Note: Descriptions are shown in the official language in which they were submitted.
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METHOD FOR TREATING HEADACHE PAIN WITH TOPICAL
LOCAL ANESTHETIC COMPOSITIONS
INTRODUCTION
Field of the Invention
The field of this invention is the treatment of
headache pain.
Backcrround
Headaches are a common problem affecting a large
segment of the population. Headaches, such as tension
type and migraine headaches, occur both intermittently
and chronically, and can arise in response to variety of
stimulants, including stress, injury, toxins in the
environment and the like.
A variety of therapeutic agents have been
developed for use in the treatment of patients suffering
from headache pain. Some agents, such as aspirin,
acetaminophen, vasoconstrictors and NSAIDs, e.g.
ibuprofen and naprosyn, are administered systemically.
Despite the prevalence of this form of treatment for
headache pain, in some cases, systemic administration is
not recommended. For example, oral administration of
aspirin can result in stomach upset and patient
discomfort. Furthermore, the agent can exert host
systemic toxicity which may outweigh any therapeutic
benefits provided by the agent. Finally, since the agent
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is administered systemically, its~effects are also
systemic, which may not be desired.
In view of the above problems and disadvantages
associated with therapeutic agents that are administered
systemically, regional administration of local
anesthetics which selectively block conduction in target
nerves is a desirable alternative for the treatment of
headache pain. Use of local anesthetics is desirable
because nerve conduction can be selectively blocked in
only those nerves associated with the headache pain.
Although use of local anesthetics in the treatment of
headache pain is desirable, administration of an
effective amount of the local anesthetic to the target
nerves is difficult and/or inconvenient.
Z5 For example, a local anesthetic can be injected
directly at the site of nerves associated with headache
pain, e.g. the occipital and supraorbital nerves to
effect a nerve block and thereby provide pain relief. See
Garron, "Relieving Pain with Nerve Blocks," Geriatrics
(1978) 33: 49-57. Although this method is effective in
providing headache pain relief, because the local
anesthetic is injected it must be administered by trained
personnel. Furthermore, the patient must bear the
discomfort associated with the injection of the local
anesthetic.
Because of these disadvantages of administration
by injection, the topical administration of local
anesthetics is a desirable alternative mode of
administration. However, local anesthetics by themselves .
r ~ . _,
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do not readily penetrate the keratinized layer of the
skin. See Review of Medical Pharmacology (Meyers et al.
ed., 1978) pp. 217-226. Thus, intranasal application of
local anesthetics has found use in the treatment of
headache pain. See Brandt et al., "Cluster headache and
chronic paroxysmal hemicrania: current therapy,"
Nervenarzt (1991) 62: 329-339.
For topical administration of local anesthetics to
keratinized skin surfaces, additional measures must be
taken to provide for penetration of the local anesthetic
across the keratinized skin surface. One means of
providing for penetration of the local anesthetic across
the skin surface is to employ iontophoretic techniques,
where an electric field is applied to the topical local
anesthetic composition. The local anesthetic penetrates
the keratinized skin surface under the influence of the
applied electric field.
Another means of providing for penetration of
keratinized skin is to employ formulations which promote
local anesthetic penetration. Although such formulations
are available and have been employed for a variety of
applications, currently available topical local
anesthetic formulations have not found widespread use for
the treatment of headache pain. One reason that currently
available formulations have not found widespread use for
the treatment of headache pain is that an effective
amount of the anesthetic agent does not penetrate the
skin rapidly enough to provide pain relief in a
sufficiently short period of time. For example, when EMLA
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(a eutectic mixture crf lidocaine~and prilocaine) is
topically applied to a keratinized skin surface, it must
be applied under an occlusive dressing for at least one
hour before analgesia is experienced by the host. See
Physician's Desk Reference, 1994, pp 544.
Thus, there is continued interest in the
identification of topical local anesthetic formulations
which are suitable for use in the treatment of headache
pain. Such topical formulations should provide for rapid
penetration of an effective amount of the local
anesthetic through the skin surface, and thereby provide
for rapid pain relief.
Relevant Literature
U.S. Patent No. 4,440,777 describes topical
applications comprising eucalyptol as an enhancing agent.
Other patents of interest include U.S. Pat. Nos.:
4,588,580; 4,911,707; 5,069,909; 5,070,084; 5,330,452;
and 5,368,860.
Kittrelle et al., "Cluster Headache. Local
Anesthetic Abortive Agents, " Arch. Neurol. (1985) 42
496-498 reports the application of a 4% lidocaine
solution to the sphenopalantine fossa in order to treat
nitrate induced cluster headache pain.
