0045] The therapeutically effective amount of the botulinum toxin
according to the present method can vary according to the potency
of a particular botulinum toxin, as commercially available
Botulinum toxin formulations do not have equivalent potency units.
For example, one unit of BOTOX.RTM. (onabotulinumtoxinA), a
botulinum toxin type A available from Allergan, Inc., has a potency
unit that is approximately equal to 3 to 5 units of DYSPORT.RTM.
(abobotulinumtoxinA), also a botulinum toxin type A available from
Ipsen Pharmaceuticals. In some embodiments, the amount of
abobotulinumtoxinA, (such as DYSPORT.RTM.), administered in the
present method is about three to four times the amount of
onabotulinumtoxinA (such as BOTOX.RTM.) administered, as
comparative studies have suggested that one unit of
onabotulinumtoxinA has a potency that is approximately equal to
three to four units of abobotulinumtoxinA. MYOBLOC.RTM., a
botulinum toxin type B available from Elan, has a much lower
potency unit relative to BOTOX.RTM.. In some embodiments, the
botulinum neurotoxin can be a pure toxin, devoid of complexing
proteins, such as XEOMIN.RTM. (incobotulinumtoxinA). One unit of
incobotulinumtoxinA has potency approximately equivalent to one
unit of onabotulinumtoxinA. The quantity of toxin administered and
the frequency of its administration will be at the discretion of
the physician responsible for the treatment and will be
commensurate with questions of safety and the effects produced by a
particular toxin formulation.
[0046] The amount of the botulinum toxin administered according to
a method within the scope of embodiments of the invention can vary
according to the particular characteristics of the pain being
treated, including its severity and other various patient variables
including size, weight, age, and responsiveness to therapy.
[0047] To guide the practitioner, typically, no less than about 1
unit and no more than about 25 units of a botulinum toxin type A
(such as BOTOX.RTM.) is administered per injection site per patient
treatment session. For a botulinum toxin type A such as
DYSPORT.RTM., no less than about 2 units and no more than about 25
units of the botulinum toxin type A are administered per injection
site, per patient treatment session. For a botulinum toxin type A
such as DYSPORT.RTM., no less than about 2 units and no more than
about 125 units of the botulinum toxin type A are administered per
injection site, per patient treatment session. For a botulinum
toxin type B such as MYOBLOC.RTM., no less than about 40 units and
no more than about 1500 units of the botulinum toxin type B are
administered per injection site, per patient treatment session.
[0048] Preferably, for BOTOX.RTM. no less than about 2 units and no
more about 20 units of a botulinum toxin type A are administered
per injection site per patient treatment session; for DYSPORT.RTM.
no less than about 4 units and no more than about 100 units are
administered per injection site per patient treatment session; and;
for MYOBLOC.RTM., no less than about 80 units and no more than
about 1000 units are administered per injection site, per patient
treatment session.
[0049] More preferably, for BOTOX.RTM. no less than about 5 units
and no more about 15 units of a botulinum toxin type A; for
DYSPORT.RTM. no less than about 20 units and no more than about 75
units, and; for MYOBLOC.RTM., no less than about 200 units and no
more than about 750 units are, respectively, administered per
injection site, per patient treatment session.
[0050] Generally, the total amount of BOTOX.RTM., DYSPORT.RTM. or
MYOBLOC.RTM., suitable for administration to a patient according to
the methods of the invention disclosed herein should not exceed
about 300 units, about 1,500 units or about 15,000 units
respectively, per treatment session.
[0051] The treatment effects of the botulinum toxin can persist for
between about 1 month and about 5 years.
[0052] Embodiments of the present disclosure provide a targeted,
fixed injection paradigm directed to a specific set of muscles with
a specific minimum number and volume of injections, and further
provides for the additional/optional administration of additional
botulinum toxin to specific site of selected muscles. In one
embodiment, the fixed dosage (that is, a minimum dosage amount in
accordance with the fixed amounts and locations specified in a
package insert or prescribing information) of botulinum toxin is
administered to the frontalis, corrugator, procerus, occipitalis,
temporalis, trapezius and cervical paraspinal muscles of a patient,
and further a variable amount of additional botulinum toxin can be
added to four or less of the seven head/neck areas such that the
total amount of botulinum toxin administered does not exceed a
maximum total dosage as indicated in the package insert or
prescribing information accompanying a botulinum toxin-containing
medicament.
[0053] The botulinum toxin can be selected from the group
consisting of botulinum toxin types A, B, C, D, E, F and G.
Botulinum toxin type A is a preferred botulinum toxin. The
botulinum toxin can be administered in an amount of between about 1
unit and about 3,000 units, or between about 2 units and about 2000
units, or between about 5 units and about 1000 units, or between
about 10 units and about 500 units, or between about 15 units and
about 250 units, or between about 20 units and about 150 units, or
between 25 units and about 100 units, or between about 30 units and
about 75 units, or between about 35 units and about 50 units, or
the like, and the alleviation of the symptoms can persist for
between about 1 month and about 5 years.
[0054] In one embodiment, a method is disclosed that utilizes a
dose and injection paradigm of 155 units of BOTOX.RTM. (typically
provided as 100 Units of Clostridium botulinum type A neurotoxin
complex, with 0.5 mg of human serum albumin, and 0.9 mg of sodium
chloride in a sterile, vacuum-dried state for reconstitution),
administered as 31 fixed-site, fixed-dose (5 units) injections, and
an optional 40 units in up to 8 additional injection sites using a
follow-the-pain regimen per treatment cycle (for up to 39 injection
sites and up to 195 units total). The total dose is divided across
7 head/neck muscles and is repeated every 12 weeks.
