U.S. patent application number 12/077492 was filed with the patent office on 2008-10-23 for infiltration of capsaicin into surgical sites and open wounds.
This patent application is currently assigned to AlgoRx. Invention is credited to Ronald M. Burch, Richard B. Carter, Jeff Lazar.
Application Number | 20080262091 12/077492 |
Document ID | / |
Family ID | 32685309 |
Filed Date | 2008-10-23 |
United States Patent
Application |
20080262091 |
Kind Code |
A1 |
Burch; Ronald M. ; et
al. |
October 23, 2008 |
Infiltration of capsaicin into surgical sites and open wounds
Abstract
The present invention provides compositions and methods for
attenuating or relieving pain at a site in a human or animal in
need thereof by infiltrating at a surgical site or open wound in a
human or animal a dose of capsaicinoid in an amount effective to
denervate the surgical site or open wound substantially without
eliciting an effect outside the surgical site or open wound.
Inventors: |
Burch; Ronald M.; (Wilton,
CT) ; Carter; Richard B.; (Washington Crossing,
PA) ; Lazar; Jeff; (Austin, TX) |
Correspondence
Address: |
Davidson, Davidson & Kappel, LLC
485 7th Avenue, 14th Floor
New York
NY
10018
US
|
Assignee: |
AlgoRx
Cranbury
NJ
|
Family ID: |
32685309 |
Appl. No.: |
12/077492 |
Filed: |
March 18, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10741195 |
Dec 18, 2003 |
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12077492 |
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60434453 |
Dec 18, 2002 |
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60461164 |
Apr 8, 2003 |
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Current U.S.
Class: |
514/627 |
Current CPC
Class: |
A61K 31/05 20130101;
A61P 25/04 20180101; A61P 29/02 20180101; A61K 31/5415 20130101;
A61K 31/165 20130101; A61P 25/00 20180101; A61K 31/165 20130101;
A61K 45/06 20130101; A61P 19/02 20180101; A61K 31/551 20130101;
A61P 25/02 20180101; A61K 31/16 20130101; A61K 9/0019 20130101;
A61K 36/81 20130101; A61K 47/10 20130101; A61K 31/05 20130101; C07C
231/02 20130101; C07C 231/02 20130101; A61P 23/02 20180101; A61K
31/5415 20130101; A61K 36/81 20130101; A61K 31/16 20130101; A61K
31/551 20130101; A61K 2300/00 20130101; C07C 233/20 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61P 29/00 20180101; A61P
43/00 20180101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61P
23/00 20180101; A61K 2300/00 20130101 |
Class at
Publication: |
514/627 |
International
Class: |
A61K 31/16 20060101
A61K031/16; A61P 25/00 20060101 A61P025/00 |
Claims
1-35. (canceled)
36. An pharmaceutical composition for attenuating pain at a
surgical site in a human or animal in need thereof, comprising a
capsaicinoid selected from the group consisting of from 1 .mu.g to
15,000 .mu.g of capsaicin, a therapeutically equivalent amount of
one or more other capsaicinoids, and therapeutically equivalent
combinations thereof; in from about 1 ml to about 100 ml of a
pharmaceutically acceptable vehicle for infiltration.
37. The pharmaceutical composition of claim 36 wherein said
capsaicinoid comprises from about 500 .mu.g to 5000 .mu.g
capsaicin, a therapeutically equivalent amount of one or more other
capsaicinoids, and therapeutically equivalent combinations
thereof.
38. The pharmaceutical composition of claim 36, wherein the
capsaicinoid is at least about 97% trans-capsaicin.
39-40. (canceled)
Description
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 60/434,453, filed Dec. 18, 2002, and U.S.
Provisional Patent Application No. 60/461,164, filed Apr. 8, 2003,
the disclosures of which is hereby incorporated by reference in
their entirety.
FIELD OF THE INVENTION
[0002] This application is directed to compositions and methods for
relieving pain at a specific site, for example, associated with
inflammation of joints, tendons, nerves, muscle, and other soft
tissues, nerve injury and neuropathies, and pain from tumors in
soft tissues or bone.
BACKGROUND OF THE INVENTION
[0003] Capsaicin, a pungent substance derived from the plants of
the solanaceae family (hot chili peppers) has long been used as an
experimental tool because of its selective action on the small
diameter afferent nerve fibers C-fibers and A-delta fibers that are
believed to signal pain. From studies in animals, capsaicin appears
to trigger C-fiber membrane depolarization by opening cation
channels permeable to calcium and sodium. Recently one of the
receptors for capsaicin effects has been cloned. Capsaicin can be
readily obtained by ethanol extraction of the fruit of capsicum
frutescens or capsicum annum. Capsaicin is known by the chemical
name N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-trans-6-enamide.
Capsaicin is practically insoluble in water, but freely soluble in
alcohol, ether, benzene and chloroform. Therapeutically capsaicin
has been used as a topical analgesic. Capsaicin is available
commercially as Capsaicin USP from Steve Weiss & Co., 315 East
68' Street, New York, N.Y. 10021 and can also be prepared
synthetically by published methods. See Michalska et al.,
"Synthesis and Local Anesthetic Properties of N-substituted
3,4-Dimethoxyphenethylamine Derivatives", Diss Pharm. Pharmacol.,
Vol. 24, (1972), pp. 17-25, (Chem. Abs. 77: 19271a), discloses
N-pentyl and N-hexyl 3,4-dimethoxyphenylacetamides which are
reduced to the respective secondary amines.
[0004] Capsaicin is listed in the pharmacopoeias of the United
Kingdom, Australia, Belgium, Egypt, Germany, Hungary, Italy, Japan,
Poland, Portugal, Spain, and Switzerland and has previously been
listed in the United States Pharmacopoeia and the National
Formulary. The FDA proposed monographs on analgesic drug products
for over-the-counter (OTC) human use. These include capsaicin and
capsicum preparations that are regarded as safe and effective for
use as OTC external analgesics. Capsaicin is the only chemical
entity of Capsicum recognized by the FDA. Capsaicin (USP) contains
not less than 110% total capsaicinoids which typically corresponds
to 63% pure capsaicin. USP capsaicin is trans-capsaicin (55-60%)
and also contains the precursors dihydrocapsaicin and
nordihydrocapsaicin.
[0005] Capsaicin mediated effects include: (i) activation of
nociceptors in peripheral tissues; (ii) eventual desensitization of
peripheral nociceptors to one or more stimulus modalities; (iii)
cellular degeneration of sensitive A-delta and C-fiber afferents;
(iv) activation of neuronal proteases; (v) blockage of axonal
transport; and (vi) the decrease of the absolute number of
nociceptive fibers without affecting the number of non-nociceptive
fibers.
[0006] The dosage forms of capsaicin which have been most widely
studied clinically are capsaicin containing creams (Zostrix,
Zostrix-HP, and Axsain). These products have been examined in a
broad spectrum of painful conditions including osteoarthritis.
However the efficacy of topically administered capsaicin in
arthritis in general has proven to be limited.
[0007] Prior publications describe topical administration of
capsaicin for the treatment of various conditions. For example,
U.S. Pat. No. 4,997,853 (Bernstein) describes methods and
compositions utilizing capsaicin as an external analgesic. U.S.
Pat. No. 5,063,060 (Bernstein) describes compositions and methods
for treating painful, inflammatory or allergic disorders. U.S. Pat.
No. 5,178,879 (Adekunle, et al.) describes methods for preparing a
non-greasy capsaicin gel for topical administration for the
treatment of pain. U.S. Pat. No. 5,296,225 (Adekunle, et al.)
describes indirect methods of treating orofacial pain with topical
capsaicin. U.S. Pat. No. 5,665,378 (Davis, et al.) describes
transdermal therapeutic formulations comprising capsaicin, a
nonsteroidal anti-inflammatory agent and pamabrom for the treatment
of pain. U.S. Pat. No. 6,248,788 (Robbins, et al.) describes
administration of 7.5% capsaicin cream in combination with marcaine
epidural injections in patients suffering from long-term persistent
foot pain. U.S. Pat. No. 6,239,180 (Robbins) describes combining
capsaicin loaded patches with local anesthesia to treat peripheral
neuropathy. The use of topical capsaicin has also been described in
the art to treat conditions as diverse as post mastectomy pain
syndrome (Watson and Evans, Pain 51: 375-79 (1992)); painful
diabetic neuropathy (Tandan et al., Diabetes Care 15: 8-13 (1992));
The Capsaicin Study Group, Arch Intern Med 151: 2225-9 (1991);
post-herpetic neuralgia (Watson et al., Pain 33: 333-40 (1988)),
Watson et al., Clin. Ther. 15: 510-26 (1993); Bernstein et al., J.
Am. Acad Dermatol 21: 265-70 (1989) and pain in Guillian-Barre
syndrome (Morganlander et al., Annals of Neurology 29:199 (1990)).
Capsaicin has also been used in the treatment of osteoarthritis
(Deal et al., Clin Ther 13: 383-95 (1991); McCarthy and McCarthy,
J. Rheumatol 19: 604-7 (1992); Altman et al., Seminars in Arthritis
and Rheumatism 23: 25-33 (1994). In addition, U.S. Pat. No.
4,599,342 (LaHann) describes oral and subcutaneous or intramuscular
administration of a combination of capsaicin or a capsaicin analog
with an opioid analgesic. U.S. Pat. No. 4,313,958 (LaHann)
describes intrathecal, epidural, intramuscular, intravenous,
intraperitoneal and subcutaneous administration of capsaicin
utilizing a "stair-step" dosing pattern.
[0008] Humans have long been exposed to dietary sources of
capsaicin-containing spices and to topical preparations used for a
variety of medical indications. This vast experience has not
revealed significant or lasting adverse effects of capsaicin
exposure. The recent determination of capsaicin's potential
therapeutic effects on unmyelinated sensory afferent nerve fibers
require diligent consideration of this compound for further
pharmaceutical development.
[0009] Because of capsaicin's ability to desensitize nociceptors in
peripheral tissues, its potential analgesic effects have also been
assessed in various clinical trials. However, since the application
of capsaicin itself frequently causes burning pain and hyperalgesia
apart from the neuropathic pain being treated, patient compliance
has been poor and the drop out rates during clinical trials have
exceeded fifty percent. The spontaneous burning pain and
hyperalgesia are believed to be due to intense activation and
temporary sensitization of the peripheral nociceptors at the site
of capsaicin application. This activation and sensitization occur
prior to the desensitization phase. The activation phase could be a
barrier to use of capsaicin because of the pain produced.
[0010] It would therefore be advantageous to provide methods and
compositions including capsaicin or capsaicin analogues thereof
with effective concentrations to cause an analgesic effect without
the side effects normally associated with the use of capsaicin.
OBJECTS AND SUMMARY OF THE INVENTION
[0011] It is an object of the present invention to provide
compositions and methods for providing pain relief in humans and
animals by administering via infiltration a dose of capsaicin or
capsaicin analogue to a surgical site or open wound for the
treatment of acute or chronic pain, nociceptive and neuropathic
pain, pre- and post-operative pain, cancer pain, pain associated
with neurotransmitter dysregulation syndromes and orthopedic
disorders.
[0012] It is another object of the present invention to provide
compositions and methods for attenuating pain at a surgical site in
a human or animal via the administration of a capsaicinoid via
infiltration at the surgical site.
[0013] It is another object of the present invention to provide
compositions and methods for attenuating pain at an open wound in a
human or animal via the administration of a capsaicinoid via
infiltration at the open wound.
[0014] It is a further object of the invention to provide
compositions and methods for treatment of pain associated with
median sternotomy utilizing infiltratable capsaicinoids.
[0015] It is a further object of the invention to provide
compositions and methods for treatment of pain associated with
mastectomy utilizing infiltratable capsaicinoids.
[0016] It is a further object of the invention to provide
compositions and methods for treatment of pain associated with
orthopedic surgical procedures utilizing infiltratable
capsaicinoids.
[0017] It is a further object of the invention to provide
compositions and methods for treating acute traumatic pain
utilizing infiltratable capsaicinoids.
[0018] It is a further object of the invention to provide
compositions and methods for treating neuropathic pain utilizing
infiltratable capsaicinoids.
[0019] It is a further object of the invention to provide
compositions and methods for treating nociceptive pain utilizing
infiltratable capsaicinoids.
[0020] It is a further object of the invention to provide
compositions and methods for treating
neurotransmitter-dysregulation syndromes utilizing infiltratable
capsaicinoids.
[0021] In accordance with the above objects and others, in certain
embodiments of the present invention, there is provided a method
for attenuating pain at a surgical site or an open wound in a human
or animal, comprising infiltrating a dose of a capsaicinoid in an
amount effective to denervate a site selected from a surgical site
or an open wound without eliciting an effect outside the site, said
effective dose being from about 1 .mu.g to about 15,000 .mu.g of
capsaicin or a therapeutically equivalent dose of a capsaicinoid
other than capsaicin. In other words, the term "capsaiciniod" is
meant to encompass formulations where the drug is capsaicin, a
capsaicinoid other than capsaicin, or a mixture of capsaicin with
one or more other capsaicinoids (the total amount of all
capsaicinoid drug being based on a therapeutically equivalent dose
to dose from about 1 .mu.g to about 15,000 .mu.g capsaicin).
[0022] In certain preferred embodiments, the effective dose of
capsaicinoid is from about 500 to about 15,000 .mu.g capsaicin, or
from about 600 to about 10,000 .mu.g capsaicin, or a
therapeutically equivalent dose of a capsaicinoid other than
capsaicin. In certain preferred embodiments, the dose of
capsaicinoid is administered in a pharmaceutically acceptable
vehicle for infiltration in a volume from about 0.1 to about 1000
ml. In certain preferred embodiments, the dose of capsaicinoid is
administered in a pharmaceutically acceptable vehicle for
infiltration in a volume from about 1 ml to about 100 ml. In other
further preferred embodiments, the dose of capsaicinoid is
administered in a pharmaceutically acceptable vehicle for
infiltration in a volume from about 5 ml to about 30 ml.
[0023] In certain preferred embodiments, the method further
comprises administering a local or general anesthetic prior to or
concurrently with said dose of capsaicinoid. The dose of local
anesthetic may be, e.g., an amount and location effective to
attenuate an initial hyperalgesic effect of said administered dose
of capsaicinoid. The local anesthetic may be administered by
infiltration to the surgical or wound site.