SUMMARY OF THE INVENTION
Methods are provided for the treatment of a host
suffering from headache pain with topical local
anesthetic compositions. Topical local anesthetic
_ .~.. . r .
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compositions employed in the subject methods comprise an
effective amount of a local anesthetic in combination with
eucalyptol as a penetration enhancing agent. The local
anesthetic compositions are applied to a keratinized skin site
proximal to target nerves associated with the headache pain.
Upon application, the local anesthetic rapidly penetrates the
skin surface to reach, and block conduction in, the target
nerves and provide for rapid pain relief.
In various embodiments there is provided the use of a
composition comprising a local anesthetic in combination with
eucalyptol as a penetration enhancing agent for blocking
conduction in target nerves selected from the group consisting
of occipital and supraorbital nerves in the topical treatment
of headache pain in a host, wherein the composition is for
topical application at a keratinized skin site proximal to the
target nerves.
In various embodiments there is provided the use of a
local anesthetic, wherein the local anesthetic is an amine
linked through a connecting group to an aromatic group, in
combination with eucalyptol as a penetration enhancing agent,
and with an additional penetration enhancing agent, for
blocking the conduction in target nerves selected from the
group consisting of occipital and supraorbital nerves in the
topical treatment of headache pain in a host suffering from
headache pain, wherein the local anesthetic is for topical
application at a keratinized skin site proximal to the target
nerves.
In various embodiments there is provided the use of a
composition comprising (a) an effective amount of benzocaine,
(b) eucalyptol and (c) N,N-diethyl-m-toluamide for blocking
conduction in target nerves selected from the group consisting
of occipital and supraorbital nerves in the topical treatment
of headache pain in a host suffering from headache pain,
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wherein the composition is for topical application at a
keratinized skin site proximal to said target nerves.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
Methods are provided for the treatment of a host suffering
from headache pain through application of topical local
anesthetic compositions. The local anesthetic compositions
employed in the subject methods comprise an effective amount of
a local anesthetic in combination with eucalyptol as a
penetration enhancing agent and provide for rapid penetration
of the local anesthetic agent through a keratinized skin
surface. In the subject methods, the local anesthetic
composition is topically applied to a skin site proximal to
target nerves associated with the headache pain. Upon
application, the local anesthetic agent penetrates the skin to
block conduction in the target nerves and provide pain relief
to the host.
Topical compositions employed in the subject method will
include a local anesthetic as the active agent. Although two
or more local anesthetic agents may be present in the subject
compositions, generally the
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subject compositions will comprise a single local
anesthetic agent. The local anesthetic employed in the
subject methods will be an anesthetic which, when
administered in the topical formulations, rapidly
penetrates a keratinized skin surface to block conduction
in nerves underlying the skin surface. The local
anesthetic will have a molecular weight and melting point
that is compatible with transport across the keratinized
skin surface. Generally, the molecular weight of the
l0 local anesthetic will not exceed about 300 dal, and will
more usually not exceed about 250 dal. The melting point
of the local anesthetic will be less than about 100 °C.
Generally, the local anesthetic will be a compound
comprised of a secondary or tertiary amine linked through
a connecting group to an aromatic group. The local
anesthetic will be an alkanyl compound of from about 9 to
carbon atoms. Because the composition is applied
topically, the local anesthetic will generally be present
in the composition as a free base to promote penetration
20 of the agent through the skin surface. A large number of
local anesthetics are known in the art, many of which are
suitable for topical application. Suitable local
anesthetics include lidocaine, butamben, butanilicaine,
ethyl aminobenzoate, fomocaine, hydroxyprocaine, isobutyl
p-aminobenzoate, naepaine, octacaine, parethoxycaine,
piridocaine, prilocaine, procaine, risocaine, tolycaine,
trimecaine, particularly ethylaminobenzoate (benzocaine).
The amount of local anesthetic present in the subject
compositions will be sufficient to provide an effective
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amount of the agent when topically administered according
to the subject methods. The precise amount of anesthetic
agent present in the topical formulation will depend on
the particular agent employed, but will generally range
from 5 to 50 % by weight, usually from about 10 to 40
by weight.
Critical to the topical applications employed in
the subject methods is eucalyptol, which serves as a
penetration enhancing agent for the local anesthetic.
Eucalyptol (1,3,3-trimethyl-2-oxabicyclo[2,2,2]-octane)
is the chief constituent of oil of eucalyptus and is also
known as cineole and cajeputol. Eucalyptol is known in
the art, having found use as an insect repellant and as a
flavoring agent. The amount of eucalyptol present in the
composition will range from about 10 to 80%, usually from
about 10 to 50 % by weight, and more usually from about
to 40 % by weight of the composition.
