U.S. patent application number 12/287746 was filed with the patent office on 2009-05-07 for injectable capsaicin with non-steroidal anti-inflammatory adjunctive agent.
This patent application is currently assigned to AlgoRx. Invention is credited to Ronald Burch, Richard B. Carter, Jeff Lazar.
Application Number | 20090118242 12/287746 |
Document ID | / |
Family ID | 32686433 |
Filed Date | 2009-05-07 |
United States Patent
Application |
20090118242 |
Kind Code |
A1 |
Burch; Ronald ; et
al. |
May 7, 2009 |
Injectable capsaicin with non-steroidal anti-inflammatory
adjunctive agent
Abstract
Disclosed in certain embodiments is a method for relieving pain
at a site in a human or animal in need thereof, comprising
administering by injection or infiltration, a dose of a
capsaicinoid and coadministering an effective amount of a NSAID to
decrease an undesired effect of the capsaicinoid.
Inventors: |
Burch; Ronald; (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: |
32686433 |
Appl. No.: |
12/287746 |
Filed: |
October 14, 2008 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10742441 |
Dec 18, 2003 |
|
|
|
12287746 |
|
|
|
|
60434453 |
Dec 18, 2002 |
|
|
|
60434530 |
Dec 18, 2002 |
|
|
|
60434500 |
Dec 18, 2002 |
|
|
|
60434828 |
Dec 18, 2002 |
|
|
|
60434452 |
Dec 18, 2002 |
|
|
|
60434501 |
Dec 18, 2002 |
|
|
|
60461164 |
Apr 8, 2003 |
|
|
|
Current U.S.
Class: |
514/162 ;
514/567; 514/627 |
Current CPC
Class: |
A61K 31/551 20130101;
A61P 29/00 20180101; A61K 31/5415 20130101; A61P 25/02 20180101;
A61K 45/06 20130101; A61K 31/165 20130101; A61K 36/81 20130101;
A61K 31/167 20130101; A61K 31/16 20130101; A61P 25/00 20180101;
A61P 43/00 20180101; A61K 31/05 20130101; C07C 231/02 20130101;
A61K 31/05 20130101; A61K 2300/00 20130101; A61K 31/16 20130101;
A61K 2300/00 20130101; A61K 31/165 20130101; A61K 2300/00 20130101;
A61K 31/5415 20130101; A61K 2300/00 20130101; A61K 31/551 20130101;
A61K 2300/00 20130101; A61K 36/81 20130101; A61K 2300/00 20130101;
C07C 231/02 20130101; C07C 233/20 20130101 |
Class at
Publication: |
514/162 ;
514/627; 514/567 |
International
Class: |
A61K 31/60 20060101
A61K031/60; A61K 31/135 20060101 A61K031/135; A61K 31/196 20060101
A61K031/196 |
Claims
1. A method for relieving pain at a site in a human or animal in
need thereof, comprising: administering at a discrete painful site
in a human or animal in need thereof a single injectable or
implantable dose of a capsaicinoid in an amount effective to
denervate said discrete site without eliciting an effect outside
the discrete location and to attenuate pain emanating from said
site, said effective dose being from about 1 mcg to about 5000 mcg
of capsaicin or a therapeutically equivalent dose of a capsaicinoid
other than capsaicin; and coadministering an effective amount of a
non-steroidal anti-inflammatory agent to decrease an undesired
effect of the capsaicinoid.
2. The method of claim 1, wherein the NSAID is in the same
formulation as the capsaicinoid.
3. The method of claim 1, wherein the NSAID is in a different
formulation than the capsaicinoid.
4. The method of claim 1, wherein the NSAID is administered by a
different route than the capsaicinoid.
5. The method of claim 1, wherein the NSAID is administered by the
same route as the capsaicinoid.
6. The method of claim 1, wherein the NSAID is administered orally,
via implant, parenterally, sublingually, rectally, topically, or
via inhalation.
7. The method of claim 3, wherein the administration of the
capsaicinoid and the coadministration of the NSAID have overlapping
durations of effect.
8. The method of claim 1, wherein the NSAID is selected from the
group consisting of aspirin, ibuprofen, diclofenac, naproxen,
benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,
indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,
muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,
fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin,
zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac,
oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,
niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam,
sudoxicam or isoxicam, pharmaceutically acceptable salts thereof,
and mixtures thereof.
9. The method of claim 1, wherein the NSAID is selected from the
group consisting of rofecoxib, celecoxib, DUP-697, flosulide,
meloxicam, 6-MNA, L-745337, nabumetone, nimesulide, NS-398,
SC-5766, T-614, L-768277, GR-253035, JTE-522, RS-57067-000,
SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367, SC-5766,
PD-164387, etoricoxib, valdecoxib and parecoxib or pharmaceutically
acceptable salts thereof.
10. The method of claim 8, wherein the NSAID is administered
orally.
11. The method of claim 9, wherein the NSAID is administered
parenterally.
12. The method of claim 1, wherein the NSAID is in an effective
amount to reduce pain and/or inflammation at the site of
administration of the capsaicinoid.
13. The method of claim 1, further comprising administering a local
anesthetic to the human or animal.
14. The method of claim 1, wherein said dose of capsaicin is from
about 10 to about 3000 mcg.