[0055] In an embodiment, a method for treating a migraine such as,
for example, CM, can encompass administration of a botulinum toxin
to 31 fixed injection sites across seven head/neck muscles.
Optionally, up to 8 additional injection sites into three specific
muscles, where these three muscles are subset of the above seven
head/neck muscles, are administered utilizing a follow-the pain
regimen to provide flexibility in the dose/muscle for the three
muscles, to address individual patient needs. In particular
embodiments, a minimum of 155 units of a botulinum toxin type A up
to about 195 units of a botulinum toxin type A, are administered in
accordance with a particular injection paradigm herein
disclosed.
[0056] In a specific embodiment, a method for treating CM comprises
the step of local administration of a botulinum neurotoxin to the
frontalis, corrugator, procerus, occipitalis, temporalis, trapezius
and cervical paraspinal muscles of the CM patient such that the
botulinum neurotoxin is administered to the frontalis at about
twenty units divided among four sites of injection, to the
corrugator at about ten units divided among two sites of injection,
to the procerus at about five units to one site of injection, to
the occipitalis at about thirty units divided among six sites of
injection to about forty units divided among eight sites of
injection; to the temporalis at about forty units divided among
eight sites of injection up to fifty units divided among ten sites
of injection, to the trapezius at about thirty units divided among
six sites of injection up to about fifty units divided among ten
sites of injection and to the cervical paraspinal muscles at about
twenty units divided among four sites of injection, such that the
total amount of botulinum neurotoxin administered is from about 155
units to about 195 units injected at from 31 to 39 injection sites,
respectively.
[0057] Embodiments of the invention can also be used as part of a
detoxification protocol whereby a patient who is being weaned off
acute pain medications is facilitated in this goal by concurrent
administration of a botulinum toxin. Additional embodiments of the
invention can be used to treat other chronic pain conditions,
including, for example, back pain, neuropathic pain, allodynia,
fibromyalgia, and the like.
[0058] In an embodiment, a method for treating an MOU patient can
encompass administration of a botulinum toxin to 31 fixed injection
sites across seven head/neck muscles. Optionally, up to 8
additional injection sites into three specific muscles, where these
three muscles are subset of the above seven head/neck muscles, are
administered utilizing a follow-the pain regimen to provide
flexibility in the dose/muscle for the three muscles, to address
individual patient needs. In particular embodiments, a minimum of
155 units of a botulinum toxin type A up to about 195 units of a
botulinum toxin type A, are administered in accordance with a
particular injection paradigm herein disclosed.
[0059] In a specific embodiment, a method for treating MOU
comprises the step of local administration of a botulinum
neurotoxin to the frontalis, corrugator, procerus, occipitalis,
temporalis, trapezius and cervical paraspinal muscles of the MOU
patient such that the botulinum neurotoxin is administered to the
frontalis at about twenty units divided among four sites of
injection, to the corrugator at about ten units divided among two
sites of injection, to the procerus at about five units to one site
of injection, to the occipitalis at about thirty units divided
among six sites of injection to about forty units divided among
eight sites of injection; to the temporalis at about forty units
divided among eight sites of injection up to fifty units divided
among ten sites of injection, to the trapezius at about thirty
units divided among six sites of injection up to about fifty units
divided among ten sites of injection and to the cervical paraspinal
muscles at about twenty units divided among four sites of
injection, such that the total amount of botulinum neurotoxin
administered is from about 155 units to about 195 units injected at
from 31 to 39 injection sites, respectively.
[0060] In an embodiment, a method for treating depression can
encompass administration of a botulinum toxin to 31 fixed injection
sites across seven head/neck muscles. Optionally, up to 8
additional injection sites into three specific muscles, where these
three muscles are subset of the above seven head/neck muscles, are
administered utilizing a follow-the pain regimen to provide
flexibility in the dose/muscle for the three muscles, to address
individual patient needs. In particular embodiments, a minimum of
155 units of a botulinum toxin type A up to about 195 units of a
botulinum toxin type A, are administered in accordance with a
particular injection paradigm herein disclosed.
[0061] In a specific embodiment, a method for treating
neuropsychiatric disorders (ND) such as, for example, depression,
in a patient in need thereof comprises the step of local
administration of a botulinum neurotoxin to the frontalis,
corrugator, procerus, occipitalis, temporalis, trapezius and
cervical paraspinal muscles of the patient such that the botulinum
neurotoxin is administered to the frontalis at about twenty units
divided among four sites of injection, to the corrugator at about
ten units divided among two sites of injection, to the procerus at
about five units to one site of injection, to the occipitalis at
about thirty units divided among six sites of injection to about
forty units divided among eight sites of injection; to the
temporalis at about forty units divided among eight sites of
injection up to fifty units divided among ten sites of injection,
to the trapezius at about thirty units divided among six sites of
injection up to about fifty units divided among ten sites of
injection and to the cervical paraspinal muscles at about twenty
units divided among four sites of injection, such that the total
amount of botulinum neurotoxin administered is from about 155 units
to about 195 units injected at from 31 to 39 injection sites,
respectively.
[0062] A method for treating or reducing the occurrence of a
headache in a patient with chronic migraine has been disclosed in
U.S. Pat. No. 8,501,195 to Turkel (hereinafter "the '195 patent" or
"the Turkel patent").