[0024] In certain preferred embodiments, the administration of
capsaicinoid at the site provides attenuation of pain in proximity
to the surgical or wound site for at least about 48 hours, and
preferably for at least about one week.
[0025] In certain preferred embodiments, the capsaicinoid is
capsaicin. In certain preferred embodiments, the capsaicin consists
essentially of trans-capsaicin.
[0026] In certain preferred embodiments, the capsaicinoid
administration provides an effect selected from the group
consisting of: a) producing a selective, highly-localized
destruction or incapacitation of C-fibers and/or A-delta fibers in
a localized area responsible for the initiation of pain for the
purpose of reducing or eliminating pain arising from the area, and
b) minimizing potential adverse consequences of C-fiber and/or
A-delta activation and or damage outside of the locus of pain.
[0027] In certain embodiments, the surgical site is a median
sternotomy, and the method further comprises infiltrating said dose
of capsaicinoid in an amount effective to denervate said sternal
edges without eliciting an effect outside the sternal edge
location. In other embodiments, the site of administration is
wound, such as a long bone fracture. The surgical site may be
involve any site where localized attenuation of pain is deemed
desirable. Such surgical sites include but are not limited to a
laparoscopy, a mastectomy, an arthroplasty, cancer surgery,
bunionectomy, and the like. The surgical site may also be
associated with an injury selected from the group consisting of a
tear of the anterior cruciate ligament, a tear of the posterior
cruciate ligament, a tear of the medial collateral ligament, a tear
of the lateral collateral ligament; a meniscal cartilage tear; a
cartilage defect of the knee; an orthopedic disorder of the
shoulder selected from the group consisting of bursitis,
dislocation, separation, impingement and tear of the rotator cuff,
tendonitis, adhesive capsulitis, shoulder fracture, or may be
associated with tendonitis, bursitis or bursitis injury, etc. Such
surgery may be performed via laproscopy or otherwise.
[0028] In certain preferred embodiments, the dose of capsaicinoid
is from about 500 .mu.g to about 5000 .mu.g capsaicin, or a
therapeutically equivalent dose of another capsaicinoid.
[0029] In certain preferred embodiments, the capsaicinoid is a
purified capsaicin, and more preferably is at least about 97%
trans-capsaicin.
[0030] The invention is further directed to a pharmaceutical
composition for attenuating pain at a surgical site in a human or
animal in need thereof, comprising a capsaicinoid selected from the
group consisting of from 1 .mu.g to 15,000 .mu.g of capsaicin, a
therapeutically equivalent amount of one or more other
capsaicinoids, and therapeutically equivalent combinations thereof;
in from about 1 ml to about 100 ml of a pharmaceutically acceptable
vehicle for infiltration.
[0031] In certain preferred embodiments, the pharmaceutically
acceptable vehicle for infiltration comprises effective
concentrations of polyethylene glycol, histidine and sucrose, in
water for injection. In certain preferred embodiments, the
capsaicinoid comprises greater than 5001 .mu.g to about 15,000
.mu.g capsaicin, a therapeutically equivalent amount of one or more
other capsaicinoids, and therapeutically equivalent combinations
thereof.
[0032] In order that the invention described herein may be more
fully understood, the following definitions are provided for the
purposes of this disclosure:
[0033] The term "infiltration" or "infiltratable" shall mean
administration into a discrete surgical site or open wound in a
human or animal.
[0034] As used herein, the term "capsaicinoid" means capsaicin,
capsaicin USP and purified capsaicin, capsaicin analogues and
derivatives thereof (collectively referred to as capsaicinoids in
this specification and appended claims) that act at the same
pharmacologic sites, e.g., VR1, as capsaicin, unless otherwise
specified.
[0035] Acute pain shall mean any pain that presents with a rapid
onset followed by a short, severe course, e.g., headache, pain
associated with cancer, fractures, strains, sprains, and
dislocations of bones, joints, ligaments and tendons.
[0036] Chronic pain shall mean pain that lasts for a long period of
time or is marked by frequent recurrence, e.g., pain associated
with terminal illnesses, arthritis, autoimmune diseases; or
neuropathic pain caused by degenerative diseases such as diabetes
mellitus or spinal degeneration, or resulting from neural
remodeling following traumatic injury or surgery.
[0037] As used herein, the term "local anesthetic" means any drug
or mixture of drugs that provides local numbness and/or
analgesia.
[0038] By co-administration it is meant either the administration
of a single composition containing both the capsaicin and an
additional therapeutically effective agent(s), e.g., local
anesthetic or phenol, or the administration of a capsaicin and the
additional therapeutically effective agent(s) as separate
compositions within short enough time periods that the effective
result is equivalent to that obtained when both compounds are
administered as a single composition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] The following drawings are illustrative of embodiments of
the invention and are not meant to limit the scope of the invention
as encompassed by the claims.
[0040] FIG. 1 is a graph displaying the plasma concentration of the
10 .mu.g, 100 .mu.g and 300 .mu.g doses of capsaicin administered
to study subjects entered into the Osteoarthritis Safety Study
exemplified in Example 1.
[0041] FIG. 2 is a graph displaying the percent reduction in VAS
score compared to baseline in study subjects entered into the
Osteoarthritis Safety Study exemplified in Example 1.
[0042] FIG. 3 is a graph displaying the NRS Pain Score in study
subjects entered into the Osteoarthritis Efficacy Study exemplified
in Example 2.
[0043] FIG. 4 is a graph displaying a comparison of VAS Pain Score
between subjects entered into the Bunionectomy Efficacy study
exemplified in Example 3.
[0044] FIG. 5 is a graph displaying a comparison of the percent of
subjects entered in to the Bunionectomy Efficacy study exemplified
in Example 3 requiring rescue medication.
DETAILED DESCRIPTION OF THE INVENTION
[0045] The compositions and methods disclosed herein can be used
for treating pain at a surgical site or open wound with an
effective amount of capsaicin or capsaicin analogue, hereinafter
collectively referred to as "capsaicinoids". In one preferred
embodiment, the methods involve administration of an effective
amount of capsaicinoid to a surgical site or open wound in a human
or animal for relieving pain at the surgical site or open
wound.
[0046] In another embodiment, the methods involve providing
anesthesia to the surgical site or open wound where the
capsaicinoid is to be administered, and then administering an
effective amount of capsaicinoid to the surgical site or open
wound. The anesthesia can be provided directly to the surgical site
or open wound, or at a remote site that causes anesthesia at the
surgical site or open wound where the capsaicinoid is to be
administered. General anesthesia may also be used. Epidural
regional anesthesia can be provided to patients to which the
capsaicinoid is to be administered at a surgical site or open wound
located from the waist down. Alternatively, a local anesthetic may
be administered as a regional block, a proximal block, a somatic
block, or a neuraxial block. The anesthetic may be administered as
a general anesthetic, as a spinal block, as an epidural block, or
as a nerve block. Preferably, in the embodiments in which a local
anesthetic is administered, the local anesthetic is administered
prior to administration of the capsaicinoid, such that the local
anesthetic has provided temporary anesthesia to the area to be
treated with the capsaicinoid.
[0047] Examples of local anesthetic agents which can be used
include bupivacaine, ropivacaine, dibucaine, procaine,
chloroprocaine, prilocalne, mepivacaine, etidocaine, tetracaine,
lidocaine, and xylocaine, and mixtures thereof and any other
art-known pharmaceutically acceptable local anesthetic. The local
anesthetic can be in the form of a salt, for example, the
hydrochloride, bromide, acetate, citrate, carbonate or sulfate.
More preferably, the local anesthetic agent is in the form of a
free base. Preferred local anesthetic agents include, e.g.,
bupivacaine. For bupivacaine, the free base provides a slower
initial release and avoids an early "dumping" of the local
anesthetic at the infiltration site. Other local anesthetics may
act differently. Local anesthetic agents typically administered
systematically may also be used in those cases where the means of
administration results only in a local effect, rather than
systemic.
[0048] The dose of local anesthetic will depend on the anesthetic
being administered as well as the site where the local anesthetic
is administered. For example, in embodiments where the local
anesthetic is administered via a regional block (e.g., an ankle
block), the dose of anesthetic ranges from about 1 ml up to about
30 ml of a 0.5% solution (e.g., bupivacaine). In other embodiments
a 3 mg/kg dose (maximum 200 mg) of a 2% solution (e.g., lidocaine)
can be administered by intra-articular infiltration. In other
embodiments the dose of local anesthetic can range between 0.5 ml
to about 60 ml of a 0.25% to 5% solution.
[0049] Alternatively, phenol can be administered at the surgical
site or open wound to be treated in place of (or in addition to) a
local anesthetic to anesthesize the area. Phenol can preferably be
administered prior to administration of the capsaicinoid, or can be
co-administered with the dose of capsaicinoid. By co-administration
it is meant either the administration of a single composition
containing both the capsaicinoid and the phenol, or the
administration of the capsaicinoid and the phenol as separate
compositions within short enough time periods that the effective
result is equivalent to that obtained when both compounds are
administered as a single composition.
[0050] Prior to the present invention, for example, in U.S. Pat.
No. 4,313,958 (LaHann), capsaicin is described as producing
analgesia when administered via "systemic administration" (i.e.,
intrathecal, epidural, intramuscular, intravenous, intraperitoneal
and subcutaneous). Animal testing was accomplished via "stair-step
dosing" which purportedly was said to reduce or eliminate some of
the side affects of capsaicin. It is reported therein that
capsaicin, when systemically delivered in final doses of 25 mg/kg
or less prior to ultra violet radiation, prevented radiation
induced hyperalgesia, but did not elevate the pain threshold above
normal range. Only when larger doses of capsaicin were administered
systemically, i.e. final doses of capsaicin being 50 mg/kg or
greater, was the pain threshold elevated. LaHann hypothesized (but
did not exemplify), that for clinical use in humans, total doses
from 0.05 mg/kg to 1,000 mg/kg were acceptable and total doses from
0.25 mg/kg to 500 mg/kg were preferred. The rats weighed between
125 and 175 grams and the total administered dose of capsaicin
ranged from 27 mg/kg to 102 mg/kg (or a total dose injected
subcutaneously of about 3.375 mg to about 17.85 mg capsaicin).
[0051] More recently, U.S. Pat. No. 5,962,532 (Campbell et al)
describes an injection volume of 0.1 to 20 ml and a concentration
of capsaicin between 0.01 to 10% for parenteral administration,
which calculates to a total dose of capsaicin of between 0.01 mg to
2,000 mg, based on volume and concentration.
[0052] In contrast, in the present invention, the administration of
microgram quantities of capsaicin into discrete localized areas
responsible for the treatment and/or attenuation of pain recognizes
significant advantages over system-wide exposure to milligram
quantities in order to produce a therapeutic effect through
alteration of sensory nerve function in a limited area.
[0053] In the present invention, a single dose of from about 1
.mu.g to 15,000 .mu.g of capsaicin, or a therapeutically equivalent
dose of one or more other capsaicinoids, is administered via
infiltration to produce a selective, highly-localized destruction
or incapacitation of C-fiber and/or A-delta-fiber in discrete
localized areas responsible for the initiation of pain for the
purpose of eliminating pain arising from that locus, while
minimizing potential adverse consequences of C-fiber and/or
A-delta-fiber activation and/or damage outside of the locus of
pain. In certain preferred embodiments, from about 600 to about
15,000 micrograms of capsaicin, or a therapeutically equivalent
dose of one or more other capsaicinoids, is administered at the
surgical site or open wound. In certain preferred embodiments, the
amount of capsaicin and/or preferably the range of capsaicin
administered at the surgical site or open wound is from about 1,000
to about 1000 micrograms. In other words, the present invention is
directed to administration of a single dose of capsaicin or other
capsaicinoid(s) in an amount that is greatly reduced as compared to
the dosage range previously considered useful by those skilled in
the art to denervate the nerve fibers in a discrete, localized area
without eliciting a systemic effect (e.g., an effect beyond that
discrete, localized location).
[0054] Capsaicinoids (capsaicin analogues) with similar
physiological properties, i.e., triggering C fiber membrane
depolarization by opening of cation channels permeable to calcium
and sodium, are known. For example, resiniferatoxin is described as
a capsaicin analoguein U.S. Pat. No. 5,290,816 to Blumberg. U.S.
Pat. No. 4,812,446 to Brand (Procter & Gamble Co.) describes
other capsaicin analogues and methods for their preparation. U.S.
Pat. No. 4,424,205 cites capsaicin analogues. Ton et al., Brit. J.
Pharm. 10:175-182 (1955) discusses the pharmacological actions of
capsaicin and its analogues. Capsaicin, capsaicin analogues and
other capsaicinoids are also described in detail in WO 96/40079,
the disclosure of which is hereby incorporated by reference.
Capsaicinoids are also described in EP0 149 545, the disclosure of
which is also hereby incorporated by reference.
[0055] Alternatively, capsaicin analogues may be administered at
the site in replacement of, part of, or all of the dose of
capsaicin, the capsaicin analogue being administered in a
therapeutically equivalent amount of capsaicin for which it is
substituted. Where a capsaicin analogue is selected to replace some
or all of the capsaicin, the capsaicin analogue can be selected
from those compounds with similar physiological properties to
capsaicin as are known in the art. Resiniferatoxin also shows a
somewhat different spectrum of action, providing greater relief of
pain at a given dose. Therefore, the dose of resiniferatoxin should
be at least 100 fold less than a dose of capsaicin alone.
Resiniferatoxin qualitatively resembles capsaicin in its activity,
but differs quantitatively in potency (i.e. 10.sup.3-10.sup.4 fold
more potent) and in relative spectrum of actions. When the
capsaicinoid used is resiniferatoxin, the dose administered may be,
e.g., 0.1.times.10.sup.-3 to 5.times.10.sup.-2 mg/kg, preferably
0.1.times.10.sup.-3 to 5.times.10.sup.-3 mg/kg, body weight of the
subject (patient) for single application, or less upon multiple
application. In certain embodiments, resiniferatoxin is
administered in the range of 1.times.10.sup.-5 mg/kg to
5.times.10.sup.-2 mg/kg to the patient.