15. The method of claim 1, wherein said dose of capsaicin is from
about 300 to about 1200 mcg.
16. The method of claim 1, wherein said dose of capsaicinoid is
administered in a pharmaceutically acceptable vehicle for injection
or implantation.
17. The method of claim 16, wherein said pharmaceutically
acceptable vehicle is an aqueous vehicle is selected from the group
consisting of Sodium Chloride Injection, Ringers Injection,
Isotonic Dextrose Injection, Sterile Water Injection, Dextrose,
Lactated Ringers Injection and any combinations or mixtures
thereof.
18. An injectable or implantable pharmaceutical composition for
attenuating pain at a site in a human or animal in need thereof,
comprising from 1 mcg to 5000 mcg of a capsaicinoid, an effective
amount of an NSAID to decrease an undesired effect of the
capsaicinoid, and a pharmaceutically acceptable vehicle for
injection or implantation.
19. The composition of claim 18, wherein the NSAID is selected from
the group consisting of aspirin, ibuprofen, diclofenac, naproxen,
benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,
indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,
muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,
fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin,
zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac,
oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,
niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam,
sudoxicam or isoxicam, pharmaceutically acceptable salts thereof,
and mixtures thereof.
20. The composition of claim 18, wherein the NSAID is selected from
the group consisting of rofecoxib, celecoxib, DUP-697, flosulide,
meloxicam, 6-MNA, L-745337, nabumetone, nimesulide, NS-398,
SC-5766, T-614, L-768277, GR-253035, JTE-522, RS-57067-000,
SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367, SC-5766,
PD-164387, etoricoxib, valdecoxib and parecoxib or pharmaceutically
acceptable salts thereof.
21-40. (canceled)
Description
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 60/434,453, filed Dec. 18, 2002, U.S.
Provisional Patent Application No. 60/434,530, filed Dec. 18, 2002,
U.S. Provisional Patent Application No. 60/434,500, filed Dec. 18,
2002, U.S. Provisional Patent Application No. 60/434,828, filed
Dec. 18, 2002, U.S. Provisional Patent Application No. 60/434,452,
filed Dec. 8, 2002, U.S. Provisional Patent Application No.
60/434,501, 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.sup.th 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 an injectable or implantable dose of
capsaicin or capsaicin analogue to a site 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 invention to provide
compositions and methods for attenuating pain at a discrete site in
a human or animal via the administration of a capsaicinoid via
injection or implantation at the discrete site.
[0013] It is another object of the present invention to provide
compositions and methods for relieving pain at an intra-articular
site or at a body space by administering an injectable or
implantable single dose of capsaicin or capsaicin analogue to the
intra-articular site or body space.
[0014] 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.
[0015] 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.
[0016] 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.
[0017] It is a further object of the invention to provide
compositions and methods for treatment of sports related injuries
utilizing injectable or implantable capsaicinoids.
[0018] It is a further object of the invention to provide
compositions and methods for treatment of pain associated with
median sternotomy utilizing infiltratable capsaicinoids.
[0019] It is a further object of the invention to provide
compositions and methods for treatment of pain associated with
mastectomy utilizing infiltratable capsaicinoids.
[0020] 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.
[0021] It is a further object of the invention to provide
compositions and methods for treatment of orthopedic disorders or
injuries utilizing injectable or implantable capsaicinoids.
[0022] It is a further object of the invention to provide
compositions and methods for treating acute traumatic pain
utilizing injectable, implantable or infiltratable
capsaicinoids.
[0023] It is a further object of the invention to provide
compositions and methods for treating neuropathic pain utilizing
injectable, implantable or infiltratable capsaicinoids.
[0024] It is a further object of the invention to provide
compositions and methods for treating nociceptive pain utilizing
injectable, implantable or infiltratable capsaicinoids.
[0025] It is a further object of the invention to provide
compositions and methods for treating
neurotransmitter-dysregulation syndromes utilizing injectable,
implantable or infiltratable capsaicinoids.
[0026] In accordance with the above objects and others, the
invention is directed in part to a method for attenuating or
relieving pain at a site in a human or animal in need thereof,
comprising administering via injection, implantation or
infiltration at a discrete site, a surgical site, or an open wound
in a human or animal in need thereof a single dose of capsaicin in
an amount effective to denervate the discrete site without
eliciting an effect outside the discrete location and to attenuate
pain emanating from said site, the dose ranging from about 1 .mu.g
to about 5,000 .mu.g capsaicin or a therapeutically equivalent dose
of a capsaicinoid other than capsaicin when said dose is injected
or infiltrated into a discrete site in the human or animal, and the
dose ranging from about 1 .mu.g to about 15,000 .mu.g capsaicin or
a therapeutically equivalent dose of a capsaicinoid other than
capsaicin when said dose is infiltrated into a surgical site or an
open wound. In other words, the term "capsaicinoid" 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 5,000 .mu.g capsaicin for injection or
infiltration, and 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 for infiltration).