[0063] The '195 patent teaches a method for treating a headache in
a patient suffering from chronic migraine headaches, the method
essentially consisting of local administration of a botulinum
neurotoxin to the frontalis, corrugator, procerus, occipitalis,
temporalis, trapezius and cervical paraspinal muscles of the
patient that suffers from the migraine headache, where the
botulinum neurotoxin is administered, to the frontalis at about
twenty units divided among four sites of injection, to the
corrugator at about ten units divided among two sites of injection;
to the procerus at about five units to one site of injection; to
the occipitalis at about thirty units divided among six sites of
injection to about forty units divided among eight sites of
injection; to the temporalis at about forty units divided among
eight sites of injection up to fifty units divided among ten sites
of injection; to the trapezius at about thirty units divided among
six sites of injection up to about fifty units divided among ten
sites of injection and to the cervical paraspinal muscles at about
twenty units divided among four sites of injection, and where the
botulinum neurotoxin is injected at 31 to 39 injection sites.
[0064] The treatment taught by the '195 patent (hereinafter "the
'195 treatment" or "the Turkel treatment") has been practiced by
health care practitioners with high efficacy to treat or reduce the
occurrence of a headache in a patient with chronic migraine. In one
embodiment, the '195 patent teaches a method for treating chronic
migraine that utilizes a dose and injection paradigm of 155 units
of onabotulinumtoxinA, administered as 31 fixed-site, fixed-dose (5
units per) injections, and an optional 40 units in up to 8
additional injection sites using a follow-the-pain regimen per
treatment cycle (for up to 39 injection sites and up to 195 units
total). The total dose is divided across 7 head/neck muscles and is
repeated every 12 weeks.
[0065] The inventors of the present disclosure have discovered that
compliance to the treatment protocol of "a minimum dose of 155
units divided across 7 head/neck muscles and repeated every 12
weeks" is not optimally consistent due to adverse effects which
will be described herein. These adverse effects are attributable to
improper, imprecise or inaccurate implementation of the '195
protocol, which results in inadvertent and undesirable
administration of the botulinum toxin into an area adjacent to an
administration target site and/or too deep injections into
sensitive structures. Because of these adverse effects, selected
administration targets of the '195 treatment method may be
intentionally left out (such as for example some forehead and neck
muscles), which reduces the efficacy of the treatment method. These
adverse effects may also discourage patients from timely seeking
re-treatments. This delay further reduces the efficacy of the
headache treatment.
[0066] In some aspects, the present disclosure provides a method
for minimizing adverse effects associated with the administration
of a botulinum toxin for treating or alleviating a headache in a
patient with chronic migraine. In some embodiments, the adverse
effects comprise ptosis, neck pain and/or weakness, headache, or
combinations thereof. By minimizing the adverse effects associated
with administration of a botulinum toxin for treating or
alleviating a headache, the present method enhances efficacy of the
treatment and increases patient compliance in timely getting
re-treatment, which further increases efficacy treatment.
[0067] The present method also comprises assessing a patient for
pre-existing conditions prior to botulinum toxin treatment for
expectation management, selecting a suitable injection protocol to
minimize aggravating the pre-existing conditions or delaying the
botulinum toxin administration until the pre-existing conditions
improve. The pre-existing conditions include ptosis, neck pain or
weakness, headache, or combinations thereof.
[0068] The present method further comprises identifying a patient
who may be prone to having botulinum toxin administration
associated adverse effects, including ptosis, neck pain or
weakness, headache, or combination thereof, informing the patient
of the risk of adverse effects, selecting a suitable injection
protocol to prevent or minimize the risk of adverse effects, or
delay the botulinum toxin until the risk of adverse effects is
reduced.
[0069] To increase efficacy of botulinum toxin treatment for
headache/migraine and/or to minimize or eliminate the
above-identified adverse effects, the present method comprises
locating the administration target, isolating the administration
target so that the botulinum toxin is administered only to the
isolated target area without inadvertently impacting an adjacent
area; controlling the injection depth, and angling the needle as to
aim away from sensitive structures. In some embodiments, the
administration target includes the 7 head/neck muscles taught by
the '195 patent.
[0070] FIGS. 1A and 1B show the forehead anatomy, identifying the
location of exemplary administration target sites, including the
corrugator, procerus and frontalis muscles.
[0071] Corrugator:
[0072] In one exemplary embodiment, as shown schematically in FIG.
2C, the present method comprises local administration of a
botulinum neurotoxin to the corrugator at about ten units divided
among two sites of injection. As shown in FIG. 2A, the corrugator
muscle is located about 1.5 cm or .about.1 fingerbreadth above the
medial inferior edge of the orbital rim, a bony landmark which can
be used to localize the corrugator. This distance may vary
depending on individual anatomy. Thus, administrating of the
botulinum neurotoxin based solely on the approximated distance of
1.5 cm or fingerbreadth approach may lead to inadvertent
penetration of the frontalis muscle, which can result in brow
ptosis. Furthermore, pointing the needle upward at a 45 degree
angle laterally may also result in inadvertent penetration of the
frontalis. Corrugators are thin muscles, thus injecting too deep
can hit the periosteum and may trigger a headache/migraine.