[0056] Other suitable capsaicin analogues preferably include, but
are not limited to, N-vanillylnonanamides, N-vanillylsulfonamides,
N-vanillylureas, N-vanillylcarbamates, N[(substituted
phenyl)methyl]alkylamides, methylene substituted N[(substituted
phenyl)methyl]alkanamides, N[(substituted
phenyl)methyl]-cis-monosaturated alkenamides, N[(substituted
phenyl)methyl]diunsaturated amides, 3-hydroxyacetanilide,
hydroxyphenylacetamides, pseudocapsaicin, dihydrocapsaicin,
nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin I,
anandamide, piperine, zingerone, warburganal, polygodial,
aframodial, cinnamodial, cinnamosmolide, cinnamolide, civamde,
nonivamide, olvanil, N-oleyl-homovanillamidia, isovelleral,
scalaradial, ancistrodial, .beta.-acaridial, merulidial, scutigeral
and any combinations or mixtures thereof.
[0057] In certain embodiments, the capsaicinoid utilized in the
compositions and methods of the invention is capsaicin itself. In
certain preferred embodiments, the capsaicin is in a purified form
obtained from the chemical purification of Capsaicin USP. In
certain preferred embodiments, the purified capsaicin used in the
compositions and methods of the invention consists essentially of
the trans isomer. The trans-isomer of capsaicin has its activity at
the vanilloid receptor, and this embodiment, the methods and
formulation of the present invention are especially useful for
treating disorders or pain that can be alleviated through
activation of the vanilloid receptors via the VR-1 mechanism.
Whereas Capsaicin USP contains only about 55-60% trans-capsaicin,
with the remainder comprising the precursors dihydrocapsaicin and
nordihydrocapsaicin, in such embodiments the formulation preferably
consists essentially of trans-capsaicin, e.g., preferably having a
purity of greater than about 97%, preferably greater than about
98%, more preferably greater than about 99% trans-capsaicin.
[0058] The trans isomer is preferably prepared in accordance with
the method for synthesizing the trans isomer of capsaicin from a
four step process and purified as describe in U.S. Provisional
Application No. 60/461,164 filed Apr. 8, 2003, the disclosure of
which is hereby incorporated by reference in its entirety. In
accordance with U.S. Provisional Application No. 60/461,164 said
method for synthesizing the trans isomer of capsaicin comprises a)
alkylating 3-methyl butyne with halovaleric acid and/or
-haloalkanic acid to obtain 8-methyl-6-nonynoic acid and/or
alkynoic acid analogues thereof; b) reducing said
8-methyl-6-nonynoic acid to obtain trans-8-methyl-nonenoic acid; c)
activating the 8-methyl-nonenoic acid to obtain an acid chloride;
and d) acylating 4-hydroxy-3-methoxybenzylamine hydrochloride with
the acid chloride to obtain trans-capsaicin.
[0059] In certain embodiments, step a) of the method for
preparation of the capsaicin for use in the present invention
comprises the steps of: i) mixing anhydrous tetrahydrofuran (THF)
with hexamethylphosphoramide (HMPA) and cooling the mixture to
about -78.degree. C. to about -75.degree. C.; ii) adding to the
mixture of step i) 3-methyl butyne followed by a dropwise addition
of a base at a temperature from about -78.degree. C. to about
-65.degree. C. to obtain a second mixture; iii) warming the second
mixture up to about -30.degree. C. and stirring for about 30
minutes; and iv) adding dropwise a solution of a halovaleric acid
in anhydrous tetrahydrofuran at a temperature of about -30.degree.
C. for about 10 to about 15 minutes, then gradually warming to room
temperature and stirring overnight to obtain a reaction
mixture.
[0060] In certain other embodiments, there is provided a method for
obtaining a crude step a) intermediate product further comprising
the steps of: i) adding 3M hydrochloric acid (HCl) to a reaction
mixture and extracting the reaction mixture with ethyl acetate; and
ii) washing the extracted reaction mixture with brine to yield a
crude product.
[0061] In certain embodiments, step b) of the method for
preparation of the capsaicin for use in the present invention
comprises the steps of: i) dissolving said 8-methyl-6-nonynoic acid
in a mixture of anhydrous tetrahydrofuran and tertiary-butyl
alcohol (t-BuOH) to obtain a solution and cooling the solution to
about -55.degree. C. to about -40.degree. C.; ii) condensing
ammonia (NH3) to the solution to a temperature of about -50.degree.
C. to about -40.degree. C.; iii) adding sodium drips piece-wise and
stirring from about 30 minutes to about 2 hours at a temperature
from about -45.degree. C. to about -30.degree. C., and iv) adding
ammonium chloride (NH4Cl), warming to room temperature and allowing
the NH3 to evaporate overnight to obtain a reaction mixture. Step
iii) of the step b) reaction may further comprise adding piece-wise
lithium and stirring from about 30 minutes to about 2 hours at a
temperature from about -65 C to about -45 C.
[0062] In certain other embodiments crude step b) intermediate
product further comprises the steps of: i) adding water to a
reaction mixture; ii) acidifying the reaction mixture with 6N HCl
to a pH of about 2 to about 3; iii) extracting the reaction mixture
with ethyl acetate, washing with brine and drying over anhydrous
sodium sulfate (Na2SO4); and iv) filtering and removing solvents
under vacuum to obtain a crude step b) intermediate product.
[0063] In certain embodiments, step c) of the method for
preparation of the capsaicin for use in the present invention
comprises the steps of: i) adding dropwise a thionyl halide to the
8-methyl-nonenoic acid at room temperature for about 15 minutes to
about 30 minutes to form a solution; ii) heating the solution at
about 50.degree. C. to about 75 C for a period of about 1 hour; and
iii) removing excess thionyl halide under vacuum at about 4.degree.
C. to about 45 C to obtain a step c) intermediate product.
[0064] In certain embodiments, step d) of the method for
preparation of the capsaicin for use in the present invention
comprises the steps of: i) mixing 4-hydroxy-3-methoxy benzylamine
hydrochloride and dimethylformamide (DMF); ii) adding portion-wise
at room temperature to the mixture of step i) 5N sodium hydroxide
(NaOH) and stirring for about 30 minutes; iii) adding acid-halide
in anhydrous ether dropwise at a temperature of about 0.degree. C.
to about 10.degree. C. for about 20 minutes to about 1 hour; and,
thereafter, iv) gradually warming the mixture to room temperature
and stirring overnight. In certain embodiments step d) further
comprises the steps of: i) adding water to the mixture and
extracting the mixture with ethyl acetate to obtain an ethyl
acetate extract; ii) washing said extract with 1N HCl and,
thereafter, washing with sodium bicarbonate (NaHCO3); iii) washing
the solution with brine and drying over anhydrous sodium sulfate
(Na2SO4); and iv) filtering and removing solvents under vacuum to
obtain a crude product.
[0065] In certain preferred embodiments, the method of preparing
the trans-capsaicin or capsaicin intermediate after one or more of
the steps (e.g., a), b), c) and/or d)) further comprises purifying
the crude product by column chromatography, flash chromatography,
or the like, using silica gel and eluting with a mixture of ethyl
acetate/hexane to obtain a crude trans-capsaicin product.
[0066] Preferably after the capsaicin is formed via the 4 step
process as described above, the trans-capsaicin product is
subjected to purification process comprising the steps of: i)
dissolving the crude trans-capsaicin product in a mixture of
ether/hexane and heating the mixture to about 40.degree. C. to
about 45.degree. C.; ii) cooling the mixture to room temperature
while stirring for about 2 hours; and iii) filtering the mixture to
provide a purified trans-capsaicin product.
[0067] Alternatively, or additionally to the purification
process(es) as described above, the capsaicin is subjected to a
further purification process also referred to as a "semi-prep
purification" or "semi-preparative purification" of capsaicin. In
the semi-prep purification, the capsaicin or previously purified
capsaicin is purified via the use of a semi-preparative HPLC (high
performance liquid chromatography), which preferably provides for a
trans-capsaicin product having a purity of greater than about 97%,
preferably greater than about 98%, more preferably greater than
about 99% capsaicin.
[0068] In certain preferred embodiments, the active ingredient in
the preparation comprises substantially pure trans-capsaicin (e.g.
having no more than about 10% precursors or other capsaicin
compounds such as cis-capsaicin). In more preferred embodiments,
the preparation includes at least about 95% pure trans-capsaicin.
In most preferred embodiments, the preparation includes at least
about 99% pure trans-capsaicin. While the cis-isomer of capsaicin
has activity via a number of mechanisms, VR-1 is not considered to
comprise a major effect of this agent.
[0069] In view of the collective activity of the trans-isomer of
capsaicin at the VR-1 receptor, it is contemplated that it is
possible in certain embodiments of the present invention that the
amount of trans-capsaicin included in the methods and formulations
of the present invention will be reduced in comparison to a
preparation which includes a less pure form of capsaicin (e.g.,
capsaicin USP).
[0070] In other embodiments of the present invention, the
formulations and methods of the invention contemplate the use of a
capsaicin agent consisting essentially of cis-capsaicin.
[0071] Capsaicin, in either crude extract form, Capsaicin USP, or
as purified capsaicin, has been comprehensively studied in a
variety of tests in vitro, and in several animal species in
vivo.
[0072] Administration of a single dose of capsaicinoid according to
the methods of the present invention minimizes and/or prevents
systemic delivery of the capsaicin for the purposes of: a)
producing a selective, highly-localized destruction or
incapacitation of C-fibers and/or A-delta fibers in a discrete,
localized area responsible for the initiation of pain (e.g.,
intra-articular joints, intrabursally) for the purpose of reducing
or eliminating pain arising from a discrete locus (i.e., producing
antinociception), and b) minimizing potential adverse consequences
of C-fiber and/or A-delta activation and or damage outside of the
locus of pain (i.e., damage to homeostatic mechanisms, such as
cardiac reflex [e.g., Bezold-Jarisch reflex] or micturation reflex
[e.g., urge to void] or to nerve fibers in the central nervous
system). The analgesic effect preferably provides pain relief for
at least about 48 to about 120 hours, preferably from about 10 to
about 21 days, more preferably from about 4 to about 5 weeks, even
more preferably for at least about 6 to about 8 weeks, and most
preferably for at least about 16 weeks or more.
[0073] Delivery systems can also be used to administer capsaicin
and local anesthetics that produce modality-specific blockade, as
reported by Schneider, et al., Anesthesiology, 74:270-281 (1991),
or possess physical-chemical attributes that make them more useful
for sustained release then for single injection blockade, as
reported by Masters, et al., Soc. Neurosci. Abstr., 18:200 (1992),
the teachings of which are incorporated herein. An example of a
delivery system includes microspheres wherein the anesthetic is
incorporated into a polymer matrix in a percent loading of 0.1% to
90% by weight, preferably 5% to 75% by weight. It is possible to
tailor a system to deliver a specified loading and subsequent
maintenance dose by manipulating the percent drug incorporated in
the polymer and the shape of the matrix, in addition to the form of
local anesthetic (free base versus salt) and the method of
production. The amount of drug released per day increases
proportionately with the percentage of drug incorporated into the
matrix (for example, from 5 to 10 to 20%). Other forms of delivery
systems include microcapsules, slabs, beads, and pellets, which in
some cases can also be formulated into a paste or suspension.
[0074] The delivery systems are most preferably formed of a
synthetic biodegradable polymer, although other materials may also
be used to formulate the delivery systems, including proteins,
polysaccharides, and non-biodegradable synthetic polymers. It is
most preferable that the polymer degrade in vivo over a period of
less than a year, with at least 50% of the polymer degrading within
six months or less. Even more preferably, the polymer will degrade
significantly within a month, with at least 50% of the polymer
degrading into non-toxic residues which are removed by the body,
and 100% of the capsaicin and anesthetic being released within a
two week period. Polymers should also preferably degrade by
hydrolysis by surface erosion, rather than by bulk erosion, so that
release is not only sustained but also linear. Polymers which meet
this criteria include some of the polyanhydrides, poly(hydroxy
acids) such as co-polymers of lactic acid and glycolic acid wherein
the weight ratio of lactic acid to glycolic acid is no more than
4:1 (i.e., 80% or less lactic acid to 20% or more glycolic acid by
weight), and polyorthoesters containing a catalyst or degradation
enhancing compound, for example, containing at least 1% by weight
anhydride catalyst such as maleic anhydride. Other polymers include
protein polymers such as gelatin and fibrin and polysaccharides
such as hyaluronic acid. Polylactic acid is not useful since it
takes at least one year to degrade in vivo. The polymers should be
biocompatible. Biocompatibility is enhanced by recrystallization of
either the monomers forming the polymer and/or the polymer using
standard techniques.
[0075] Other local carrier or release systems can also be used, for
example, the lecithin microdroplets or liposomes of Haynes, et al.,
Anesthesiology 63, 490-499 (1985), or the polymer-phospholipid
microparticles of U.S. Pat. No. 5,188,837 to Domb.
[0076] Methods for manufacture of suitable delivery systems for
administration of capsaicin alone or together with the local
anesthetic are known to those skilled in the art. The formulations
may also be designed to deliver both the anesthetic and the
capsaicin, either simultaneously or sequentially.
[0077] The local anesthetic can preferably be administered by
direct injection or implantation to the site where the capsaicin or
capsaicin analogue is to be administered, for example, by
administering the local anesthetic directly in the diseased or pain
producing structure or the injured nerve or the nerve that provides
inervation to the painful area, or to effect a regional block of
the area including the site where the capsaicin is to be
administered.
[0078] In another embodiment, the local anesthetic can preferably
be administered by injection or implantation of the anesthetic into
the epidural space adjacent to the spine for pain originating below
a patient's waist, or directly into a joint for pain originating
above the patient's waist. The prior administration of a proximal
neural block sufficiently desensitizes C fibers to the expected
pungent side effects of the subsequent capsaicin
administration.
[0079] In the embodiment wherein the anesthetic is administered as
microspheres, the microspheres may be injected, implanted or
infiltrated through a trochar, or the pellets or slabs may be
surgically placed adjacent to nerves, prior to surgery or following
repair or washing of a wound. The microspheres can be administered
alone when they include both the capsaicin and local anesthetic or
in combination with a solution including capsaicin in an amount
effective to prolong nerve blockade by the anesthetic released from
the microspheres. The suspensions, pastes, beads, and
microparticles will typically include a pharmaceutically acceptable
liquid carrier for administration to a patient, for example,
sterile saline, sterile water, phosphate buffered saline, or other
common carriers.
[0080] The expected side effects of the dose of capsaicin are
believed to be from the intense nociceptor discharge occurring
during the excitatory phase before nociceptor desensitization.