[0027] The present invention is further directed in part to a
method for attenuating or relieving pain at a site in a human or
animal in need thereof, comprising administering at a discrete
painful site in a human or animal in need thereof a single
injectable or implantable dose of a capsaicinoid in an amount
effective to denervate said discrete site without eliciting an
effect outside the discrete location and to attenuate pain
emanating from said site, said effective dose being from about 1
.mu.g to about 5,000 .mu.g of capsaicin or a therapeutically
equivalent dose of a capsaicinoid other than capsaicin. In certain
preferred embodiments, the dose of capsaicin for injection or
implantation is from about 10 to about 3000 .mu.g, and preferably
from about 300 to about 1200 .mu.g. In preferred embodiments, the
dose of capsaicinoid is administered in a pharmaceutically and
physiologically acceptable vehicle for injection or implantation,
which may optionally further include one or more pharmaceutical
excipient. In certain preferred embodiments, a local anesthetic may
be administered prior to or concurrently with said dose of
capsaicinoid in an amount and location effective to attenuate an
initial hyperalgesic effect of the administered dose of
capsaicinoid. The local anesthetic may be administered, e.g., by
direct injection into the site where said dose of capsaicinoid is
administered, or as a proximal, regional, somatic, or neuraxial
block. General anesthesia may be used, if necessary. The dose of
capsaicinoid may be injected or implanted subcutaneously,
intramuscularly, itrathecally, epidurally, intraperitoneally,
caudally intradermally or intracutaneously, intercostally at a
single nerve, intra-articularly, intrasynovially, intraspinally,
intra-arterially 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, sternoclavicular, temporomandibular, carpal, tarsal, wrist,
ankle, intervertebral disk, ligamentum flavum and any other joint
subject to pain.
[0028] In certain other embodiments of the present invention, there
is provided a method for attenuating or relieving pain at a
surgical site or open wound in a human or animal in need thereof,
comprising administering via infiltration at a surgical site or
open wound in a human or animal in need thereof a single dose of
capsaicin in an amount effective to denervate the surgical site or
open wound without eliciting an effect outside the surgical site or
open wound, the dose ranging from about 1 .mu.g to about 15,000
.mu.g. 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. In certain
preferred embodiments where the capsaicinoid is infiltrated into a
surgical site or an open wound, 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. 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.
[0029] The present invention is further directed in part to a
method for attenuating or relieving pain at a surgical site or open
wound in a human or animal in need thereof, comprising
administering at a surgical site or open wound in a human or animal
in need thereof a single infiltratable dose of a capsaicinoid in an
amount effective to denervate said surgical site or open wound
without eliciting an effect outside the surgical site or open
wound, 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.
[0030] The dose of capsacinoid administered by infiltration into
the surgical site or open wound may be administered directly onto
the tissue, muscle or bone. 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, sternoclavicular, temporomandibular, carpal,
tarsal, wrist, ankle, intervertebral disk, ligamentum flavum and
any other joint subject to pain.
[0031] The invention, is further directed in part to a method of
treating acute traumatic pain associated with an injury, comprising
injecting a capsaicinoid in a physiologically compatible vehicle
through the skin of a patient in proximity to an injury, said dose
of capsaicinoid being sufficient to attenuate the dull, aching pain
associated with C-fibers in proximity to the injury and such that
the patient continues to have sensation in proximity to the injury
and without affecting sharp protective pain associated with A-delta
fibers in proximity to the site, the dose of capsaicinoid being
therapeutically equivalent to a dose of capsaicin in an amount from
about 300 to about 1500 .mu.g and being effective to attenuate
dull, aching pain in proximity to the injury for at least about 48
hours.
[0032] The invention is further directed in part to a method of
treating acute traumatic pain associated with surgery or open wound
injury, comprising administering via infiltration a capsaicinoid in
a physiologically compatible vehicle at the surgical site or open
wound of a patient, said dose of capsaicinoid being sufficient to
attenuate the dull, aching pain associated with C-fibers in
proximity to the surgical site or open wound and such that the
patient continues to have sensation in proximity to the surgical
site open wound and without affecting sharp protective pain
associated with A-delta fibers in proximity to the surgical site or
open wound, the dose of capsaicinoid being therapeutically
equivalent to a dose of capsaicin in an amount from about 600 to
about 15,000 .mu.g and being effective to attenuate dull, aching
pain in proximity to the surgical site or open wound for at least
about 48 hours.
[0033] In certain preferred embodiments, the capsaicinoid is
capsaicin itself. In more preferred embodiments, the capsaicinoid
comprises trans-capsaicin. In most preferred embodiments, the
capsaicinoid is at least about 97% trans-capsaicin.
[0034] The single injectable, implantable or infiltratable dose of
a capsaicinoid administered at a discrete site, surgical site or
open wound in accordance with the present invention is preferably
in an amount effective to a) produce 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
for the purpose of reducing or eliminating pain arising from a
discrete locus, and b) minimize potential adverse consequences of
C-fiber and/or A-delta activation and or damage outside of the
locus of pain.
[0035] The present invention is also directed to an injectable or
implantable pharmaceutical composition for attenuating pain at a
site in a human or animal in need thereof, consisting essentially
of from 1 .mu.g to 5000 .mu.g of a capsaicinoid comprising
trans-capsaicin and a pharmaceutically acceptable vehicle for
injection or implantation. In certain preferred embodiments, the
dose of trans-capsaicin ranges from about 10 .mu.g to about 3000
.mu.g, from about 300 .mu.g to about 1500 .mu.g, or preferably from
about 400 .mu.g to about 1200 .mu.g.