[0073] To minimize or prevent unwarranted side effects, in some
embodiments, the present method comprises locating the corrugator,
isolating the corrugator to eliminate or minimize inadvertent
injection to the frontalis and administering a botulinum toxin to
the corrugators. As shown in FIG. 2A, the corrugator muscle is
located about 1.5 cm or .about.1 fingerbreadth above the medial
inferior edge of the orbital rim, a bony landmark which can be used
to localize the corrugator. In some embodiments, the locating step
comprises localizing the orbital rim and the corrugator muscle
situated in the proximity thereof. The corrugators produce vertical
lines on the portion of the skin below the head between the brows,
as seen in FIG. 2B. In some embodiments, the isolating step
comprises providing patient instructions to furrow her/his brow,
which activates the corrugator and causing medial and inferior
movement of the brow (FIG. 2B). In some embodiments, the isolating
step further comprises palpating and pinching the corrugator
muscle, holding them between the thumb and index finger, as shown
in FIG. 2D. The corrugators are brow depressors, meaning they pull
the brow down. They attach to the nasal frontal bone medially and
the skin of the eye brow laterally. To further minimize or
eliminate brow ptosis, in some embodiments, the administering step
comprises targeting the belly of the corrugators (FIG. 2B). In some
embodiments, the administrating step comprises injecting at a
90.degree. angle into the belly of the corrugator muscles, as shown
in FIGS. 2B and 2D. In some embodiments, the administering step
further comprises controlling the penetration depth of the needle
such that it remains above the periosteum.
[0074] In some embodiments, the present disclosure discloses a
method for minimizing or eliminating adverse effects associated
with botulinum toxin administration for treatment of headache, the
method comprises locating the corrugator muscle, isolating the
corrugator muscle, administrating a botulinum neurotoxin to the
corrugator muscle at about ten units divided among two sites of
injection, wherein the locating step comprises localizing the
orbital rim and the corrugator muscle in the proximity thereof, the
isolating step comprises providing a patient instructions to furrow
her/his brow, palpating and pinching the corrugator muscle, holding
them between the thumb and index finger; and wherein the
administrating step comprises superficially injecting at a
90.degree. degree angle into the corrugator muscle. In some
embodiments, superficially injecting comprises controlling the
penetration depth of the needle such that it remains above the
periosteum.
[0075] Procerus:
[0076] In one exemplary embodiment, as shown schematically in FIG.
3C, the present method further comprises local administration of a
botulinum neurotoxin to the procerus at about five units. As shown
in FIG. 3A, the procerus muscle is between the brows, and not in
the forehead. Relatively, the base of the procerus is located
approximately midway between the two corrugators injections (FIGS.
3C and 2C). This distance may vary depending on individual anatomy.
Thus, administrating of the botulinum neurotoxin based solely on
the approximated distance approach may lead to inadvertent
penetration of the frontalis muscle, which can result in medial
brow depression. Injecting too high in the brow area in the lower
frontalis can also lead to brow ptosis. The procerus muscle is
thin, thus injecting too deep can hit the periosteum and may
trigger a headache/migraine.
[0077] To minimize or prevent unwarranted side effects, in some
embodiments, the present method comprises locating the procerus,
isolating the procerus to eliminate or minimize inadvertent
injection to the frontalis and administering a botulinum toxin to
the procerus. In some embodiments, the locating step comprises
localizing the administration sites for the corrugators as set
forth above and finding the base of the procerus located midway
between the two corrugator injections. As shown in FIG. 3B, the
procerus draws down the medial angle of the eyebrow and produces
transverse lines over the bridge of the nose. In some embodiments,
the isolating step comprises providing a patient instructions to
furrow her/his brow, and using the resulting vertical and
horizontal lines as orientation lines (FIG. 3B). In some
embodiments, the administering step comprises targeting the belly
of the procerus muscle, which may be visible between the corrugator
lines (FIG. 3D). In some embodiments, the administrating step
comprises injecting superficially at a 90.degree. angle into the
procerus, as shown in FIG. 3D. In some embodiments, the
administering step further comprises controlling the penetration
depth of the needle such that it remains above the periosteum.
[0078] Frontalis:
[0079] In some embodiments, as shown schematically in FIG. 4C, the
present method further comprises local administration of a
botulinum neurotoxin to the frontalis at about twenty units divided
among four sites of injection. In some prior art protocol, to
localize the medial frontalis muscle for administration of
botulinum toxin, a line is drawn from the medial edge of the
supraorbital rim and the muscle areas for injections are
approximated about 1.5 cm (.about.1 fingerbreadth) above the
corrugator injection site. The lateral frontalis muscle is
localized as the area parallel and about 1.5 cm (.about.1
fingerbreadth) lateral to the medial injection area, which is
approximately in line with the midpupillary line or the lateral
limbic line. All foreheads are different shapes and sizes. Thus,
administrating of the botulinum neurotoxin based solely on the
approximated distance or fingerbreadth approach may lead to low
injections, which can cause medial brow weakness and lateral brow
elevation. Furthermore, the frontalis muscles are elevator muscles,
meaning that they pull the brow upward. Unduly, inadvertently or
improperly weakening these muscles may cause or exacerbate brow
ptosis. The frontalis muscles are thin, thus injecting too deep can
hit the periosteum and may trigger a headache/migraine.
[0080] To minimize or prevent unwarranted side effects, including
brow weakness, brow elevation, brow ptosis, in some embodiments,
the present method comprises locating the frontalis muscle,
isolating administration target area within the frontalis and
administering a botulinum toxin to the frontalis. In some
embodiments, the locating step comprises defining the medial and
lateral area for neurotoxin administration. In some embodiments,
defining the medial muscle area comprises drawing a line up from
the medial edge of the supraorbital rim and the administration
target areas are about 1.5 cm above the corrugator administration
site. In some embodiments, the lateral muscle area for neurotoxin
administration is parallel and about 1.5 cm lateral to the medial
administration site. In some embodiments, the frontalis
administration sites are in line with the midpupillary line or the
lateral limbic line. As set forth above, this approach alone may
lead to low injections. The frontalis muscles are involved in
drawing the scalp forward, creating transverse lines on the
forehead as well as in raising eyebrow and skin over the root of
the nose, as shown in FIG. 4B. In some embodiments, the isolating
step comprises providing patient instructions to raising her/his
eyebrows and skin over the root of the nose, such as creating an
expression of surprise (FIG. 4B). In some embodiments, the
isolating step comprises identifying the upper third of the
forehead (FIG. 4D). In some embodiments, the administrating step
comprises angling the needle superiorly at a 45.degree. angle into
the frontalis muscle, as shown in FIG. 4D. As the needle is angled
at 45.degree., the medication delivery site may be different from
the administration site. In some embodiments, the administration
step comprises injecting superficially by controlling the
penetration depth of the needle such that it remains above the
periosteum. In some embodiments, a local and topical anesthetic is
administered before administration of the neurotoxin to minimize
discomfort.