Optionally, the subject composition may further
comprise one or more additional penetration enhancing
20 agents which work in combination with the eucalyptol to
provide for rapid penetration of the local anesthetic.
Additional penetration enhancing agents will be capable
of rapid penetration of the skin and be pharmaceutically
acceptable, i.e. non-toxic to the host at the levels at
which they are present in the composition. Examples of
additional penetration enhancing agents which may find
use in the subject compositions include: propylene glycol
and N-methyl-2-pyrrolidone. An additional penetration
enhancing agent that finds particular use in combination _.
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with eucalyptol in the subject compositions is N,N-
diethyl-m-toluamide (DEET). When present, the amount of
this additional penetration enhancing agent in the
subject compositions will vary depending on the
particular agent, as well as the Iocal anesthetic present
in the composition. The amount of additional penetration
enhancing agent or agents in the subject compositions
will range from 10 to 80 o by weight, usually from about
30 to 60 % by weight. Generally, the ratio of eucalyptol
to additional penetration enhancing agent in the subject
compositions will be from 0.25:1 to 2:1, and will usually
be from about 1:2 to 1:1.
The compositions comprising the local anesthetic,
eucalyptol and any additional penetration enhancing agent
employed in the subject methods will be formulated in a
manner convenient for topical application. Thus, the
subject compositions may be formulated as stable
solutions or suspensions of the local anesthetic in
eucalyptol. Alternatively, the local anesthetic and
eucalyptol may be combined with one or more carrier
materials to form a solution, suspension, gel, lotion,
cream, ointment, aerosol spray or the like, as in known
in the art.
Gel vehicles in which the subject local
anesthetic and eucalyptol may be formulated to produce a
topical application useful in the subject methods will
physiologically acceptable and will generally comprise a
solvent in combination with a thickening agent. The
solvent will generally be an alkanol, such as an alcohol .
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or polyol, including:' ethanol, isopropanol, propylene
glycol, glycerol, and the like. These alcohols and
polyols may be used individually or in combination. In
' the gel vehicle, the solvent will generally be present in
from about 1 to 80 weight o, more commonly 10 to 40
weight % of the topical composition.
Conventional gelling or thickening agents may be
employed to provide for a formulation which can be
conveniently applied to the skin. Gelling agents which
have been found to be effective and are illustrative of
conventionally used gelling agents for skin application
include Carbomer 940 (neutralized with
diisopropanolamine), neutralized polyacrylic acid, etc.
The gelling agent will be used in an amount sufficient to
provide the appropriate viscosity, generally being in the
range of about 0.1-5 weight percent of the formulation.
Non-ionic surfactants may be included in the
compositions, where the nonionic surfactants may serve as
cosolvents and epidermal penetration enhancers, in
addition to the eucalyptol and any optional penetration
enhancing agent described above. Conventional
surfactants may be employed, which are physiologically
acceptable, such as sorbitan esters, etc. When present,
the nonionic surfactant will generally be present in an
amount of from about 2-20 weight percent of the
formulation.
The topical composition may also contain other
physiologically acceptable excipients or other minor
additives, particularly associated with organoleptic
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properties, such as fragrances, dyes, emulsifiers,
buffers, cooling agents (e. g. menthol), antibiotics,
stabilizers or the like. The excipients and minor
additives will be present in conventional amounts ranging
from about 0.001% to 50, more commonly 0.001-2%, by
weight, usually not exceeding a total of 10% by weight.
Where convenient, e.g. with a gel formulation, the
topical application may be covered with an occlusive
dressing, which may be porous or non-porous, so as to
protect the gel from mechanical removal during the period
of treatment. Various inert coverings may be employed,
which include the various materials which may find use in
plasters, described below. Alternatively, non-woven or
woven coverings may be employed, particularly elastomeric
coverings, which allow for heat and vapor transport.
These coverings allow for cooling of the pain site, which
provides for greater comfort, while protecting the gel
from mechanical removal.
Instead of a gel, a plaster may be employed, where
the composition comprising the local anesthetic and
eucalyptol, and any additional penetration enhancers, may
be formulated into the adhesive of the plaster. In the
case of plasters, the coverings may include polyvinyl
chloride, polyvinylidene chloride, (SARAN~),
polyethylene, synthetic rubber, woven or nonwoven
polyester fabric, etc. The local anesthetic and the
eucalyptol may be combined with the adhesive with the aid
of a cosolvent, or a combination of cosolvents, such as
propylene glycol, glycerin, methyl salicylate, glycol ..