[0036] The present invention is also directed to an infiltratable
pharmaceutical composition for attenuating pain at a surgical site
or open wound in a human or animal in need thereof, consisting
essentially of from 1 .mu.g to 15,000 .mu.g of a capsaicinoid
comprising trans-capsaicin and a pharmaceutically acceptable
vehicle for infiltration. In certain preferred embodiments, the
dose of trans-capsaicin ranges from about 600 .mu.g to about 15,000
.mu.g, from about 600 .mu.g to about 10,000 .mu.g, or preferably
from about 1,000 .mu.g to about 10,000 .mu.g.
[0037] In order that the invention described herein may be more
fully understood, the following definitions are provided for the
purposes of this disclosure:
[0038] The term "injection" shall mean administration of capsaicin
to a discrete site through the skin of a human or animal.
[0039] The term "implantation" shall mean administration of
capsaicin to a discrete site by embedding the dose of capsaicin
into the skin, tissue, muscles, tendons, joints, or other body
parts of a human or animal.
[0040] The term "infiltration" or "infiltratable" shall mean
administration into a discrete surgical site or open wound in a
human or animal.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] As used herein, the term "local anesthetic" means any drug
or mixture of drugs that provides local numbness and/or
analgesia.
[0045] 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
[0046] 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.
[0047] 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.
[0048] 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.
[0049] FIG. 3 is a graph displaying the NRS Pain Score in study
subjects entered into the Osteoarthritis Efficacy Study exemplified
in Example 2.
[0050] FIG. 4 is a graph displaying a comparison of VAS Pain Score
between subjects entered into the Bunionectomy Efficacy study
exemplified in Example 3.
[0051] 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
[0052] The compositions and methods disclosed herein can be used
for treating pain at a specific site 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
site in a human or animal for relieving pain at the site.
[0053] In another embodiment, the methods involve providing
anesthesia to the site where the capsaicinoid is to be
administered, and then administering an effective amount of
capsaicinoid to the site. The anesthesia can be provided directly
to the site, or at a remote site that causes anesthesia at the site
where the capsaicinoid is to be administered. For example, epidural
regional anesthesia can be provided to patients to which the
capsaicinoid is to be administered at a site 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.
[0054] Examples of local anesthetic agents which can be used
include bupivacaine, ropivacaine, dibucaine, procaine,
chloroprocaine, prilocaine, 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.
[0055] 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.
[0056] 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 anesthetize 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.
[0057] 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).
[0058] 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.
[0059] In contrast, in the present invention, the administration of
microgram quantities of capsaicin into discrete localized areas,
surgical sites or open wounds 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.
[0060] In the present invention, a single dose from about 1 .mu.g
to 5,000 .mu.g of capsaicin, or a therapeutically equivalent dose
of one or more other capsaicinoids, is administered via injection
or implantation 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 10 to about 3000
micrograms of capsaicin, or a therapeutically equivalent dose of
one or more other capsaicinoids, is administered at the site. In
certain preferred embodiments, the amount of capsaicin administered
at the site is preferably from about 100 to about 1000 micrograms.
In certain other embodiments the amount of capsaicin administered
at the site is preferably from about 10 to about 1000 micrograms,
more preferably from 20 to about 300 micrograms, and most
preferably from about 35 to about 200 micrograms. In other words,
the present invention is directed to administration of a single
dose of capsaicin or other capsaicinoid(s) by injection or
implantation 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).
[0061] In other embodiments of 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 f 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 10,000 micrograms. In other words, the present
invention is directed to administration of a single dose of
capsaicin or other capsaicinoid(s) by infiltration 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).
[0062] 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 analogue in 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.
[0063] Alternatively, capsaicinoids (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 qualitatively
resembles capsaicin in its activity, but differs quantitatively in
potency (i.e. 103-104 fold more potent) and in relative spectrum of
actions. For resiniferatoxin it is recommended to administer
0.1.times.10-3 to 5.times.10-2 mg/kg, preferably 0.11.times.10-3 to
5.times.10-3 mg/kg, body weight of the subject for single
application, or less upon multiple application. In certain
embodiments, resiniferatoxin is administered in the range of
1.times.10-5 mg/kg to 5.times.10-2 mg/kg to the subject.
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.
[0064] 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.
[0065] 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.
[0066] 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.
[0067] 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.
[0068] 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.
[0069] 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.
[0070] 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.
[0071] 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 40 C. to
about 45 C to obtain a step c) intermediate product.
[0072] 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.
[0073] 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.
[0074] 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.
[0075] 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.
[0076] 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.
[0077] 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).
[0078] 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.
[0079] 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.
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.
[0080] 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 0.01% 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.
[0081] 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.
[0082] 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.
[0083] 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.
[0084] The local anesthetic can preferably be administered by
direct injection, implantation or infiltration 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.
[0085] 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.
[0086] 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.
[0087] 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.
[0088] 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.
[0089] The compositions and methods of the present invention can be
used for treating various conditions associated with pain by
providing pain relief at a specific site, 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.
[0090] 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.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] 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
37:34-51, 1975; Wolfe et al., 1990; Wolfe et al., J Rheum 23:3,
1996; Yunus et al., Semin Arthritis Rheum 11:151-71, 1981).