[0081] In some embodiments, the present method further comprises
assessing a patient's forehead for signs or symptoms of ptosis
prior to botulinum toxin administration botulinum toxin, informing
the patient of the existence of ptosis, and administrating a
botulinum toxin to the administration targets, including the
corrugators, procerus, frontalis muscles, or combinations thereof,
as disclosed herein.
[0082] FIGS. 5A-5D show pictures of various manifestations of
ptosis. Manifestations of ptosis comprise a drooping eyelid as
shown in FIG. 5A, excessive skin under the brow as shown in FIG.
5B, medial brow depression and/or lateral brow elevation as shown
in FIG. 5C. The lid ptosis (FIG. 5A), eyebrow ptosis (FIG. 5b) and
medial brow ptosis (FIG. 5C) can result from prior botulinum toxin
administrations. Senile ptosis (FIG. 5D) can occur independently of
prior botulinum toxin administrations. If the ptosis is due to a
prior botulinum toxin administration, it will resolve over 12
weeks. Senile ptosis, with lid drooping and soft tissue excess
around the eyelid, is pre-existing and does not change over
time.
[0083] In some embodiments, the present method prevents non-senile
ptosis from recurring or senile ptosis from worsening, the method
comprises locating the administration targets, including the
corrugators, the procerus, the frontalis, or combinations thereof
as disclosed herein, isolating the administration targets so that
the botulinum toxin is administered only to the intended target
area without inadvertently impacting an adjacent area as disclosed
herein; controlling the injection depth, and angling the needle as
to aim away from sensitive structures, including the periosteum, as
disclosed herein.
[0084] In some embodiments, the assessing step comprises inspecting
the eyelid and/or the eyebrow of the patient. In some embodiments,
the inspecting step comprises determining whether the eyelid is
drooping, whether there is excessive skin under the brow and
whether the eyebrow depresses or elevates. In some embodiments, the
present method further comprises informing the patient of the
existence of the ptosis. In some embodiments, the present method
further comprises providing a time interval between the assessment
step and the administration of the botulinum toxin to the
administration target muscles. In some embodiments, the time
interval ranges from 1 week to 5 months. In one embodiment, the
time interval between the assessment step and the administration
step is about 12 weeks. In some embodiments, the time interval is
less than 12 weeks. In some embodiments, the time interval is more
than 12 weeks. Preferably, as delaying re-treatment may compromise
treatment efficacy, in some embodiments, the present method
comprises evaluating the patient for ptosis, informing the patient
of the pre-existing ptosis condition, and administering a botulinum
toxin to the target muscles, wherein the administering is
specifically targeted so as to prevent non-senile ptosis from
recurring or senile ptosis from worsening, as disclosed herein.
[0085] In some embodiments, subsequent to the assessing step for
pre-existing ptosis and informing the patient, the present method
further comprises administering a botulinum toxin to the target
muscles, including and in particular the corrugators, procerus and
frontalis muscles, or combinations thereof, wherein the target
muscles are carefully isolated as disclosed herein so that the
botulinum toxin is administered only to the intended target area
without inadvertently impacting an adjacent area; and wherein the
injection depth is controlled as disclosed herein, and wherein the
needle is specifically angled to aim away from sensitive
structures, including the periosteum, as disclosed herein.
[0086] Temporalis:
[0087] In one exemplary embodiment, the present method further
comprises local administration of a botulinum neurotoxin to the
temporalis at about forty units divided among eight sites of
injection bilaterally, or 4 sites on each side (as shown in FIG.
6C) up to fifty units divided among ten sites of injection. The
tragus is an important landmark for temporalis injections. This
muscle area commonly bleeds during injections because it is
surrounded by many blood vessels.