However, the prior administration of an anesthetic, such as a nerve
block, proximally or directly to the site of administration,
eliminates or substantially reduces such side effects. If some
"breakthrough pain" occurs despite the anesthetic, this pain may be
treated by administering an analgesic such as a nonsteroidal
anti-inflammatory agent or narcotic analgesic (i.e., the various
alkaloids of opium, such as morphine, morphine salts, and morphine
analogues such as normorphine). The administration of the capsaicin
can be repeated if necessary.
[0081] The administration of the anesthetic along with the
subsequent administration of capsaicin or capsaicin-like compounds
alleviates pain at the site for a prolonged period of time.
Patients can be monitored for pain relief and increased movement,
in the situation where treatment is in a joint. The treatment can
be repeated as necessary to control the symptoms.
[0082] The compositions and methods of the present invention can be
used for treating various conditions associated with pain by
providing pain relief at a surgical site or open wound. Examples of
conditions to be treated include, but are not limited to,
nociceptive pain (pain transmitted across intact neuronal
pathways), neuropathic pain. (pain caused by damage to neural
structures), pain from nerve injury (neuromas and neuromas in
continuity), pain from neuralgia (pain originating from disease
and/or inflammation of nerves), pain from myalgias (pain
originating from disease and/or inflammation of muscle), pain
associated with painful trigger points, pain from tumors in soft
tissues, pain associated with neurotransmitter-dysregulation
syndromes (disruptions in quantity/quality of neurotransmitter
molecules associated with signal transmission in normal nerves) and
pain associated with orthopedic disorders such as conditions of the
foot, knee, hip, spine, shoulders, elbow, hand, head and neck that
require surgery.
[0083] The receptors involved in pain detection are aptly enough
referred to as nociceptor-receptors for noxious stimuli. These
nociceptors are free nerve endings that terminate just below the
skin as to detect cutaneous pain. Nociceptors are also located in
tendons and joints, for detection of somatic pain and in body
organs to detect visceral pain. Pain receptors are very numerous in
the skin, hence pain detection here is well defined and the source
of pain can be easily localized. In tendons, joints, and body
organs the pain receptors are fewer. The source of pain therefore
is not readily localized. Apparently, the number of nociceptors
also influences the duration of the pain felt. Cutaneous pain
typically is of short duration, but may be reactivated upon new
impacts, while somatic and visceral pain is of longer duration. It
is important to note that almost all body tissue is equipped with
nociceptors. As explained above, this is an important fact, as pain
has primary warning functions. If we did not feel pain and if pain
did not impinge on our well-being, we would not seek help when our
body aches. Nociceptive pain preferably includes, but is not
limited to post-operative pain, cluster headaches, dental pain,
surgical pain, pain resulting from severe burns, postpartum pain,
angina, genitor-urinary tract pain, pain associated with sports
injuries (tendonitis, bursitis, etc. . . . ) and pain associated
with joint degeneration and cystitis.
[0084] Neuropathic pain generally involves abnormalities in the
nerve itself, such as degeneration of the axon or sheath. For
example, in certain neuropathies the cells of the myelin sheath
and/or Schwann cells may be dysfunctional, degenerative and may
die, while the axon remains unaffected. Alternatively, in certain
neuropathies just the axon is disturbed, and in certain
neuropathies the axons and cells of the myelin sheath and/or
Schwann cells are involved. Neuropathies may also be distinguished
by the process by which they occur and their location (e.g. arising
in the spinal cord and extending outward or vice versa). Direct
injury to the nerves as well as many systemic diseases can produce
this condition including AIDS/HIV, Herpes Zoster, syphilis,
diabetes, and various autoimmune diseases. Neuropathic pain is
often described as burning, or shooting type of pain, or tingling
or itching pain and may be unrelenting in its intensity and even
more debilitating than the initial injury or the disease process
that induced it.
[0085] Neuropathies treatable by the methods of the present
invention include: syndromes of acute ascending motor paralysis
with variable disturbance of sensory function; syndromes of
subacute sensorimotor paralysis; syndromes of acquired forms of
chronic sensorimotor polyneuropathy, syndromes of determined forms
of genetic chronic polyneuropathy; syndromes of recurrent or
relapsing polyneuropathy; and syndromes of mononeuropathy or
multiple neuropathies (Adams and Victor, Principles of Neurology,
4th ed., McGraw-Hill Information Services Company, p. 1036, 1989).
Syndromes of acute ascending motor paralysis are selected from the
group consisting of acute idiopathic polyneuritis,
Landry-Guillain-Barre Syndrome, acute immune-mediated polyneuritis,
infectious mononucleosis polyneuritis, hepatitis polyneuritis;
diptheric polyneuropathy; porphyric polyneuropathy; toxic
polyneuropathy (e.g., thallium); acute axonal polyneuropathy; acute
panautonomic neuropathy; vaccinogenic, serogenic, paraneoplastic,
polyarteretic and lupus polyneuropathy.
[0086] Syndromes of subacute sensorimotor paralysis are selected
from the group consisting of deficiency states (e.g., beriberi,
pellagra, vitamin B12); heavy metal/industrial solvent poisonings
(e.g., arsenic, lead); drug overdose (e.g., isoniazid, disulfuram,
vincristine, taxol, chloramphenicol); uremic polyneuropathy;
diabetes; sarcoidosis; ischemic neuropathy and peripheral vascular
disease; AIDS; and radiation (radiotherapy). Syndromes of chronic
sensorimotor are selected from the group consisting of carcinoma,
myeloma and other malignancies; paraproteinemias; uremia; beriberi
(usually subacute), diabetes, hypo/hyperthyroidism; connective
tissue disease; amyloidosis; leprosy and sepsis. Genetic chronic
polyneuropathies are selected from the group consisting of dominant
mutilating sensory neuropathy (adult); recessive mutilating sensory
neuropathy (childhood); congenital insensitivity to pain;
spinocerebellar degenerations, Riley Day Syndrome; Universal
Anesthesia Syndrome; polyneuropathies w/metabolic disorder; and
mixed sensorimotor-autonomic type polyneuropathies.
Recurrent/relapsing polyneuropathy are selected from the group
consisting of idiopathic polyneuritis; porphyria; chronic
inflammatory polyradiculoneuropathy; mononeuritis multiplex;
beriberi/drug overdose; refsum disease and tangier disease.
Mono/multiple neuropathies are selected from the group consisting
of pressure palsies; traumatic neuropathies (e.g., irradiationor
electrical injury); serum, vaccinogenic (e.g., rabies, smallpox);
herpes zoster; neoplastic infiltration; leprosy; diptheretic wound
infections; migrant sensory neuropathy; shingles and post herpetic
neuralgia.
[0087] Neurotransmitter-dysregulation pain syndromes, rather than
involving abnormal or damaged nerves, result from normal nerves
having disruptions in the quantity and/or quality of the various
neurotransmitter molecules associated with signal transmission from
one neuron to another. More specifically, sensory transmitters are
released from the afferent nerve ending of one nerve cell and
received by receptors at the afferent end of another nerve cell.
They are chemical messengers which transmit the signal. There are
numerous transmitters, including glutamate, serotonin, dopamine,
norepinephrine, somatostatin, substance P, calcitonin gene-related
peptide, cholecystokinin, opiates and saponins. Alterations in the
quantity of transmitters and neuropeptide release, changes in the
afferent receptor, changes of re-uptake of the transmitter and/or
neuropeptides can all yield qualitative change of the neural
signaling process. As a result, the aberrant signal transmission is
interpreted by the body as pain. A representative neurotransmitter
dysregulation syndrome that may be treated by the present invention
includes fibromyalgia, which is a common condition characterized by
a history of chronic generalized pain and physical exam evidence of
at least 11 of 18 defined "tender point" sites in muscles and
connective tissue (Wolfe et al., Arthritis Rheum 33:160-72, 1990).
Commonly associated conditions include irritable bowel syndrome,
headache, irritable bladder syndrome (interstitial cystitis), sleep
disturbance, and fatigue (Goldenberg, Current Opinion in
Rheumatology 8:113-123, 1996; Moldofsky et al., Psychosom Med
37:341-51, 1975; Wolfe et al., 1990; Wolfe et al., J Rheum 23:3,
1996; Yunus et al., Semin Arthritis Rheum 11:151-71, 1981).
[0088] A predominant theory regarding the etiology of fibromyalgia
holds that an imbalance and/or dysregulation of neurotransmitter
function may occur within the central nervous system (CNS), either
in the brain or spinal cord and in the relation of the CNS to
muscle and connective tissue via regulatory nerve pathways
(Goldenberg, 1996; Russell, Rheum Dis Clin NA 15:149-167, 1989;
Russell et al., J Rheumatol 19:104-9, 1992; Vaeroy et al., Pain
32:21-6, 1988; Wolfe et al., 1996). Neurotransmitters are chemical
messengers, amino acids, biogenic amines and neuropeptides, emitted
from nerve cells that interact with receptors on other nerve cells,
as well as other cell types, including muscle and immune cells.
Neurotransmitter imbalance, which leads to increased pain
experience, may include a qualitative and/or quantitative decrease
in the function of such neurotransmitters as glutamate, serotonin,
dopamine, norepinephrine, somatostatin, substance P, calcitonin
gene-related peptide, cholecystokinin, opiates and saponins.
Fibromyalgia is characterized by a relative deficit of serotonin
effect and relative excess of substance P effect. This imbalance
results in amplified modulation of pain-signaling in the central
nervous system, resulting in neurogenic pain (Matucci-Cerinic,
Rheumatic Disease Clinics of North America 19:975-991, 1993;
Bonica, The Management of pain, Lea and Febiger, 2d ed.,
Philadelphia, pp. 95-121, 1990). Similar mechanisms may be at work
to cause associated conditions; for example, dysregulation of
neurotransmitter signaling in the bowel musculature, leading to
irritable bowel syndrome symptoms such as cramping, diarrhea,
and/or constipation.
[0089] Neurotransmitter-dysregulation pain syndromes include, but
are not limited to the following: generalized syndromes, localized
syndromes; craniofascial pain; vascular disease; rectal, perineum
and external genitalia pain; and local syndromes of the
leg/foot.
[0090] Generalized syndromes are selected from the group consisting
of stump pain, causalgia, reflex sympathetic dystrophy,
fibromyalgia or diffuse myofascial pain and burns. Localized
syndromes are selected from the group consisting of trigeminal
neuralgia; acute herpes zoster; panautonomic neuralgia; geniculate
neuralgia (Romsay Hunt Syndrome); glossopharyngeal neuralgia; vagus
nerve neuralgia and occipital neuralgia. Craniofacial pain includes
temporomandibular pain. Suboccipital and cervical muskuloskeletal
disorders are selected from the group consisting of myofascial
syndrome, which includes cervical sprain cervical hyperextension
(whiplash); sternocleidomastoid muscle; trapezius muscle; and
stylohyoid process syndrome (Eagle's syndrome). Vascular disease is
selected from the group consisting of Raynaud's disease; Raynaud's
phenomenon; frosbite; erythema pernio (chilblains); acrocyanosis
and livedo reticularis. Rectal, perineum and external genitalia
pain are selected from the group consisting of iliohypogastric
neuralgia; iliolinguinal nerve; genotifemoral nerve and testicular
pain. Local syndromes of the leg/foot are selected from the group
consisting of lateral cutaneous neuropathy (neuralgia
paresthetica); oobturator neuralgia; femoral neuralgia; sciatica
neuralgia; interdigital neuralgia of the foot (Morton's
metatarsalgia or neurma); injection neuropathy and painful legs and
moving toes.
[0091] Pain Intensity assessment scales are typically used by those
of ordinary skill in the art to evaluate analgesic choices and
therapeutic effects.
[0092] A Visual Analogue Scale (VAS) is a measurement instrument
that measures a characteristic that is believed to range across a
continuum of values and cannot easily be directly measured. For
example, the amount of pain that a patient feels ranges across a
continuum from none to an extreme amount of pain may be indirectly
measured via the use of a VAS. Operationally a VAS is usually a
horizontal line, 160 mm in length, anchored by word descriptors at
each end, for example "no pain" at one end and "very severe pain"
at the other end. The patient, marks on the line the point that
they feel represents their perception of their current state. The
VAS score is determined by measuring in millimeters from the left
hand end of the line to the point that the patient marks. The
100-mm visual analog scale (VAS), a unidimensional scale that is
versatile and easy to use, has been adopted in many settings.
[0093] The capsaicinoid formulations and methods described herein
may be used to treat many conditions where the capsaicinoid can be
administered via infiltration into a surgical site or open wound of
the patient, including but not limited to the treatment of acute or
chronic pain, nociceptive and neuropathic pain, pre- and
post-operative pain, cancer pain, pain associated with
neurotransmitter dysregulation syndromes and orthopedic disorders,
sports-related injuries, acute traumatic pain, nociceptive pain,
and neurotransmitter-dysregulation syndromes.
Treatment of Pain Associated with Mastectomy
[0094] In a preferred embodiment, the capsaicinoid formulations and
methods disclosed herein can be used for the treatment/attenuation
of pain associated with mastectomy. Mastectomy results in
significant pain and requires substantial doses of opioids
postoperatively. Analgesic techniques that provide good pain
control while minimizing opioid side effects are thus highly
desirable. The administration of capsaicinoid in a patient
requiring a mastectomy may reduce the amount of opioid consumption
and postoperative pain scores associated with the procedure. In
patients requiring a mastectomy, the dose of capsaicinoid can be
administered to the site where the surgery was performed or to the
muscle, tissue and bones surrounding the surgical site.
Treatment of Pain Associated with Median Sternotmy
[0095] In another preferred embodiment, the capsaicinoid
formulations and methods disclosed herein can be used for the
treatment/attenuation of pain associated with median sternotomy.
Median sternotomy is performed in patients undergoing cardiac,
pulmonary, or mediastinal surgery for various indications. The
procedure is performed through a vertical midline incision over the
sternum. After dividing the overlying midline fascia and muscle the
sternum is divided in its midline, from the sternal notch to the
xiphoid process, using either a sternal saw or a Lebsche knife.
Bleeding edges in the periosteum are controlled with point
electrocautery. Hemostasis of the marrow may be achieved using bone
wax or a Gel-foam/Thrombin mixture pressed into the marrow. A
sternal retractor is then placed to spread the sternal edges apart
and to maintain the surgical exposure. The dose of capsaicinoid can
be administered directly to the sternal edges, the muscle and/or
tissue surrounding the surgical site or directly to the bone (e.g.,
sternum). At completion of the procedure the sternal edges are
reapproximated with stainless steel wire. The remaining wound is
closed in fascial layers. Median sternotomy results in sternal
instability and pain requiring not only substantial doses of
opioids postoperatively, but also substantial amounts of nursing
and physical therapy time in order to ambulate the patients.