[0095] 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.
[0096] 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.
[0097] 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.
[0098] Pain Intensity assessment scales are typically used by those
of ordinary skill in the art to evaluate analgesic choices and
therapeutic effects.
[0099] 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, 100 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.
[0100] The capsaicinoid formulations and methods described herein
may be used to treat many conditions where the capsaicinoid can be
administered via injection, implantation or infiltration into a
specific site, 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 Chronic Post-Herniorrhaphy Pain
[0101] In a preferred embodiment, the capsaicinoid formulations and
methods disclosed herein can be used for the treatment/attenuation
of chronic post-herniorrhaphy pain. Chronic post-herniorrhaphy pain
occurs in between 5-30% of patients, with social consequences
limiting some type of activity in about 10% of patients and 1-4% of
patients are referred to chronic pain clinics. Nerve damage is
probably the most plausible pathogenic factor, but specific
principles for therapy have not been evidence-based and range from
usual analgesics to re operation with mesh removal and various
types of nerve sections without any demonstrated efficacy in
sufficient follow-up studies with or without randomized data. In
patients suffering from pain associated with chronic
post-herniorrhapy, the dose of capsaicinoid can be administered to
the site where the surgery was performed or to the immediate area
surrounding the incision.
Treatment of Pain Associated with Morton's Neuroma
[0102] In another preferred embodiment, the capsaicinoid
formulations and methods disclosed herein can be used for the
treatment/attenuation of pain associated with Morton's Neuroma.
Morton's Neuroma is considered to be most likely a mechanically
induced degenerative neuropathy which has a strong predilection for
the third common digital nerve in middle-aged women. It is
considered a well-defined model of neuropathic pain. The usual
medical treatment of Morton's neuroma includes local injection of
steroids, often with lidocaine. When nonsurgical means fail to
relieve patient's symptoms, surgical removal of this offending
neuroma through a dorsal approach can produce dramatic relief of
symptoms in approximately 80% of patients. However, 20% of patients
experience neuroma recurrence (referred to as stump or amputation
neuroma) that often causes more severe pain that the original
neuroma and is generally treatment resistant. Administration of
capsaicinoid in accordance with the invention is useful for the
treatment of the neuropathic pain associated with Morton's Neuroma
and may reduce the re-occurrence of pain associated with stump or
amputation neuroma.
Treatment of Pain Associated with Mastectomy
[0103] 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
[0104] 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 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
[0105] 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.
[0106] A. Bursitis
[0107] 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.
[0108] 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. Reaspiration 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.
[0109] The capsaicinoid may be administered via injection in a
location and fashion similar to that currently utilized with
respect to localized injections of corticosteroids. For example, in
certain embodiments, the dose of capsaicin is administered by
intra-articular injection into the bursa.
[0110] In another embodiments, the capsaicinoid may be administered
via infiltration into the bursa and/or the tissue and muscle
surrounding the bursa.
[0111] B. Tendonitis
[0112] 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.
[0113] 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 (eg, 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).
[0114] In one embodiment of the present invention, pain associated
with tendonitis of the knee, shoulders, hip, pelvis, spine, elbows,
leg and foot is treated with a capsaicinoid injection undertaken in
similar fashion as a localized corticosteroid injection. For
example, in embodiments where the capsaicinoid formulation is used
for the treatment/attenuation of pain associated with tendonitis or
bursitis of the shoulder, the dose of capsaicinoid can be
administered by injection into the subacromial bursa with the
needle inserted into the space between the acromium and the humerus
on the lateral aspect of the shoulder.
[0115] In another 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.
[0116] C. Osteoarthritis
[0117] 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.
[0118] 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).
[0119] 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 injection at the affected site or by
intra-articular infiltration and/or to the tissue and muscle
surrounding the affected joint, including but not limited to
osteoarthritis disorders of the knee
[0120] D. Rheumatoid Arthritis
[0121] 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.
[0122] 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.
[0123] 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.
[0124] 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.
[0125] E. Back Pain
[0126] The capsaicinoid formulations and methods disclosed herein
may be used to treat/attenuate pain associated with back pain. Back
pain is the second most common reason for doctor visits in the U.S.
The causes of lower back pain are numerous. Some of the more common
causes of lower back pain are: sudden injury to the back such as
may occur in an auto accident, fall, sports, or other manner;
gynecological conditions such as endometriosis, menstrual cramps,
fibroid tumors, and pregnancy are sometimes the cause of lower back
pain in women; and stress to the muscles, nerves, or ligaments in
the lower back. Slipped discs, pinched nerves, sciatica, aging, and
infections are other common causes of lower back pain. The
treatment of lumbar strain consists of resting the back (to avoid
re-injury), medications to relieve pain and muscle spasm, local
heat applications, massage, and eventual (after the acute episode
resolves) reconditioning exercises to strengthen the low back and
abdominal muscles Zygapophysial joints, better known as facet or
"Z" joints, are located on the back (posterior) of the spine on
each side of the vertebrae where it overlaps the neighboring
vertebrae. The facet joints provide stability and give the spine
the ability to bend and twist. They are made up of the two surfaces
of the adjacent vertebrae, which are separated by a thin layer of
cartilage. The joint is surrounded by a sac-like capsule and is
filled with synovial fluid (a lubricating liquid that reduces the
friction between the two bone surfaces when the spine moves and
also nourishes the cartilage.) A problem (such as inflammation,
irritation, swelling or arthritis) in the facet joint may cause low
back pain. Diagnostic tests can show an abnormality in a facet
joint, which may suggest that the facet joint is the source of the
pain. However, sometimes normal study results can be present while
the facet joint is still the source of pain, and abnormal results
do not always implicate the facet joint.