[0088] In some embodiments, the present method comprises localizing
the temporalis and administering a botulinum toxin to the
temporalis. In some embodiments, the localizing step comprises
locating the tragus. In some embodiments, the localizing step
comprises providing instructions to a patient to clench his/her
teeth, which activates the temporalis. In some embodiment, the
present method comprises localizing a first administration site of
the temporalis muscle, the localizing step comprises locating the
tragus and moving a finger vertically up the side of the head of
the patient about 3 cm (or about 2 fingerbreadths) and injecting
the botulinum toxin at the first administration site (FIG. 6C). In
some embodiments, the present method further comprises localizing a
second administration site of the temporalis muscle, the localizing
the second administration site comprises moving vertically in line
with the tragus from about 1.5 cm up to about 3 cm (or about 1-2
fingerbreadths) from the first administration site, and injecting
the botulinum toxin at the second administration site. In some
embodiments, the present method further comprises localizing a
third administration site of the temporalis muscle, the localizing
the third administration site comprises moving from about 1.5 cm up
to about 3 cm (or about 1-2 fingerbreadths) forward toward the face
from the first and second administration sites and injecting the
botulinum toxin at the third administration site. In some
embodiments, the present method further comprises localizing a
fourth administration site of the temporalis muscle, the localizing
the fourth administration site comprises moving back about 1.5 cm
from the second administration site and in line with the midportion
(helix) of the ear; and injecting the botulinum toxin at the fourth
administration site. In one embodiment, the localizing step further
comprises placing a finger in the middle of the helix of the ear to
locate the fourth administration site. In some embodiments, the
administrating step is carried out as posterior as possible and
stays within the hairline, as shown in FIG. 6D. In one embodiment,
the local administration of botulinum toxin to the temporalis
comprises injecting superficially at a 45.degree. angle, as shown
in FIG. 6D. In some embodiments, the present method further
comprises applying pressure on the administration site to stop
bleeding if bleeding occurs. In some embodiments, the present
method further comprises inspecting the patient following
administration of the botulinum toxin for bleeding. In some
embodiments, the administrating step further comprises drawing back
on the needle to assess for a blood flush in the muscle area. In
some embodiments, the penetration depth of the needle is controlled
such that it remains above the periosteum. In some embodiments, a
local and topical anesthetic is administered before administration
of the neurotoxin to minimize discomfort.
[0089] FIGS. 7A and 7B show the back-of-head and neck anatomy,
identifying the location of exemplary administration target sites,
including the occipitalis, cervical paraspinal and trapezius
muscles. As shown in FIG. 7A, several landmarks can be used to
localize the administration target sites. For example, the acromion
extends from the spine to the deltoid and can be felt through the
skin.
[0090] Occipitalis:
[0091] In one exemplary embodiment, the present method further
comprises local administration of a botulinum neurotoxin to the
occipitalis at about thirty units divided among six sites of
injection bilaterally, or 3 sites on each side (as shown in FIG.
8A) to about forty units divided among eight sites of injection.
The function of the occipitalis is to serve as an anchor for the
frontalis. The occipitalis muscles are in proximity of the
occipital nerves, which may cause pain in some patients. The
occipitalis muscle is shallow. If occipitalis injections are given
too low, they can cause neck pain and weakness. The nuchal ridge
(FIG. 7B) is an important landmark for occipitalis injections.
[0092] In some embodiments, the present method comprises localizing
the occipitalis, and administering a botulinum toxin to the
occipitalis. In some embodiment, the localizing step comprises
locating the nuchal ridge. The present method comprises localizing
a first administration site of the occipitalis muscle, the
localizing step comprises palpating the occipital protuberance and
finding the most posterior point, which is the inion (FIG. 7B);
palpating the nuchal ridge and locating the tip of the mastoid
process behind the ear (FIG. 7A), placing the thumb on the midpoint
of the occipital protuberance (inion) and the index finger on the
tip of the mastoid process; dividing the space between the thumb
and the index finger in half and identifying a midpoint; and
locating the first administration site above the nuchal ridge at
the midpoint; and injecting the botulinum toxin at the first
administration site. In some embodiments, the present method
further comprises localizing a second administration site of the
occipitalis muscle, the localizing the second administration site
comprises measuring a diagonal fingerbreadth up and out toward the
helix of the ear (at the 10 o'clock position), and injecting the
botulinum toxin at the second administration site. In some
embodiments, the present method further comprises localizing a
third administration site of the occipitalis muscle, the localizing
the third administration site comprises measuring a diagonal
fingerbreadth up and medial (at the 2 o'clock position), and
injecting the botulinum toxin at the third administration site. To
prevent low occipitalis injections which can cause neck pain and
weakness, in a preferred embodiment, the administrating step is
carried out above the nuchal ridge. In one embodiment, the local
administration of botulinum toxin to the occipitalis comprises
injecting superficially at a 45.degree. angle, as shown in FIG. 8B.
In some embodiments, the needle is angled upward, away from the
neck, as shown in FIG. 8B. In some embodiments, the penetration
depth of the needle is controlled such that it is just upon
penetration of the dermis. As the occipitalis muscles are in
proximity of the occipital nerves, which may cause pain, in some
embodiments, a local and topical anesthetic is administered before
administration of the neurotoxin to minimize discomfort.
[0093] Cervical Paraspinal Muscle Group
[0094] In one exemplary embodiment, the present method further
comprises local administration of a botulinum neurotoxin to the
cervical paraspinal muscles at about twenty units divided among
four sites of injection (as shown in FIG. 9A). The cervical
paraspinals should be considered as a muscle group, not a specific
muscle. Injecting the cervical paraspinals too low or too deep can
lead to muscle weakness. To ensure the muscles are not injected too
low, the cervical paraspinals should be considered as suboccipital
muscles. In some prior art protocol, the muscle areas for injection
are identified by localizing a first administration site of the
cervical paraspinals, the localizing step comprises measuring about
1 cm left of the midline of the cervical spine (FIG. 9A) and about
3 cm (or about 2 fingerbreadths) inferior to the occipital
protuberance (FIG. 7B); and injecting the botulinum toxin at the
first administration site. A second administration site is
identified by measuring about 1.5 cm (or about 1 fingerbreadth)
diagonally up at a 45.degree. angle toward the helix of the ear
from the first injection; and injecting the botulinum toxin at the
second administration site. Administrating of the botulinum
neurotoxin based solely on the approximated distance or
fingerbreadth approach may lead to too low or too deep injections,
which can cause muscle weakness.