Analgesic techniques that provide good pain control while
minimizing opioid side effects are thus highly desirable. The
administration of a capsaicinoid in a patient requiring a median
sternotomy may reduce the amount of opioid consumption and
postoperative pain scores associated with the procedure.
Orthopedic Disorders
[0096] The capsaicinoid formulations and methods disclosed herein
may be utilized to treat/attenuate pain associated with orthopedic
disorders. Orthopedic disorders treatable via the use of the
formulations and methods of the invention include but are not
limited to disorders of the knee, shoulders, back, hip, spine,
elbows, foot, hand and other disorders, which involve pain at a
specific site or body space. Orthopedic disorders affecting these
locations include, but are not limited to bursitis, tendonitis;
osteoarthritis, and rheumatoid arthritis.
[0097] A. Bursitis
[0098] Bursitis is the inflammation of a bursa. Bursae are saclike
cavities or potential cavities that contain synovial fluid located
at tissue sites where friction occurs (e.g., where tendons or
muscles pass over bony prominences). Bursae facilitate normal
movement, minimize friction between moving parts, and may
communicate with joints. In the normal state, the bursa provides a
slippery surface that has almost no friction. A problem arises when
a bursa becomes inflamed. The bursa loses its gliding capabilities,
and becomes more and more irritated when it is moved. When the
condition called bursitis occurs, the slippery bursa sac becomes
swollen and inflamed. The added bulk of the swollen bursa causes
more friction within already confined spaces. Also, the smooth
gliding bursa becomes gritty and rough. Movement of an inflamed
bursa are painful and irritating. Bursitis usually occurs in the
shoulder (subacromial or subdeltoid bursitis). Other sites include
the olecranon (miners' elbow), prepatellar (housemaid's knee) or
suprapatellar, retrocalcaneal (Achilles), iliopectineal (iliopsoas)
of the hip, ischial (tailor's or weaver's bottom) of the pelvis,
greater trochanteric of the femur, and first metatarsal head
(bunion). Bursitis may be caused by trauma, chronic overuse,
inflammatory arthritis (eg, gout, rheumatoid arthritis), or acute
or chronic infection (eg, pyogenic organisms, particularly
Staphylococcus aureus; tuberculous organisms, which now rarely
cause bursitis). Orthopedic disorders of the foot include, but are
not limited to, heel spurs, corns, bunions, Morton's neuroma,
hammertoes, ankle sprain, fractures of the ankle or metatarsals or
sesamoid bone or toes, plantar fascitis and injuries to the
achilles tendon. Orthopedic disorders of the hand include, but are
not limited to, arthritis, carpal tunnel syndrome, ganglion cysts,
tendon problems such as lateral epicondylitis, medial
epicondylitis, rotator cuff tendonitis, DeQuervian's tenosynovitis,
and trigger finger/trigger thumb. Other orthopedic disorders
include, but are not limited to, Paget's disease, scoliosis,
soft-tissue injuries such as contusions, sprains and strains, long
bone fractures and various other sports injuries some of which
include patellar tendonitis and lumbar strain.
[0099] Treatment of non-infected acute bursitis has mainly
consisted of temporary rest or immobilization and high-dose NSAIDs,
sometimes narcotic analgesics, may be helpful. Voluntary movement
should be increased as pain subsides. Pendulum exercises are
particularly helpful for the shoulder joint. Aspiration and
intrabursal injection of depot corticosteroids 0.5 to 1 ml
(triamcinolone diacetate 25 or 40 mg/ml) mixed with at least 3 to 5
ml of local anesthetic after infiltration with 1% local anesthetic
(e.g., lidocaine) is the treatment of choice when rest alone is
inadequate. The depot corticosteroid dose and volume of mixture are
gauged to the size of the bursa. Respiration and injection may be
required with resistant inflammation. Systemic corticosteroids
(prednisone 15 to 30 mg/day or equivalent for 3 days) are
occasionally indicated in resistant acute cases after infection and
gout have been excluded. Chronic bursitis is treated as acute
bursitis, except that splinting and rest are less likely to be
helpful. Surgery is rarely needed to treat bursitis and is usually
done only in the chronic cases that have not improved with
traditional therapy. The most common surgical treatment, if needed,
is an Incision and Drainage (called an I and D) and is used only in
cases of infected bursa. The surgeon first numbs the skin with an
anesthetic and then opens the bursa with a scalpel. Finally, the
surgeon drains the fluid present in the inflamed bursa. Sometimes
it is necessary to excise the entire bursa surgically. This is
indicated only if the bursal swelling causes problems.
[0100] The capsaicinoid may be administered via infiltration into
the bursa and/or the tissue and muscle surrounding the bursa.
[0101] B. Tendonitis
[0102] The capsaicinoid formulations and methods disclosed herein
may be utilized to treat/attenuate pain associated with tendonitis
(inflammation of the tendons) and tendonitis surgery. When tendons
become inflamed, the action of pulling the muscle becomes
irritating and painful. The cause is often unknown. Most instances
tendonitis occurs in middle-aged or older persons as the
vascularity of tendons attenuates; repetitive microtrauma may
increase injury. Repeated or extreme trauma (short of rupture),
strain, or excessive (unaccustomed) exercise is most frequently
implicated. The most common cause of tendonitis is overuse.
Commonly, individuals begin an exercise program, or increase their
level of exercise, and begin to experience symptoms of tendonitis.
The tendon is unaccustomed to the new level of demand, and this
overuse will cause an inflammation and tendonitis. Tendonitis
produces pain, tenderness and stiffness near a joint which is
aggravated by movement.
[0103] General practitioners commonly use non-steroidal
anti-inflammatory drugs (NSAIDs) to treat tennis elbow, but there
are no trials to date that have compared them with other
painkillers and one study found no clinically important benefit
over placebo. Symptomatic relief is provided by rest or
immobilization (splint or cast) of the tendon, application of heat
for chronic inflammation or cold for acute inflammation (whichever
benefits the patient should be used), local analgesic drugs, and
NSAIDs for 7 to 10 days. A critical review of the role of various
anti-inflammatory medications in tendon disorders found limited
evidence of short-term pain relief and no evidence of their
effectiveness in providing even medium term clinical resolution.
Use of corticosteroid injections provides mixed results in relief
of pain and at times insufficient evidence to support their use.
Injection of the tendon sheath with a depot corticosteroid (eg,
dexamethasone acetate, methylprednisolone acetate, hydrocortisone
acetate) 0.5 to 1 mL mixed with an equal or double volume of 1%
local anesthetic (e.g., lidocaine) has been utilized as a
treatment, depending on severity and site. The injection is made
blindly or proximal to the site of maximum tenderness if the
specific inflammation site cannot be identified. Particular care
should be taken not to inject the tendon per se (which offers
greater resistance) because it may be weakened and rupture in
active persons. Reexamination of a less inflamed site 3 or 4 days
later often discloses the specific lesion, and a second injection
can be made with greater precision. Rest of the injected part is
advisable to diminish risk of tendon rupture. Although
complications associated with intrarticular and soft tissue steroid
injection are relatively uncommon, when a complication does occur,
it can result in severe and disabling consequences for the subject.
A small proportion of subjects fail to respond to only one
injection of corticosteroid and some subjects who initially improve
at four weeks had worst symptoms by six months. Therefore with this
lack of consensus, no good evidence to support the use of local
corticosteroid injections and the unknown long-term side-effects of
using steroids, an alternative treatment must be sought. Surgery is
rarely necessary, except for release of fibro-osseous tunnels (as
in de Quervain's disease) or for tenosynovectomy of chronic
inflammation (as in rheumatoid arthritis).
[0104] In one embodiment of the present invention, when surgery for
the treatment of tendonitis is required, pain associated with
tendonitis and tendonitis surgery of the knee, shoulders, hip,
pelvis, spine, elbows, leg and foot is treated with administration
via infiltration of a capsaicinoid directly into the affected
tendon. In other embodiments, and in addition to administration to
the affected tendon, the capsaicin can be administered by
infiltration to the muscle and tissue surrounding the affected
tendon.
[0105] C. Osteoarthritis
[0106] The capsaicinoid formulations and methods disclosed herein
may be used to treat/attenuate pain associated with osteoarthritis
(degenerative joint disease) and osteoarthritis surgery.
Osteoarthritis is characterized by the breakdown of the joint's
cartilage. Cartilage is the part of the joint that cushions the
ends of bones. Cartilage breakdown causes bones to rub against each
other, causing pain and loss of movement. Most commonly affecting
middle-aged and older people, osteoarthritis can range from very
mild to very severe. It affects hands and weight-bearing joints
such as knees, hips, feet and the back. There are many factors that
can cause osteoarthritis, including but not limited to age,
genetics, obesity, sports-related activities, work-related
activities, or accidents. Treatment of osteoarthritis focuses on
decreasing pain and improving joint movement, and may include:
Exercises to keep joints flexible and improve muscle strength; Many
different medications are used to control pain, including
corticosteroids and NSAIDs, glucocorticoids injected into joints
that are inflamed and not responsive to NSAIDS. For mild pain
without inflammation, acetaminophen may be used; heat/cold therapy
for temporary pain relief; joint protection to prevent strain or
stress on painful joints; surgery (sometimes) to relieve chronic
pain in damaged joints; and weight control to prevent extra stress
on weight-bearing joints.
[0107] Surgical treatment to replace or repair damaged joints is
indicated in severe, debilitating disease. Surgical options
include: arthroplasty (total or partial replacement of the
deteriorated joint with an artificial joint; arthroscopic surgery
to trim torn and damaged cartilage and wash out the joint;
osteotomy (change in the alignment of a bone to relieve stress on
the bone or joint); and arthrodesis (surgical fusion of bones,
usually in the spine).
[0108] Pain associated with osteoarthritis and osteoarthritis
surgery may be treated/attenuated with the capsaicinoid
formulations administered via infiltration into the affected joint,
e.g., by intra-articular infiltration and/or to the tissue and
muscle surrounding the affected joint, including but not limited to
orthopedic disorders of the knee such as osteoarthritis, shin
splints, medial tibial stress syndrome, bursitis, tendonitis
(patellar tendnitis); tears of the anterior cruciate ligament
(blown out knee), posterior cruciate ligament, medial collateral
ligament and lateral collateral ligament; arthritis of the knee;
meniscal cartilage tear; Runner's conditions such as iliotibial
band syndrome and Pes Anserine bursitis; torn meniscus and limited
cartilage defects of the knee; orthopedic disorders of the
shoulders including, but not limited to, bursitis, dislocation,
separation, impingement and tear of the rotator cuff, tendonitis,
adhesive capsulitis (frozen shoulder) and fractures.
[0109] D. Rheumatoid Arthritis
[0110] The capsaicinoid formulations and methods disclosed herein
may be used to treat/attenuate pain associated with rheumatoid
arthritis and surgery to treat or attenuate rheumatoid arthritis.
Rheumatoid arthritis is a chronic, systemic, inflammatory disease
that chiefly affects the synovial membranes of multiple joints in
the body. Because the disease is systemic, there are many
extra-articular features of the disease as well. Rheumatoid
Arthritis can affect many joints in the body, including the knee,
ankle, elbow, and wrist. Joints that are actively involved with the
disease are usually tender, swollen, and likely demonstrate reduced
motion. The disease is considered an autoimmune disease that is
acquired and in which genetic factors appear to play a role.
[0111] In patients with progressive rheumatoid arthritis, joint
pathology may occur despite appropriate conservative measures. In
such patients, loss of joint function usually causes a loss of
functional ability. Therefore, surgery is usually performed on
joints that have caused the patient a significant loss of function.
Surgery is not without risks however, and therefore the decision to
operate must be carefully made. Synovectomy is done to remove
diseased portions of the joint synovium. Ideally, this type of
surgery is performed before there is destruction of cartilage.
Total joint arthroplasty is performed when there is significant
destruction of the bones forming the joint resulting in loss of
function, or there is significant pain in the joint limiting
function. "Total" means that the ends of both bones that comprise
the joint have diseased portions that are surgically removed and
replaced with man-made components (i.e., a prosthesis). The hip and
knee are common sites for total joint arthroplasty in the patient
with rheumatoid arthritis and therefore are the sites of many
complications of the surgery. Complications include: infections,
dislocation, loosening of the prosthetic components from the bone,
breakage of the prosthetic components, and fractures of bones
caused by the prosthetic devices, usually the result of a loss of
bone density. In some cases where the total joint replacement
fails, the prosthetic components are removed from the bone. In the
case of the hip joint, this procedure (Girdlestone Excision) leaves
the femur without the anatomical neck or head resulting in a soft
tissue "joint" between the femur and pelvis. In some patients, the
shoulder becomes very painful and/or mechanically non-functional.
Total shoulder arthroplasty may be indicated in these patients.
There is evidence that a majority patients that have had total
shoulder arthroplasty secondary to significant pain have obtained
substantial pain relief.
[0112] There are several different classes of drugs utilized to
treat patients with the various types of rheumatic disease. These
classes include analgesics to control pain, corticosteroids, uric
acid-lowering drugs, immunosuppressive drugs, nonsteroidal
anti-inflammatory drugs, and disease-modifying antirheumatic
drugs.
[0113] Pain associated with rheumatoid arthritis and rheumatoid
arthritis surgery may be treated/attenuated with the capsaicinoid
formulations administered via infiltration into the affected joint.
In other embodiments, and in addition to administration to the
affected joint, the capsaicinoid can be administered by
infiltration to the muscle and tissue surrounding the affected
joint.
[0114] E. Heel Spur
[0115] The capsaicinoid formulations and methods disclosed herein
may be used to treat/attenuate pain associated with a heel spur,
which is a projection or growth of bone where certain muscles and
soft tissue structures of the foot attach to the bottom of the
heel, or heel spur surgery. Most commonly, the plantar fascia, a
broad, ligament-like structure extending from the heel bone to the
base of the toes becomes inflamed, and symptoms of heel pain begin.