[0127] To determine if a facet joint is truly the source of back
pain, an injection of local anesthetic (e.g, as a block) may be
utilized. If an injection of a small amount of anesthetic or
numbing medication into the facet joint reduces or removes the
pain, it indicates that the facet joint may be the source of the
pain. This is diagnostic use of the facet joint injection. Once a
facet joint is pinpointed as a source of pain therapeutic
injections of anesthetic agents and anti-inflammatory medications
may give pain relief for longer periods of time. The capsaicinoid
formulations may be administered in such situations to attenuate
such pain.
[0128] Facet joint injections are performed while the patient is
awake, under a local anesthetic, and able to communicate.
Sometimes, the health care provider may also administer drugs to
make the patient more comfortable during the procedure. The
injection is usually performed while the patient is lying on his or
her stomach on an X-ray table. EKG, blood pressure cuffs and
blood-oxygen monitoring devices may be hooked up prior to the
injection process. Once the proper site has been determined, the
physician will inject the anesthetic (often lidocaine or
bupivicaine) and the anti-inflammatory (usually a corticosteroid).
This process may then be repeated depending on the number of
affected facet joints.
[0129] F. Heel Spur
[0130] 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 sign s 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.
[0131] When a capsaicinoid is used for plantar fascia, the dose of
capsaicinoid is preferably administered by injection into the
affected area. When surgery is required, the dose of capsaicinoid
is preferably administered by infiltration into 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
[0132] 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 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 either by injection,
infiltration or both injection and infiltration. When the dose of
capsaicinoid is administered by injection, the capsaicinoid may be
injected directly the site of incision or to the immediate area
surrounding the surgical site. In other embodiments, the dose of
capsaicinoid can be administered to the site where the surgery is
being performed or to the muscle, tissue and bones surrounding the
surgical site prior to closure of the wound. 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 surgery than a
laparoscopy.
Infiltration Dose
[0133] In preferred embodiments of the present invention, the dose
of capsaicinoid contained in a unit dose for infiltration is from
about 1 .mu.g to about 15,000 .mu.g of capsaicin, preferably from
about 600 .mu.g to about 15,000 .mu.g capsaicin, more preferably
from about 600 .mu.g to about 10,000 .mu.g capsaicin, or a
therapeutically equivalent amount of one or more capsaicinoids. In
certain preferred embodiments, the dose of capsaicin is from about
1000 .mu.g to about 10,000 .mu.g, or a therapeutically equivalent
amount of one or more capsaicinoids. Preferably, the capsaicinoid
is administered in a pharmaceutically and physiologically
acceptable vehicle for injection or implantation.
[0134] In certain other embodiments, suitable doses of
capsaicin/capsaicinoid for infiltration for the treatment of
nociceptive pain, neuropathic pain, pain from nerve injury, pain
from myalgias, pain associated with painful trigger points, pain
from tumors in soft tissues, pain associated with
neurotransmitter-dysregulation syndromes and pain associated with
orthopedic disorders range from about 600 .mu.g to about 15,000
.mu.g of capsaicin (trans 8-methyl-N-vanillyl-6-noneamide),
preferably from about 600 to about 10,000 micrograms, more
preferably from about 1000 to 10,000 micrograms, with 5,000 .mu.g
most preferred.
[0135] In certain preferred embodiments, an injection of local
anesthetic can be administered in proximity to the site prior to
administration of the capsaicinoid, e.g., as described above and in
the appended examples. In other embodiments, phenol can be used
instead of or in addition to the local anesthetic.
Injectable Dose
[0136] In preferred embodiments of the present invention, the dose
of capsaicinoid contained in a unit dose injection/implantation is
from about 1 .mu.g to about 5000 .mu.g of capsaicin, preferably
from about 10 .mu.g to about 3000 .mu.g capsaicin, more preferably
from about 300 .mu.g to about 1500 .mu.g capsaicin, or a
therapeutically equivalent amount of one or more capsaicinoids. In
certain preferred embodiments, the dose of capsaicin is from about
400 .mu.g to about 1200 .mu.g, or a therapeutically equivalent
amount of one or more capsaicinoids. Preferably, the capsaicinoid
is administered in a pharmaceutically and physiologically
acceptable vehicle for injection or implantation.
[0137] In certain other embodiments, suitable doses of
capsaicin/capsaicinoid for injection or implantation for the
treatment of nociceptive pain, neuropathic pain, pain from nerve
injury, pain from myalgias, pain associated with painful trigger
points, pain from tumors in soft tissues, pain associated with
neurotransmitter-dysregulation syndromes and pain associated with
orthopedic disorders range from about 1 .mu.g to about 3000 .mu.g
of capsaicin (trans 8-methyl-N-vanillyl-6-noneamide), preferably
from about 20 to about 300 micrograms, more preferably from about
35 to 200 micrograms, with 100 .mu.g most preferred.