[0095] To minimize or prevent unwarranted side effects, in some
embodiments, the present method comprises localizing the cervical
paraspinal muscles and administering a botulinum toxin to the
cervical paraspinal muscles. In some embodiments, the localizing
step comprises visualizing a line across the neck, about 2
fingerbreadths down from the occipital protuberance and injecting
above that line. In some embodiments, the localizing step comprises
providing instructions to the patient to sit upright, with his/her
head in a neutral position. If the neck is flexed far forward, the
injections may be too deep. In some embodiments, the administrating
step comprises injecting superficially at a 45.degree. angle, as
shown in FIG. 9B. In some embodiments, the administrating occurs in
the hairline. In some embodiments, the penetration depth of the
needle is controlled such that it penetrates the dermis and targets
the superficial muscle layer.
[0096] In some embodiments, the present method further comprises
evaluating the patient for neck weakness and neck pain subsequent
to the administrating step, the evaluating comprises positioning
the patient upright, with the head in the neutral position,
determining whether the neck is flexed far forward. If the neck is
flexed far forward, the injections may be too deep. In some
embodiments, a local and topical anesthetic is administered before
administration of the neurotoxin to minimize discomfort.
[0097] Trapezius:
[0098] In one exemplary embodiment, the present method further
comprises local administration of a botulinum neurotoxin to the
trapezius about thirty units divided among six sites of injection
up (as shown in FIG. 10A) to about fifty units divided among ten
sites of injection. In some embodiments, the present method
comprises localizing a first administration site of the trapezius,
the localizing step comprises dividing the upper portion of the
trapezius muscle in half, from the inflection point of the neck
(necklace line) to the acromion (FIG. 7A), the first administration
site is located at this midpoint; and injecting the botulinum toxin
at the first administration site. In some embodiments, the present
method further comprises localizing a second administration site of
the trapezius, the localizing the second administration site
comprises splitting the difference between the first injection site
and the acromion; and injecting the botulinum toxin at the second
administration site. In some embodiments, the present method
further comprises localizing a third administration site of the
trapezius, the localizing the third administration site comprises
splitting the difference between the first injection site and the
necklace line.
[0099] To prevent or minimize unwarranted side effects, in some
embodiments, the local administration of botulinum toxin to the
trapezius comprises injecting horizontally to the muscle to avoid
injecting too deep, as shown in FIG. 10B. In some embodiments, the
local administration of botulinum toxin comprises injecting the
supraclavicular portion of the muscle, lateral to the necklace line
and medial to the deltoid/acromion joint (FIG. 7A). In some
embodiments, a local and topical anesthetic is administered before
administration of the neurotoxin to minimize discomfort.
[0100] In some embodiments, the present method further comprises
evaluating the patient for neck weakness prior to administrating
botulinum toxin to the target muscles. In some embodiments, the
evaluating step comprises positioning the patient upright, with the
head in the neutral position and determining whether the neck is
flexed far forward. If the tragus of the ear lines up with the
anterior ridge of the trapezius muscle in profile, as shown in FIG.
11, there is no apparent neck weakness. If the tragus of the ear is
more than 2 fingerbreadths (.about.3 cm) from the anterior ridge of
the trapezius muscle, that shows neck weakness. In some
embodiments, the present method further comprises informing the
patient of the neck weakness. In some embodiments, the present
method further comprises providing a time interval between the
assessment step and the administration of the botulinum toxin to
the administration target muscles. In some embodiments, the time
interval ranges from 1 week to 5 months. In one embodiment, the
time interval between the assessment step and the administration
step is about 12 weeks. In some embodiments, the time interval is
less than 12 weeks. In some embodiments, the time interval is more
than 12 weeks. Preferably, as delaying re-treatment may compromise
treatment efficacy, in some embodiments, the present method
comprises evaluating the patient for neck weakness, informing the
patient of the pre-existing neck weakness condition, and
administering a botulinum toxin to the target muscles, wherein the
administering is specifically targeted as to prevent or minimize
causing additional neck pain or weakness, as disclosed herein.
[0101] In some embodiments, subsequent to the evaluating step for
neck weakness and the informing step, the present method further
comprises administering a botulinum toxin to the target muscles as
disclosed herein, wherein the administering to the cervical
paraspinal muscle group is targeted within two fingerbreadths
(.about.3 cm) below the occipital protuberance (FIG. 7B) and the
administering to the trapezius is targeted to the supraclavicular
section (corresponding to the injection sites shown in FIG. 10A)
lateral to necklace line (FIG. 7A) to prevent or minimize causing
additional neck pain or weakness.
[0102] The present method can be used to minimize or prevent
adverse effects associated with the administration of a botulinum
toxin for treating, alleviating symptoms, or reducing the
occurrence of neuropsychiatric disorders (ND), including
depression, or medication overuse (MOU) disorders.
[0103] Significantly, a method within the scope of the present
invention can provide improved patient function. "Improved patient
function" can be defined as an improvement measured by factors such
as a reduced pain, reduced time spent in bed, increased ambulation,
healthier attitude, more varied lifestyle and/or healing permitted
by normal muscle tone. Improved patient function is may be measured
with an improved quality of life (QOL) or Health-Related Quality of
Life (HRQL). QOL can be assessed, for example, using the SF-12 or
SF-36 health survey scoring procedures, or the Migraine Specific
Quality of Life Questionnarie (MSQ). SF-36 assesses a patient's
physical and mental health in the eight domains of physical
functioning, role limitations due to physical problems, social
functioning, bodily pain, general mental health, role limitations
due to emotional problems, vitality and general health perceptions.