As this inflammation continues over a period of time, with or
without treatment, a heel spur is likely to form. If heel pain is
treated early, conservative therapy is often successful and surgery
is usually avoided. Early signs of heel pain are usually due to
plantar fasciitis, the inflammation of the plantar fascia. It is
probably the most common cause of heel pain seen by the podiatrist.
It is seen in all groups of people; runners, athletes, week-end
warriors, people who have jobs requiring a fair amount of standing,
walking, or lifting, and those who have recently gained weight.
Initially, patients receive taping of the foot and when indicated,
cortisone injections or a short course an anti-inflammatory
medication, taken orally. Exercises, night splints, and physical
therapy are used as adjunct methods to try to reduce the
inflammation. If successful, a custom made in shoe orthotic is made
to control the abnormal stress and strain on the plantar fascia
resulting in remission of the majority of the symptoms. In some
instances, conservative therapy fails, and surgery is indicated.
Many times an endoscopic procedure, called a plantar fasciotomy, is
done in which a release of some of the fibers of the plantar fascia
is performed through two, small incisions on each side of the heel.
Recovery is often 2 weeks or less, with the patient walking with
only a surgical shoe 24 hours after surgery. When the plantar
fascia undergoes mico-herniations (tears), a heel spur may develop.
Again, if treated early, even patients with spurs find satisfactory
remission of symptoms with conservative therapy such as padding,
strapping, injections and in-shoe orthotics. Unfortunately there
are those whose symptoms are severe enough to prevent them from
performing their job or recreational activities, and surgery is
then indicated. Surgery involves releasing a part of the plantar
fascia from its insertion in the heel bone, as well as removing the
spur. Many times during the procedure, pinched nerves (neuromas),
adding to the pain, are found and removed. Often, an inflamed sac
of fluid call a accessory or adventitious bursa is found under the
heel spur, and it is removed as well. Post operative recovery is
usually a slipper cast and minimal weight bearing for a period of
2-3 weeks. On some occasions, a removable short-leg walking boot is
used or a below knee cast applied. After they are removed normal
weight-bearing is allowed and the patient us treated with in-office
physical therapy.
[0116] When a capsaicinoid is used for plantar fascia surgery, the
dose of capsaicinoid is preferably administered by infiltration
into the heel bone after the surgical incision is made. In other
embodiments, the capsaicinoid may be administered to the tissue and
muscle surrounding the heel bone after the surgical incision is
made and/or to the tissue and muscle surrounding the heel bone.
Treatment of Pain Associated With Laparoscopic Cholecystectomy
[0117] In another preferred embodiment, the capsaicinoid
formulations and methods disclosed herein can be used for the
treatment/attenuation of pain associated with laparoscopic
cholecystectomy. Laparoscopic cholecystectomies (LC) have virtually
replaced open surgical cholecystectomy. However, patients
undergoing laparoscopic cholecystectomies still have pain. Pain
control following surgery typically includes use of opioids,
especially within the first several days after surgery. The
administration of a capsaicinoid in a patient who has undergone a
laparoscopic cholecystectomy may reduce the amount of opioid
consumption and postoperative pain scores associated with the
procedure. In patients requiring a laparoscopic cholecystectomy,
the dose of capsaicinoid can be administered to the site where the
surgery was performed or to the muscle, tissue and bones
surrounding the surgical site. In certain other embodiments, the
capsaicinoid formulations and methods disclosed herein can be used
for the treatment/attenuation of pain associated with
cholecystectomy requiring a more invasive incision than a lap
aroscopic incision.
Infiltratable Formulations
[0118] In embodiments where the capsaicinoid is administered by
infiltration, the capsaicinoid is administered to a surgical site
or wound opening by instillation or injection to the surgical site
or wound opening (e.g., tissue, muscle, and bone) with an
instrument known to those skilled in the art for administering
agents via infiltration, e.g., a needle and syringe.
[0119] The dose of capsaicinoid is preferably prepared for
infiltration by being incorporated into a pharmaceutically and
physiologically acceptable vehicle for administration into a
surgical site or wound opening of the patient (e.g., human or
animal). For example, the capsaicinoid may be dissolved in oils,
propyleneglycol or other solvents commonly used to prepare
infiltratable solutions. Suitable pharmaceutically acceptable
vehicles preferably include aqueous vehicles, nonaqueous vehicles,
antimicrobial agents, isotonic agents, buffers, antioxidants,
suspending and dispersing agents, emulsifying agents, sequestering
or chelating agents and any combinations or mixtures thereof.
Examples of aqueous vehicles preferably include Sodium Chloride
Injection, Bacteriostatic Sodium Chloride Injection, Ringers
Injection, Isotonic Dextrose Injection, Sterile Water Injection,
Bacteriostatic Sterile Water Injection, Dextrose Lactated Ringers
Injection and any combinations or mixtures thereof. Nonaqueous
parenteral vehicles preferably include fixed oils of vegetable
origin, cottonseed oil, corn oil, sesame oil, peanut oil and any
combinations or mixtures thereof. Antimicrobial agents in
bacteriostatic or fungistatic concentrations preferably include
phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, ethyl
and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium
chloride benzethonium chloride and mixtures thereof. Isotonic
agents preferably include sodium chloride, dextrose and any
combinations or mixtures thereof. Buffers preferably include
acetate, phosphate, citrate and any combinations or mixtures
thereof. Antioxidants preferably include ascorbic acid, sodium
bisulfate and any combinations or mixtures thereof. Suspending and
dispersing agents preferably include sodium carboxymethylcelluose,
hydroxypropyl methylcellulose, polyvinylpyrrolidone and any
combinations or mixtures thereof. Emulsifying agents preferably
include Polysorbate 80 (Tween 80). Sequestering or chelating agents
of metal ions preferably include ethylenediaminetetraacetic acid.
Additional pharmaceutically acceptable vehicles also preferably
include ethyl alcohol, polyethylene glycol, glycerin and propylene
glycol for water miscible vehicles and sodium hydroxide,
hydrochloric acid, citric acid or lactic acid for pH adjustment and
any combinations or mixtures thereof.
[0120] Depending on the pharmaceutically acceptable vehicle chosen,
the dose of capsaicinoid can be administered as an aqueous solution
or suspension for infiltration. Similar to injections, infiltration
formulations may be separated into five distinct types, generally
classified as (i) medicaments or solutions or emulsions suitable
for infiltration; (ii) dry solids or liquid concentrates containing
no buffers, diluents, or other added substances, and which upon the
addition of suitable vehicles, yield solutions conforming in all
aspects to the requirements for infiltration; (iii) preparations as
described in (ii) except that they contain one or more buffers,
diluents or other added substances; (iv) solids which are suspended
in a suitable fluid medium and which are not to be injected
intravenously or into the spinal canal; and (v) dry solids, which
upon the addition of suitable vehicles, yield preparations
conforming in all respects to the requirements of Sterile
Suspensions (see: H. C. Ansel, Introduction to Pharmaceutical
Dosage Forms, 4th Edit., 1985, pg. 238).
[0121] In certain other embodiments, a surfactant can preferably be
combined with one or more of the pharmaceutically acceptable
vehicles previously described herein so that the surfactant or
buffering agent prevents the initial stinging or burning discomfort
associated with capsaicinoid administration, as a wetting agent,
emulsifier, solubilizer and/or antimicrobial.
[0122] Suitable surfactants include, but are not limited to, sodium
stearyl fumarate, diethanolamine cetyl sulfate, polyethylene
glycol, isostearate, polyethoxylated castor oil, benzaltkonium
chloride, nonoxyl 10, octoxynol 9, polyoxyethylene sorbitan fatty
acids (polysorbate 20, 40, 60 and 80), sodium lauryl sulfate,
sorbitan esters (sorbitan monolaurate, sorbitan monooleate,
sorbitan monopalmitate, sorbitan monostearate, sorbitan
sesquioleate, sorbitan trioleate, sorbitan tristearate, sorbitan
laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate,
sorbitan dioleate, sorbitan sesqui-isostearate, sorbitan
sesquistearate, sorbitan tri-isostearate), lecithin pharmaceutical
acceptable salts thereof and combinations thereof. When one or more
surfactants are utilized in the formulations of the invention, they
may be combined, e.g., with a pharmaceutically acceptable vehicle
and may be present in the final formulation, e.g., in an amount
ranging from about 0.1% to about 20%, more preferably from about
0.5% to about 10%.
[0123] Buffering agents may also be used to provide drug stability;
to control the therapeutic activity of the drug substance (Ansel,
Howard C., "Introduction to Pharmaceutical Dosage Forms," 4.sup.th
Ed., 1985); and/or to prevent the initial stinging or burning
discomfort associated with capsaicin administration. Suitable
buffers include, but are not limited to sodium bicarbonate, sodium
citrate, citric acid, sodium phosphate, pharmaceutically acceptable
salts thereof and combinations thereof. When one or more buffers
are utilized in the formulations of the invention, they may be
combined, e.g., with a pharmaceutically acceptable vehicle and may
be present in the final formulation, e.g., in an amount ranging
from about 0.1% to about 20%, more preferably from about 0.5% to
about 10%.
[0124] In certain embodiments, the pharmaceutical vehicle utilized
to deliver the infiltratable capsaicinoid comprises polyethylene
glycol (PEG), histidine, and sucrose, in water for injection. In
certain preferred embodiments, the pharmaceutical vehicle utilized
to deliver the infiltratable capsaicinoid comprises about 20% PEG
300, about 10 mM histidine and about 5% sucrose, in water for
injection.
[0125] In other preferred embodiments, delivery systems can be used
to administer a unit dose of capsaicinoid. The dose of capsaicinoid
can preferably be administered as infiltratable microparticles
(microcapsules and microspheres). The microparticles are preferably
in a size and distribution range suitable for infiltration. The
diameter and shape of the microparticles can be manipulated to
modify the release characteristics. For example, larger diameter
microparticles will typically provide slower rates of release and
reduced tissue penetration and smaller diameters of microparticles
will produce the opposite effects, relative to microparticles of
different mean diameter, but of the same composition. In addition,
other particle shapes, such as cylindrical shapes, can also modify
release rates by virtue of the increased ratio of surface area to
mass inherent to such alternative geometrical shapes, relative to a
spherical shape. The diameter of microparticles preferably range in
size from about 5 microns to about 200 microns in diameter.
[0126] In a more preferred embodiment, the microparticles range in
diameter from about 20 to about 120 microns. Methods for
manufacture of microparticles are well known in the art and include
solvent evaporation, phase separation and fluidized bed
coating.
[0127] When the preferred methods of the present invention provide
for administration of a single dose of capsaicinoid alone, the
single dose of capsaicinoid is preferably administered at at the
surgical site or open wound in an amount effective to denervate the
surgical site or open wound without eliciting an effect outside the
site or wound. The single dose is preferably administered onto a
nerve directly at the site where pain relief is needed, directly
into the pain producing structure, or onto a nerve that provides
inervation to the painful area via infiltration. Infiltration
preferably includes, but is not limited to, administration onto the
tissue, muscle or bone surrounding the surgical site or open wound.
In other embodiments, the dose of capsaicinoid may be administered
intra-articularly, intra-sternally, intrasynovially, intra-bursally
or into body spaces. Intra-articular administration of the
formulations of the invention may be, e.g., into a joint selected
from the group consisting of knee, elbow, hip, stemoclavicular,
temporomandibular, carpal, tarsal, wrist, ankle, intervertebral
disk, ligamentum flavum and any other joint subject to pain.
Examples of body spaces include pleura, peritoneium, cranium,
mediastinum, pericardium, and bursae or bursal. Examples of bursae
include acromial, bicipitoradial, cubitoradial, deltoid,
infrapatellar, ishchiadica, and other bursa known to those skilled
in the art to be subject to pain.
[0128] When the single dose of capsaicinoid is administered via
infiltration, the volume of capsaicinoid administered will depend
on the surgical site or size of the opened wound. Suitable
infiltration volumes to be delivered preferably range from about
0.1 to about 1000 ml, more preferably from about 1 ml to about 100
ml and most preferably from about 5 ml to about 30 ml, depending on
the site or wound opening to be treated.
[0129] The administration of the anesthetic along with the
subsequent administration of capsaicinoid alleviates pain at the
surgical site or wound opening for a prolonged period of time.
Patients can be monitored for pain relief and increased movement,
in the situation where treatment is in a joint. The treatment can
be repeated as necessary to control the symptoms.
Breakthrough Pain
[0130] The term "breakthrough pain" means pain which the patient
experiences despite the fact that the patient is being or was
administered generally effective amounts of, e.g., capsaicin. In
conjunction with the use of the capsaicinoid formulations and
methods described herein, it is contemplated that it is nonetheless
possible that the patient will experience breakthrough pain. For
the treatment of breakthrough pain, the individual may be further
administered an effective amount of an analgesic in accordance with
the treatment of pain in such situations performed by those skilled
in the art. The analgesic may be any known to the person skilled in
the art such as those selected from the group comprising gold
compounds such as sodium aurothiomalate; non-steroidal
anti-inflammatory drugs (NSAIDs) such as naproxen, diclofenac,
flurbiprofen, ibuprofen ketoprofen, ketorolac, pharmaceutically
acceptable salts thereof and the like; opioid analgesics such as
codeine, dextropropoxyphene, dihydrocodeine, morphine, diamorphine,
hydromorphone, hydrocodone, methadone, pethidine, oxycodone,
levorphanol, fentanyl and alfentanil, para-aminophenol derivatives
such as paracetamol, pharmaceutically acceptable salts thereof and
the like; and salicylates such as aspirin.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Example I
Osteoarthritis of the Knee Safety Study
[0131] The following clinical study was carried out in order to
evaluate the safety, tolerability, systemic pharmacokinetics, and
efficacy of purified capsaicin administered by intra-articular
infiltration together with a local anesthetic administered by
intra-articular infiltration in subjects with osteoarthritis of the
knee.
[0132] The primary objective of the study was to evaluate the
safety and tolerability of intra-articular capsaicin, when
co-administered with intra-articular local anesthetic, compared to
placebo, in subjects with end-stage osteoarthritis of the knee,
already scheduled to receive knee replacements.
[0133] Purified capsaicin was supplied in vials containing 5 mL of
purified capsaicin at a concentrations of 500 .mu.g/mL. Study drug
was stored at a temperature between 15.degree. C. and 25.degree. C.