[0138] The administration of the anesthetic along with the
subsequent administration of the capsaicinoid formulations and
methods of the invention alleviate or attenaute pain at the site
for a prolonged period of time. With respect to joint pain, in
certain preferred embodiments a single unit dose capsaicinoid
injection or implantation attenuates pain at the site for at least
about one month, more preferably at least about 3 months, and
typically in certain embodiments from about 3 to about 6 months.
With respect to pain associated with arthritic conditions such as
osteoarthritis, in certain preferred embodiments a single unit dose
capsaicinoid injection or implantation attenuates pain at the site
for at least about 3 months to at least about 4 months. With
respect to post-surgical pain, in certain preferred embodiments a
single unit dose capsaicinoid injection or implantation attenuates
pain at the site for at least about one week, and in certain
embodiments for at least about 1 month. 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.
[0139] In certain preferred embodiments, an injection of local
anesthetic can be administered in proximity to the site prior to
administration of the capsaicinoid, e.g., as described above and in
the appended examples. In other embodiments, phenol can be used
instead of or in addition to the local anesthetic.
Injectable/Implantable and Infiltratable Formulations
[0140] In embodiments where the capsaicinoid is administered by
injection, implantation or infiltration, the capsaicinoid is
administered to a discrete site by penetrating the outer layer of
the skin or a surgical site or wound opening by instillation or
injection to the 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.
[0141] The dose of capsaicinoid is preferably prepared for
injection, implantation or 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 injectable, implantable or 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.
[0142] Depending on the pharmaceutically acceptable vehicle chosen,
the dose of capsaicinoid can be administered as an aqueous solution
or suspension for injection, implantation or infiltration.
Injections or infiltrations 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).
[0143] 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.
[0144] Suitable surfactants include, but are not limited to, sodium
stearyl fumarate, diethanolamine cetyl sulfate, polyethylene
glycol, isostearate, polyethoxylated castor oil, benzalkonium
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%.
[0145] 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%.
[0146] In certain preferred embodiments, the pharmaceutical vehicle
utilized to deliver the capsaicinoid comprises polyethylene glycol,
histidine, and sucrose, in water for injection. In one preferred
embodiment, the pharmaceutical vehicle comprises about 20% PEG 300,
about 10 mM histidine and about 5% sucrose in water for
injection.
[0147] 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 injectable, implantable or
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.
[0148] 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.
[0149] 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 a
discrete site, a 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. Injectable or implantable administration preferably
includes, but is not limited to subcutaneous (under the skin),
intramuscular (muscle), itrathecal, epidural, intraperitoneal,
caudal, intradermal or intracutaneous (into the skin), intercostals
at a single nerve, intra-articular (joints) or body spaces,
intrasynovial (joint fluid), intraspinal (spinal column),
intra-arterial (arteries) administrations and administration into
other connective tissue compartments. As used herein "intraspinal"
means into or within the epidural space, the intrathecal space, the
white or gray matter of the spinal cord affiliated structures such
as the dorsal root and dorsal root ganglia. Infiltratable
administration of the formulations, of the invention may be, e.g.,
into a joint selected from the group consisting of knee, elbow,
hip, sternoclavicular, temporomandibular, carpal, tarsal, wrist,
ankle, intervertebral disk, ligamentum flavum and any other joint
subject to pain. Examples of body spaces include pleura,
peritoneum, 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.
[0150] When the single dose of capsaicinoid is administered via
injection, the injection volume of capsaicin will depend on the
localized site of administration. Suitable injection volumes to be
delivered preferably range from about 0.1 to about 20 ml, more
preferably from about 0.5 to about 10 ml and most preferably from
about 1.0 to about 5 ml, depending on the site to be treated.
Alternatively, 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.
[0151] The administration of the anesthetic along with the
subsequent administration of capsaicinoid alleviates pain at the
discrete site, 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.
[0152] In certain embodiments of the invention, an adjunctive agent
can be co-administered with the capsaicinoid. Suitable adjunctive
agents for use in the present invention include, but are not
limited to non-steroidal inflammatory agents ("NSAIDS"),
non-anesthetic sodium channel blockers, vasoconstrictors,
vasodilators and tricyclic anti-depressants.
[0153] In certain embodiments of the present invention, the
capsaicinoid and the adjunctive agent are administered together in
a single composition. In other embodiments, the capsaicinoid and
the adjunctive agent are administered as separate compositions
before, after or at the same time as the capsaicinoid, by the same
or different routes of administration. For example, the adjunctive
agent can be administered orally, via implant, parenterally,
sublingually, rectally, topically, or via inhalation. When
administered in separate compositions, preferably the adjunctive
agent formulation and the capsaicinoid formulation provide
overlapping duration of effect.
[0154] In certain embodiments, one or more adjunctive agents can be
co-administered with the capsaicinoid. The multiple adjunctive
agents can be selected within the same group (e.g., two NSAIDS) or
from different groups (e.g., an NSAID and a vasoconstrictor) and
can be administered by multiple routes of administration. Further a
local anesthetic can be administered with the capsaicinoid, in
addition to the adjunctive agent.