Scores obtained can be compared to published values available for
various general and patient populations. The Migraine-Specific
Quality of Life Questionnaire Version 2.1 is one of the most
frequently utilized disease-specific tools assessing the impact of
migraine on HRQL. The MSQ measures the impact of migraine on the
patient's HRQL over the past 4 weeks across three dimensions: Role
Function-Restrictive (RR), Role Function-Preventive (RP), and
Emotional Function (EF). The MSQ was developed from an expert-based
item review of the migraine literature and validated in a clinical
sample of 458 new and stable EM patients. In the validation study
the MSQ revealed high internal consistency (Cronbach's .alpha.=0.79
to 0.85), a moderate to strong convergent validity, as well as an
adequate discriminant validity. Martin and Colleagues 21 performed
a multi-center study that further supported the evidence of a high
internal consistency (Cronbach's .alpha.=0.86 to 0.96), strong
reliability and good validity of the 14-item MSQ among 267
participants.
[0104] The following non-limiting examples provide those of
ordinary skill in the art with specific preferred methods to treat
chronic migraine within the scope of the present disclosure, and it
is not intended to limit the scope of the invention. In the
following examples various modes of non-systemic administration of
a Clostridial neurotoxin can be carried out. For example, by
intramuscular injection, subcutaneous injection or by implantation
of a controlled release implant.
EXAMPLES
[0105] The following non-limiting examples provide those of
ordinary skill in the art with specific preferred methods to treat
conditions within the scope of embodiments of the present invention
and are not intended to limit the scope of the invention.
Example 1
[0106] In a clinical study for treatment of chronic migraine by
onabotulinumtoxinA using an injection protocol disclosed by the
'195 patent, it was found that 9% of the patients experienced neck
pain and 3-4% of the patient experienced ptosis. In a subsequent
study at a local headache center with 100 chronic migraine
patients, the following protocol was adopted:
[0107] The frontalis injections were done in the upper third of the
forehead with needle angle superiorly at 45 degrees. The needle was
inserted below the dermis into the superficial muscle layers and
not too deep to avoid the periosteum.
[0108] The corrugator muscle was injected by having the patient
furrow the brow. The muscle was palpated between the thumb and
index finger. The medial edge of the corrugator muscle was
injected. While pinching the muscle to isolate it, the needle was
inserted into the muscle at a 90-degree angle to the plane of the
face. This limited any diffusion from the muscle into surrounding
areas. The depth of the needle was deep to the dermis, in the
superficial muscle, above the periosteum.
[0109] Injections into the temporalis muscle can produce temporal
wasting. When this occurs in the anterior temporal fossa it
produces an hourglass appearance. This was prevented by injecting
the temporalis within the hairline, using a vertical line drawn
through the tragus of the ear as a landmark for the injections.
[0110] If the occipitalis muscle is injected too low it can produce
neck weakness and neck pain. To avoid this the muscle was localized
as follows: (a) by placing a finger on the tip of the mastoid
process (behind the ear) and a thumb on the inion (most prominent
posterior protrusion of the skull); (b) splitting the difference
between the thumb and index finger in half and locating the
midpoint on the nuchal ridge. The occipitalis muscle was injected
by angling the needle superiorly at 45 degrees starting at this
point. The injections were below the dermis and above the
periosteum.
[0111] The cervical paraspinal muscles were injected superficially
and high in the sub-occipital region to avoid neck weakness and
neck pain. The injection sites were 2 horizontal fingerbreadths (3
cm) below the occipital protuberance in the midline. The needle was
angled superiorly at 45 degrees, inserted just below the
dermis.
[0112] The trapezius muscles were injected in the supraclavicular
region to avoid neck weakness and neck pain. The trapezius muscle
has an inflection point at the necklace line. This was used as a
landmark together with the acromion. An index finger was placed in
the groove of the acromion joint and the necklace line. The
distance between the acromion and necklace line are split in half
for placement of the first injection was split in half. At this
point the first injection was done, at a 0 to 45.degree. angle to
avoid a deep injection. The injection was just below the dermis in
the superficial muscle layers. The second and third injections were
done medial and lateral to the first in an equidistant fashion.
[0113] The adverse event rates for the 100 patients receiving the
above-described protocol were 1% for the brow ptosis and 4% for the
neck pain.
Example 2
[0114] A 50 year old woman with CM has been injected with
onabotulinumtoxinA by another neurologist on one occasion. She
reported that her brow was depressed and her neck was weak with
associated pain. This developed 2 weeks after her treatment and
persisted for 6 weeks before gradually resolving. She wanted to
continue onabotulinumtoxinA treatment for CM but did not want her
neck/shoulder or forehead regions to be re-injected.
[0115] After educating the patient about the injection protocol
described in Example 1 with careful attention to the portion of the
muscles that need to be injected to maximize efficacy and decrease
side effects, she agreed to proceed. The protocol described in
Example 1 was used to treat her. She returned at 6 weeks and
reported no brow ptosis or neck pain. Her headaches were reducing
and she was satisfied to continue forward to her third
onabotulinumtoxinA treatment in 6 week time.
[0116] Many alterations and modifications may be made by those
having ordinary skill in the art, without departing from the spirit
and scope of the disclosure. Therefore, it must be understood that
the described embodiments have been set forth only for the purposes
of examples, and that the embodiments should not be taken as
limiting the scope of the following claims. The following claims
are, therefore, to be read to include not only the combination of
elements which are literally set forth, but all equivalent elements
for performing substantially the same function in substantially the
same way to obtain substantially the same result. The claims are
thus to be understood to include those that have been described
above, those that are conceptually equivalent, and those that
incorporate the ideas of the disclosure.
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