Within four hours prior to injection, vehicle was used to dilute
the drug to final concentrations of purified capsaicin, as
follows:
TABLE-US-00001 TABLE 1 Dose Level Concentration Total Volume of
Dose 10 .mu.g 2 .mu.g/mL 5 mL 100 .mu.g 20 .mu.g/mL 5 mL 300 .mu.g
60 .mu.g/mL 5 mL
[0134] Each vial was used for one infiltration administration only
and appropriately labeled. The supplier of the purified capsaicin
was FormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810. The
vials were supplied in bulk to the study center with each vial
labeled according to the contents of the vial. The Pharmacist/Study
Nurse, who prepared the injection, maintained the investigational
product in a lockable cabinet at the required temperature,
15-25.degree. C. The study blind was maintained by the
Pharmacist/Study Nurse.
[0135] Placebo vehicle for purified capsaicin was supplied in vials
containing 5 mL. Local anesthetic (Lignocaine 2%) was used for each
intra-articular infiltration.
[0136] The study was a single center, randomized, double blind,
placebo controlled, dose ranging Phase 1 study of three dose levels
(10 .mu.g, 100 .mu.g, or 300 .mu.g) of intra-articularly
administered purified capsaicin, when co-administered with
intra-articular local anesthetic, in subjects with osteoarthritis
of the knee who were scheduled to undergo total knee replacement.
The doses of purified capsaicin used in this trial were well below
(>100 fold) doses known to be toxic to animals. The study was
designed to include 16 evaluation subjects. Sixteen subjects were
enrolled in the study; 12 were treated with ultra-purified
capsaicin (4 each with 10, 100, and 300 .mu.g doses) and 4 were
treated with placebo vehicle. Sixteen subjects completed the
study.
[0137] Patients were treated randomly and in double-blind fashion
in four treatment cohorts, with each cohort having a progressively
longer interval between the intra-articular administration of study
medication and subsequent total knee replacement (2, 4, 7, and 14
days). Four subjects, 1 in each of the 4 dose groups (placebo, 10
.mu.g, 100 .mu.g, and 300 .mu.g of capsaicin), were enrolled in
each treatment cohort. Gross and microscopic pathology analysis was
completed for each treatment cohort before the next treatment coort
was treated.
[0138] Each subject had 3 study visits: a Screening Day (Day -7 to
-1), the Treatment Day (Day 0), and a Post-Treatment Day (scheduled
for Day +2, +4, +7, or +14). On the Treatment Day the subject was
randomized, pre-treatment evaluation was performed. The patients
were brought into the procedure room, and a VAS pain score was
taken (0 mm--no pain, 100 mm--extreme pain). Once the patient had
marked his or her pain on the card, he/she was prepped for knee
cannulation. Once the cannula was placed, the patient received by
intra-articular infiltration, 3 mg/kg (maximum dose of 200 mg) of
2% lignocaine into the knee scheduled to be replaced. This
administration of local anesthetic was followed in 10 minutes by an
intra-articular infiltration of placebo (vehicle) or 10 .mu.g, 100
.mu.g, or 300 .mu.g of purified capsaicin diluted with vehicle to a
total volume of 5 mL.
[0139] VAS pain scores as well as verbal reports were taken
immediately following administration, as well as prior to knee
replacement surgery. No subjects discontinued from the study due to
adverse events.
[0140] Immediately following instillation of capsaicin, some
patients (0 of 4 receiving placebo, 0 of 4 receiving 10 .mu.g
capsaicin, 1 of 4 receiving 100 .mu.g capsaicin, and 4 of 4
receiving 300 .mu.g capsaicin) reported transient burning pain
representative of capsaicin injection (onset within a few seconds
to minutes and lasting less than one hour). Pain was mild but for
some patients, the investigator chose to place ice packs on the
treated knee until the pain resolved. In particular, the subject in
the 100 .mu.g dose group and 2 of the subjects in the 300 .mu.g
dose group had burning post-administration (hyper) algesic pain
alone; two subjects in the 300 .mu.g dose group had burning pain in
conjunction with other types of post-administration (hyper) algesic
pain (1 subject had burning and stinging pain and the second
subject had burning and toothache-like pain). All of the episodes
of post-administration (hyper) algesia began immediately (within 5
minutes) after administration. All of these painful episodes were
brief: the duration of this pain was 9 minutes for the subject in
the 100 .mu.g dose group, and 17, 25, 25, and 42 minutes for the
subjects in the 300 .mu.g dose group. The 4 subjects in the 300
.mu.g dose group and 1 subject in the 100 .mu.g dose group required
intervention for their post-injection (hyper) algesia. For all but
1 of these 5 subjects, the only intervention was ice packs. One
subject in the 300 .mu.g dose group was treated with paracetamol;
no subjects were treated with intravenous morphine or granisetron
for post-administration (hyper) algesia. Most of the concomitant
medications used in the study were medications taken prior to the
study that continued to be taken during the study. The only
concomitant non-drug treatments during the study were the ice packs
used in the 5 subjects with post-administration (hyper)
algesia.
[0141] On the Post-Treatment Day, study evaluation was performed
followed by the scheduled knee replacement, with intra-operative
bone and soft tissue biopsies performed for subsequent examination.
For overall efficacy analysis, we chose to exclude the patients who
had surgery two days following administration since analgesia from
remaining lignocaine or residual pain from the actual procedure
(large volume infiltration) and lysing c-fiber endings could not be
excluded (In normal volunteers, a mild "aching" pain is sometimes
observed for up to two days following capsaicin administration).
This therefore left the 3 placebo and 9 active patients from the 4
day, 7 day, and 14 day cohorts. Examination of the VAS scores prior
to drug/placebo administration and the day of surgery (prior to
surgery) showed that pain scores were not reduced in the placebo
group (VAS decreased by only 7.+-.30%), but was reduced in the
capsaicin group (VAS reduced by 62.+-.14%). The changes in VAS
score are reported graphically as shown in FIG. 1. The plasma
concentration over time of the three dosage ranges of capsaicin are
shown in FIG. 2.
[0142] Ten-mL blood samples for subsequent assay of plasma
ultra-purified capsaicin concentrations were collected prior to
study medication administration, at 30 minutes, 1, 2, and 4 hours
after study medication injection, and immediately prior to the
first administration of pre-operative medications on the Post
Treatment Day. The pharmacokinetic parameters of Cmax, Tmax,
AUC(0-t.sub.last) and t1/2 were evaluated.
[0143] In the 10 .mu.g dose group, purified capsaicin plasma
concentrations were measurable at only 0, 1, or 2 time points;
therefore, no pharmacokinetic parameters could be estimated for any
subject in this dose group. For the 3 subjects in each of the 100
.mu.g, and 300 .mu.g dose groups for which pharmacokinetic
parameters could be estimated, the magnitude of the Cmax and AUC
(0-t.sub.last) values was similar in the 2 dose groups. T.sub.max
values were 0.5 hr in all subjects for which they could be
estimated. Terminal exponential half-lives were similarly brief in
all subjects in both the 100 .mu.g and 300 .mu.g dose groups.
[0144] The AUC (0-t.sub.last) values for the subjects in the 100
.mu.g dose group (366.10, 75.19, and 511.21 pg*hr/mL) were similar
in magnitude to the values for the 300 .mu.g dose group (449.01,
220.42, and 498.83 pg*hr/mL). Similarly, the C.sub.max values in
the 100 .mu.g dose group (292.06, 79.94, and 538.32 pg/mL) were
similar in magnitude to the values in the 300 .mu.g dose group
(207.62, 251.42, and 499.88 pg/mL). T.sub.max was 0.5 hours in all
6 subjects. The terminal exponential half lives were brief in all
subjects, with values of 0.1498, 1.1488, and 0.1014 hr in the 100
.mu.g dose group and values of 0.3268, 0.2298, and 0.1663 in the
300 .mu.g dose group.
[0145] The pharmacokinetic conclusions are necessarily limited,
because the number of timepoints at which plasma concentrations of
purified capsaicin was measurable was so limited in these study
subjects. However, there was some evidence for a pharmacokinetic
dose response over the 10 .mu.g to 300 .mu.g dose range in that the
purified capsaicin plasma concentrations in the 10 .mu.g dose group
were clearly lower than in either the 100 .mu.g or the 300 .mu.g
dose groups. However, there was little evidence for a
pharmacokinetic dose response over the 100-300 .mu.g dose
range.
[0146] Purified capsaicin was well tolerated at all dose levels.
There was low leakage of study drug from the joint space and gross
and microscopic pathology was normal. There were no treatment
related signs of erythema, edema, or hemorrhage at the site of
injection, and no treatment related effects on soft tissue,
cartilage, or bone upon histopathological examination. No treatment
related systemic side effects were seen, and there were no
treatment related effects on laboratory safety parameters or vital
signs. There was no discernable effect on proprioception at the
injected knee in any dose group at any time point.
[0147] There was a clear dose response for the incidence of post
injection hyperalgesia. This symptom occurred in 4 subjects in the
300 .mu.g-dose group, 1 subject in the 100 .mu.g dose group, and no
subjects in the 10 .mu.g dose group or placebo. In all but one
case, the hyperalgesia was described as a burning sensation, which
developed within five minutes of injection and lasted on average
less than thirty minutes. In all cases where intervention was
required, the hyperalgesia was easily and effectively controlled by
the application of ice packs to the knee.
[0148] Subjects were asked to rank their level of pain on a visual
analogue scale (VAS), anchored by "no pain" on the left and
"extreme pain" on the right, prior to receiving the intra-articular
dose of purified capsaicin and local anesthetic and then again just
prior to administration of preoperative medications on the day of
knee replacement surgery. No clear treatment related indication of
efficacy was seen at any of the dose levels (10 .mu.g, 100 .mu.g,
and 300 .mu.g) of purified capsaicin.
[0149] Since intra-articular infiltration of local anesthetic
followed by intra-articular infiltration of capsaicin was generally
well-tolerated, and the median decreases from baseline to the
pre-operative time point in the VAS for pain at the target knee in
all 3 capsaicin dose groups were all substantially greater that the
median change from baseline in the placebo group, the risk to
benefit ratio of this treatment strategy appears favorable. Further
studies of this treatment in larger numbers of subjects with
osteoarthritis appear warranted.
Example II
Osteoarthritis of the Knee Efficacy Study
[0150] The following clinical study evaluated the efficacy of
purified capsaicin administered by intra-articular infiltration
together with a local anesthetic injected by intra-articular
infiltration in subjects with osteoarthritis of the knee.
[0151] The primary objective of the study was to evaluate the
efficacy of intra-articular capsaicin, when co-administered with
intra-articular local anesthetic, compared to placebo, in subjects
with end-stage osteoarthritis of the knee, already scheduled to
receive knee replacements (21 and 42 days after injection of study
medication).
[0152] Purified capsaicin was supplied in vials containing 5 mL of
purified capsaicin at a concentrations of 500 .mu.g/mL. Study drug
was stored at a temperature between 15.degree. C. and 25.degree. C.
Within four hours prior to injection, vehicle was used to dilute
the drug to final concentrations of purified capsaicin, as
follows:
TABLE-US-00002 TABLE 2 Dose Level Concentration Total Volume of
Dose 1000 .mu.g 200 .mu.g/mL 5 mL
[0153] Each vial was used for one infiltration administration only
and appropriately labeled. The supplier of the purified capsaicin
was FormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810. The
vials were supplied in bulk to the study center with each vial
labeled according to the contents of the vial. The Pharmacist/Study
Nurse, who prepared the injection, maintained the investigational
product in a lockable cabinet at the required temperature,
15-25.degree. C. The study blind was maintained by the
Pharmacist/Study Nurse.
[0154] Placebo vehicle for purified capsaicin was supplied in vials
containing 5 mL. Local anesthetic (Lignocaine 2%) was used for each
subacromial bursa infiltration.
[0155] The study was a single center, randomized, double blind,
placebo controlled, dose ranging Phase 2 study of capsaicin (1000
.mu.g) administered by intra-articular infiltration, when
co-administered with intra-articular local anesthetic, in subjects
with osteoarthritis of the knee who were scheduled to undergo total
knee replacement from three to six weeks post study drug
administration, wherein the primary endpoint was pain reduction at
three weeks following study drug administration.
[0156] The study was designed to include 12 evaluation subjects
(Patients suffering a defined pain: >40 mm on VAS). Six (6)
subjects were treated with capsaicin 1000 .mu.g and 6 subjects were
treated with placebo vehicle. Patients were treated randomly and in
double-blind fashion. Gross and microscopic pathology analysis were
completed for each treatment group. Each subject has 3 study
visits: a Screening Day (Day -7 to -1), the Treatment Day (Day 0),
and a Post-Treatment Day (scheduled for Day +2, +4, +7, or +14). On
the Treatment Day the subject was randomized, pre-treatment
evaluation was performed. The patient was brought into the
procedure room, and a VAS pain score was taken (0 mm--no pain, 100
mm--extreme pain). Once the patient marked his or her pain on the
card, he/she was prepped for knee cannulation. Once the cannula was
placed, the patient received, by intra-articular infiltration, 3
mg/kg (maximum dose of 200 mg) of 2% lignocaine into the knee
scheduled to be replaced. This infiltration of local anesthetic was
followed in 10 minutes by an intra-articular infiltration of
placebo (vehicle) or 1000 .mu.g of purified capsaicin diluted with
vehicle to a total volume of 5 mL.
[0157] VAS pain scores as well as verbal reports were taken
immediately following administration, as well as prior to knee
replacement surgery. On the Post-Treatment Day, a study evaluation
was performed followed by the scheduled knee replacement, with
intra-operative bone and soft tissue biopsies performed for
subsequent examination. For overall efficacy analysis, patients
having surgery two days following infiltration were excluded since
analgesia from remaining lignocaine or residual pain from the
actual procedure (large volume injection) and lysing c-fiber
endings was not capable of being excluded.
[0158] Changes in NRS (Numerical Rating Scale) pain scores were
measured at three weeks following administration. Final NRS score
for placebo=7.30 (p=0.05), whereas final NRS score for
capsaicin=3.97 (P=0.03) (See FIG. 3).
Example III
Bunionectomy Efficacy Study
[0159] The following study was carried out in order to evaluate the
safety, tolerability, systemic pharmacokinetics, and efficacy of
intra-operative (infiltration) capsaicin when co-administered with
a local anesthetic in patients scheduled to undergo transpositional
osteotomy (bunionectomy).