~_ _
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salicylate, or the l ice. The particular choice of
adhesive is not critical, there being a wide variety of
physiologically acceptable adhesives, which can maintain
the local anesthetic, eucalyptol and any additional
penetration enhancing agent, in contact with the skin.
Of particular interest are the topical local
anesthetic compositions described in U.S. Pat. No.
4,440,777.
In the subject methods, the topical composition
comprising the local anesthetic is applied to a
keratinized skin site of the host proximal to target
nerves associated with the headache pain. Nerves which
are commonly associated with headache pain are the
occipital and supraorbital nerves. The skin site at which
the composition is applied will be sufficiently proximal
to the target nerves, e.g. the akin site overlies the
region innervated by the target nerves, so that upon
contact of the composition with the skin surface, the
local anesthetic can readily reach the target nerves and
exert its anti-conduction activity. Of particular
interest as skin sites of topical application are the
supraorbital and occipital regions.
The subject compositions will be applied to the
skin site for a period of time ranging from .25 to 6
hours, usually from about .5 to 5 hours, during which
time the host will experience relief from pain due to the
activity of the local anesthetic on the target nerves. If
headache pain recurs following removal of the topical "
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composition, a new topical composition may be applied.
The process may be repeated as necessary and desired to
achieve pain relief. Because of the nature of the topical
local anesthetic composition employed in the subject
methods, penetration of the local anesthetic is rapid.
Therefore, the patient experiences relief from the pain .
shortly after application. Usually the patient will
experience at least some relief from the headache pain
about .25 to 30 min following application of the topical
composition, usually about .5 to 30 min following
application of the topical composition.
The amount of composition applied will usually be
sufficient to cover a majority of the region of skin
overlying the target nerves to ensure that conduction in
a sufficient percentage of the target nerves is blocked,
so that the host experiences pain relief. The exact
amount of topical composition that is applied may be
determined empirically. For example, where the topical
application is applied to the supraorbital region of the
head, the amount of composition applied will be
sufficient to cover at least about 50 %, more usually at
least about 75 ~ of the region. For solutions,
dispersions, gels, lotions, creams and the like, the
composition will be spread over the region and a covering
optionally applied thereto. For patches, an appropriate
sized patch will be placed over the region comprising the
skin site.
Conveniently, the composition may be provided in a
unit dosage format, which formats are known in the art.
r i. . . w . . . .
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Upon application of the topical composition, the
local anesthetic rapidly penetrates the surface of the
skin and blocks conduction of the target nerves which are
proximal to the skin site. As a result, the patient will
experience at least a partial subsidence in the intensity
of headache pain, and in some cases may experience a
complete cessation of pain. Thus, application of the
topical local anesthetic compositions in accordance with
the subject methods results in treatment of the host
l0 suffering from headache pain.
The following examples are offered by way of
illustration and not by way of limitation.
EXPERIMENTAL
A mixture of DEFT (N,N-diethyl-m-toluamide) and
eucalyptol (1,3,3-trimethyl-2-oxabicyclo [2,2,2]-octane)
was prepared in a ratio of 2:1. A sufficient amount of
benzocaine free base (ca. 30% by weight) was dissolved in
the mixture to produce a saturated solution of the local
anesthetic.
The solution was topically applied to a female
patient suffering from acute migraine without aura. The
solution was applied directly to the areas of the
patient's head where the supraorbital and occipital
nerves are closest to the skin (the same area in which a
needle would be inserted to perform regional anesthesia
to these nerves). Prior to application of the solution,
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the patient rated her headache pain as "moderate°° with
"moderate" nausea and "moderate°° light sensitivity.
After 15 minutes, the headache pain had subsided
to a level described by the patient as "very mild."
Furthermore, the patient reported no nausea or light
sensitivity. In addition, the patient did not develop any
noise sensitivity, which in the past had typically became
sever during previous migraine attacks.
The patient°s relief from the pain and other
migraine symptoms lasted in excess of 2 hours. The
patient was able to continue working following
application of the topical local anesthetic solution.
This was a favorable result compared to other forms of
treatment which the patient had employed previously,
where, despite treatment, the patient had to stop
working.
It is evident from the above results and
discussion that a novel and effective method of treating
headache pain in a host is provided. The nature of the
topical applications employed provides for rapid
penetration of the skin surface by the local anesthetic.
As a result, the patient experiences pain relief shortly
after application of the composition. Furthermore, since
the local anesthetic composition is topical, the method
is convenient and tolerated well by patients.
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Although the foregoing invention has been
described in some detail by way of illustration and
example for purposes of clarity of understanding, it will
be readily apparent to those of ordinary skill in the art
in light of the teachings of this invention that certain
changes and modifications may be made thereto without
departing from the spirit or scope of the appended
claims.