[0160] The primary objective of the study was to evaluate the
safety and tolerability of capsaicin, when co-administered by
intra-articular infiltration with a local anesthetic, compared to
placebo, in subjects with hallux valgus deformity, already
scheduled to undergo transpositional osteotomy (bunionectomy). The
secondary objective of the study was to evaluate the safety,
tolerability and systemic pharmacokinetics of purified capsaicin
following intra-operative administration. The primary efficacy
endpoint was the proportion of subjects in each treatment group
requiring opioid analgesia in the first 24 hours post-operatively.
The proportions were compared amongst treatment groups using the
Cochran-Haenszel test. Secondary efficacy end points included: i)
proportion of subjects in each treatment group requiring opioid
analgesia in the first 36 hour period post-operatively (Similarly,
the proportions were compared amongst treatment groups using the
Cochran-Haenszel test); ii) proportion of subjects in each
treatment group requiring opioid analgesia in the 10 day period
post-operatively (Similarly; the proportions were compared amongst
treatment groups using the Cochran-Haenszel test); iii) time to
first usage of opioid analgesia in each treatment group (a survival
analysis approach will be used: the product-limit (Kaplan-Meier)
method will be applied to time to first usage of opioid analgesia.
The median time to first usage of opioid analgesia will be
estimated in both treatment groups. Pairwise comparisons will be
performed to test for equality of the survival curves between the 2
treatment groups using both the log-rank and the Wilcoxon test);
iv) total usage of analgesia in each treatment group (the total
usage of analgesia will be compared by an analysis of variance with
treatment and center as independent variables. A pairwise
comparison will be performed between the treatment groups); and v)
VAS assessment of pain at the site of operation in each treatment
group (The VAS score at each time point will be compared by an
analysis of variance with treatment and center as independent
variables. A pairwise comparison will be performed between the
treatment groups). Safety endpoints included: i) laboratory safety
parameters; ii) adverse events; and iii) purified capsaicin blood
levels. The efficacy analysis was performed on the data obtained
ten days postoperatively. The safety analysis was performed based
on the safety data for the entire study, including the 6 week and
12 week follow-up periods. The blind was broken at the time the
efficacy analysis was performed. However, the individual treatment
assignment was available to the statistical analysis group only.
All other personnel involved in the study, including the
Investigator, study monitor and proprietary staff, remained blinded
until the entire study was completed.
[0161] Purified capsaicin was supplied in vials containing 5 mL of
purified capsaicin at a concentrations of 500 .mu.g/mL. Study drug
was stored at a temperature between 15.degree. C. and 25.degree. C.
Within four hours prior to injection, vehicle was used to dilute
the drug to final concentrations of purified capsaicin, as
follows:
TABLE-US-00003 TABLE 3 Dose Level Concentration Total Volume of
Dose 1000 .mu.g 250 .mu.g/mL 4 mL
[0162] Each vial was used for one infiltration administration only
and appropriately labeled. The supplier of the purified capsaicin
was FormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810. The
vials were supplied in bulk to the study center with each vial
labeled according to the contents of the vial. The Pharmacist/Study
Nurse, who prepared the injection, maintained the investigational
product in a lockable cabinet at the required temperature,
15-25.degree. C. The study blind was maintained by the
Pharmacist/Study Nurse.
[0163] Placebo vehicle for purified capsaicin was supplied in vials
containing 5 mL. Local anesthetic (Lignocaine 2%) was used for each
infiltration.
[0164] The study was a single center, randomized, double blind,
placebo controlled, Phase II study of the safety and efficacy of
intra-operative capsaicin, when co-administered with local
anaesthetic, in subjects undergoing transpositional first
metatarsal osteotomy and fixation for the correction of hallux
valgus deformity. The dose of capsaicin used in the trial was 1000
.mu.g.
[0165] The study was designed to include 40 evaluation subjects.
Twenty (20) randomized to the capsaicin treatment group and twenty
(20) to the placebo control group. Each subject had six (6); study
visits: a Screening Day (Day -28 to -1), an Operation Day (Day 0),
and four (4) Follow-up visits (scheduled for Days 3, 10 and weeks 6
and 12).
[0166] On Operation Day (Day 0) the following was performed: a)
Pre-operation: Prior to the initiation of an ankle block,
inclusion/exclusion criteria assessment was performed. Eligible
subjects were randomized, pre-treatment evaluation was performed,
which included laboratory safety assessments, measurement of vital
signs, VAS assessment of pain at the target Hallux valgus, blood
sample measurement for purified capsaicin concentration, and review
of concomitant medications; b) Operation: An ankle block [lidocaine
0.5% (up to a total of 20 ml)] was initiated by the investigator to
provide surgical anesthesia, and then a transpositional osteotomy
of the first metatarsal+/-an Akin osteotomy of the proximal phalanx
in accordance with normal practices and procedures was performed.
Immediately prior to wound closure, the Investigator slowly dripped
the study medication (4 mL) from a syringe into the wound, ensuring
even tissue exposure. The wound was then closed according to normal
practices and procedures.
Post-Operation:
[0167] In the 24 hours following administration of study
medication, vital signs (supine pulse rate and blood pressure) were
recorded at 1, 2, 4 and 24 hours post administration. VAS
assessment of pain at the operation site was performed at 1, 4, 8,
12 and 24 hours post administration. In those instances where VAS
measurements coincide with blood sampling procedures, the VAS
assessment was performed first. Blood samples for measurement of
capsaicin concentration were obtained at 1, 2, and 4 hours post
administration. The quantity of each blood sample was 10 mL.
Laboratory safety assessments, e.g., haematology, biochemistry,
urinalysis were performed at 24 hours post administration. Adverse
events were spontaneously reported by the subject and recorded.
Rescue analgesia medication was provided to the subject if required
(initially diclofenac 50 mg, repeated at 8 hourly intervals if
necessary). When diclofenac was judged by the Investigator to
provide inadequate pain relief then the subject was provided with
co-codamol 30/500 (codeine phosphate 30 mg+paracetamol 500 mg),
repeated at 4 hourly intervals when necessary. Any usage of rescue
medication or concomitant medication was recorded in the subject's
CRF. At 24 hours post administration of study medication, the
subject was discharged from the clinic.
Follow Up:
[0168] Follow-up (days 1-10): Upon discharge from the clinic, the
subject was provided with a diary card for Days 1-10, and asked to
record: VAS assessment of pain at the operation site, performed
each morning; time and amount of any rescue medication taken by the
subject (at any time); usage of concomitant medications (at any
time); adverse events experienced by the subject (at any time).
Each subject was also be asked to return to the clinic on Day 3 and
on Day 10 post-operation. At these clinic visits the Investigator
examined the subject's diary card and resolved any unclear or
inconsistent entries. Data from the diary card was transcribed to
the subject's CRF. The site of the operation was inspected by the
Investigator to confirm that normal wound healing took place.
[0169] Follow Up (Week 6): The subject was asked to return to the
clinic at 6 weeks post operation. The site of the operation was
inspected by the Investigator to confirm that normal wound healing
is took place. The subject was questioned about any adverse events
he/she experienced since the last clinic visit, and any usage of
concomitant medication.
[0170] Follow Up (Week 12): The subject was asked to return to the
clinic at 12 weeks post operation. The site of the operation was
inspected by the Investigator to confirm that normal wound healing
is took place. The subject was questioned about any adverse events
he/she may experienced since the last clinic visit, and any usage
of concomitant medication. The Investigator discharge the subject
from the study.
[0171] The results of the bunionectomy study proved that capsaicin
administered at a dose of 1000 .mu.g into the wound prior to wound
closure reduced both pain score as well as the use of rescue as
shown in FIGS. 3 and 4. Reduction in rescue was almost always
associated with maintenance of VAS score, i.e., the new drug simply
substitutes for the old drug (See; Table 4 below):
TABLE-US-00004 TABLE 4 Time Placebo purified capsaicin 1 hr 3.3 +/-
2.3 11.1 +/- 7.3 4 hr 3.1 +/- 2.2 10.7 +/- 3.6 8 hr 19.7 +/- 4.9
5.5 +/- 2.3 12 hr 28.1 +/- 9.0 8.2 +/- 3.8 24 hr 11.7 +/- 4.6 1.9
+/- 1.0 48 hr 19.3 +/- 8.9 5.9 +/- 2.5 72 hr 22.9 +/- 9.9 10.6 +/-
3.5 mean +/- SEM n = 10 placebo, n = 11 purified capsaicin P <
0.05 at each time point
[0172] Administration of 1000 .mu.g of capsaicin prior to wound
closure decreased opioid rescue. Only 40% of the study subjects
randomized to receive capsaicin required rescue (one subject
required rescue at 1 hr, a second subject required rescues at 4 hr,
a third subject required rescue at 5 hr; a fourth subject required
rescue at 8 hr, and a fifth subject required rescue at 12 hr; 6
subjects did not rescue in 72 hours (n=11)), whereas 80% of the
study subjects randomized to receive placebo required rescue (one
subject required rescue at 1 hr, a second subject required rescue
at 2 hr, a third subject required rescue at 6 hr, a fourth subject
required rescue at 8 hr, a fifth subject required rescue at 12 hr,
a sixth subject required rescue at 14 hr, a seventh and eighth
subject required rescue at 16 hr, and 2 subjects did not require
rescue in 72 hours (n=10) P<0.05).
Example IV
Median Sternotomy Study
[0173] The primary objective of the study is to determine the
amount of opioid consumption and postoperative pain scores
following median sternotomy for patients receiving purified
capsaicin by infiltration and/or injection. Eligible subjects are
patients undergoing cardiac, pulmonary, or mediastinal surgery for
any indication between the ages of 20-70 years. The operation is
performed under general anesthesia and are closely observed in a
post-anesthesia care unit as per the practice of the institution.
All patients receive standard of care opioid on demand for
treatment of pain when transferred to the ward. The dose of
capsaicin is administered to the sternal edges, the muscle, the
tissues and/or bone.
[0174] Pain is assessed utilizing VAS 100 mm scale-baseline, every
60 minutes beginning when the patient first is placed in a bedside
chair (or ambulated) for 24 hours and then every 4 hours while
awake until discharge from the hospital. Patient diaries will be
used following discharge for a two-week period.
[0175] The primary study endpoint is the time to first request of
postoperative opioid. The amount of opioid rescue used is recorded
every 24 hours for the first 2 weeks, patients will complete an
opioid-related symptom distress (SDS) questionnaire.
Example V
Laparoscopic Cholecystectomy Study
[0176] The primary objective of this study evaluates the amount of
opioid consumption and postoperative pain scores following
laparoscopic cholecystectomy in patients administered purified
capsaicin by infiltration and/or injection. Study subjects will
receive a dose of purified capsaicin in proximity to the surgical
site.
[0177] This study includes 40 patients (20 randomized to receive
capsaicin study drug and 20 randomized to receive placebo study
drug) between the ages of 20-60 years old with symptomatic
gallstones. The operation is performed under general anesthesia and
the subject is closely observed in a post-anesthesia care unit for
up to 24 hours and remains in the hospital (typically for 1 to 5
days). All patients receive standard of care opioid on demand for
treatment of pain before discharge, and opioid (to be determined)
post discharge. Pain is assessed utilizing VAS 100 mm
scale-baseline, every 30 minutes till the 2nd postoperative hour
then every 4 hours the following 12 hours, an at 24 hours and at
days 2, 3, 4, 5, 6 and 7. Patient diaries are used following
discharge.
[0178] The primary study endpoint is the time to first request of
postoperative analgesia The amount of opioid rescue is every 24
hours for first 3 days, patients complete an opioid-related symptom
distress (SDS) questionnaire.
Example VI
Knee Replacement Study
[0179] The primary objective of the study evaluates the amount of
opioid consumption and postoperative pain scores following knee
replacement surgery for patients receiving administration of
purified capsaicin by infiltration.
[0180] This study includes 80 patients (20 patients are randomized
to receive placebo, 20 randomized to receive capsaicin 300 .mu.g,
20 randomized to receive capsaicin 1000 .mu.g, and 20 randomized to
receive capsaicin 2000 .mu.g). Eligible subjects are patients who
undergoing knee replacement surgery between the ages of 20-70 years
old. The knee replacement operation is performed under general
anesthesia and is closely observed in a post-anesthesia care unit
as per the practice of the institution. All patients receive
standard of care opioid on demand for treatment of pain once
transferred to the ward. The volume of capsaicin administered into
the wound opening during closure ranges from about 5 ml to about 10
ml.
[0181] Pain is assessed utilizing VAS 100 mm scale-baseline, every
60 minutes beginning when the patient first is placed on mechanical
flexion/extension for 24 hours and then every 4 hours while awake
until discharge from the hospital. Patient diaries are used
following discharge for a two-week period.
Example VII
Mastectomy Study
[0182] Mastectomy results in significant pain and requires
substantial doses of opioids postoperatively. Analgesic techniques
that provide good pain control while minimizing opioid side effects
are thus highly desirable. The primary objective of the study
determines the amount of opioid consumption and postoperative pain
scores following mastectomy for patients receiving capsaicin.
[0183] The study includes 80 patients (20 patients are randomized
to receive placebo, 20 randomized to receive capsaicin 300 .mu.g,
20 randomized to receive capsaicin 1000 .mu.g, and 20 randomized to
receive capsaicin 2000 .mu.g). Eligible patients include patients
undergoing mastectomy between the ages of 20-70 years old. The
operation is performed under general anesthesia and is closely
observed in a post-anesthesia care unit as per the practice of the
institution. All patients receive standard of care opioid on demand
for treatment of pain once transferred to the ward.
[0184] The dose of study drug is administered by infiltration in a
volume from about 5 ml to about 10 ml within the wound cavity
during closure.
[0185] Pain is assessed utilizing VAS 100 mm scale-baseline, every
60 minutes beginning when the patient first is placed on mechanical
flexion/extension for 24 hours and then every 4 hours while awake
until discharge from the hospital. Patient diaries are used
following discharge for a two-week period.
[0186] The primary endpoint is time to first request of
postoperative opioid. Opioid rescue occurs every 24 hours for the
first 2 weeks, patients complete an opioid-related symptom distress
(SDS) questionnaire.
CONCLUSION
[0187] The invention has been described in an illustrative manner,
and it is to be understood that the particular embodiments of the
capsaicinoid formulations and methods of treatment described herein
are intended to be descriptive rather than limiting. Many
modifications and variations of the methodologies and formulations
disclosed herein are possible in light of the above teachings, and
such obvious modifications are deemed to be encompassed within the
scope of the appended claims.
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