[0155] NSAIDs useful as adjunctive agents in the present invention
include aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen,
flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen,
piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,
trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,
bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,
tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac,
mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid
tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or
isoxicam, pharmaceutically acceptable salts thereof, and mixtures
thereof. Other suitable agents classified as NSAIDS include the
following, non-limiting, chemical classes of analgesic,
antipyretic, nonsteroidal antiinflammatory drugs: salicylic acid
derivatives, including aspirin, sodium salicylate, choline
magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic
acid, sulfasalazine, and olsalazin; para-aminophennol derivatives
including acetaminophen; indole and indene acetic acids, including
indomethacin, sulindac, and etodolac; heteroaryl acetic acids,
including tolmetin, diclofenac, and ketorolac; anthranilic acids
(fenamates), including mefenamic acid, and meclofenamic acid;
zenolic acids, including oxicams (piroxicam, tenoxicam), and
pyrazolidinediones (phenylbutazone, oxyphenthartazone); and
alkanones, including nabumetone. For a more detailed description of
the NSAIDs that may be included within the medicaments employed in
the present invention, see Paul A. Insel Analgesic-Antipyretic and
Antiinflammatory Agents and Drugs Employed in the treatment of Gout
in Goodman & Gilman's The Pharmacological Basis of
Therapeutics, 617-57 (Perry B. Molinhoff and Raymond W. Ruddon,
Eds., Ninth Edition, 1996), and Glen R. Hanson Analgesic,
Antipyretic and Anti-Inflammatory Drugs in Remington: The Science
and Practice of Pharmacy Vol II, 1196-1221 (A. R. Gennaro, Ed. 19th
Ed. 1995) which are hereby incorporated by reference in their
entireties.
[0156] NSAIDS exhibit inhibition of cyclooxygenases I and II, the
enzymes responsible for the biosynthesis of the prostaglandins and
certain related autacoids. NSAIDs are known to be antipyretic,
analgesic, and antiinflammatory. Specific classes of non-steroidals
useful in the present invention are also disclosed in detail in the
following U.S. patents, all incorporated by reference herein: U.S.
Pat. Nos. 4,275,059, Flora, et al, issued Jun. 23, 1983, discloses
salicylic acid, its pharmaceutically-acceptable salts, and its
pharmaceutical-acceptable esters and derivatives; U.S. Pat. No.
4,264,582, Flora, et al, issued Apr. 28, 1981, discloses
p-(isobutylphenyl)acetic acid compounds including the parent acid
(ibufenac) and its salts and esters, and derivatives thereof; U.S.
Pat. No. 4,282,214, Flora, et al, issued Aug. 4, 1981, discloses
various phenylacetic acid derivatives, their
pharmaceutically-acceptable salts, and their
pharmaceutically-acceptable ester; U.S. Pat. No. 4,216,212, Flora,
et al, issued Aug. 5, 1980, discloses prazolidine compounds, their
pharmaceutically-acceptable salts, and their
pharmaceutically-acceptable esters; U.S. Pat. No. 4,269,828, Flora,
et al, issued May 26, 1981, discloses indole compounds, their
pharmaceutically-acceptable salts, and their
pharmaceutically-acceptable esters.
[0157] Aspirin is the prototypical nonsteroidal anti-inflammatory
agent. It possesses analgesic-antipyrectc and anti-inflammatory
properties and is the standard for the comparison and evaluation of
other nonsteroidal anti-inflammatory agents. Aspirin is a member of
the class of nonsteroidal anti-inflammatory agents known as "the
salicylates." Other salicylates. include, but are not limited to
salicylic acid, methyl salicylate, diflunisal, salsalate,
olsalazine and sulfasalazine. Administration of salicylates is
generally recognized in the art for the treatment of low intensity
pain arising from integumental structures rather than from
viscera.
[0158] Another class of nonsteroidal anti-inflammatory agents is
the para-aminophenol derivatives; of which, acetaminophen
(Tylenol.TM.) and phenacetin are members. Acetaminophen and
phenacetin posses analgesic-antipyretic activity, however, they
both posses weak anti-inflammatory activity. Therefore, these
agents are a suitable substitute for the salicylates in the
treatment of low intensity pain, but are generally not recommended
for the treatment of anti-inflammatory conditions.
[0159] In addition there are several other classes of nonsteroidal
anti-inflammatory agents. These include, but are not limited to the
propionic acid derivatives, the fenamates, the oxicams, the indole
derivatives, the pyrazolon derivatives and any combinations or
mixtures thereof.
[0160] The proprionic acid derivatives include, but are not limited
to ibuprofen, naproxen, flurbiprofen, fenoprofen, ketoprofen,
oxaprozin, carprofen, fenbufen, pirprofen, indobufen, indoprofen
and tiaprofenic acid.
[0161] The fenamates include, but are not limited to meclofenamate
sodium, mefenamic acid, flufenamic acid, tolfenamic acid,
etofenamic acid, diclofenac, ketorolac and tolmetin.
[0162] The oxicams include, but are not limited to piroxicam,
meloxicam, nabumetone, lornoxicam, cinnoxicam, sudoxicam,
tenoxicam, and piroxicam prodrugs, e.g., ampiroxicam, droxicam, and
pivoxicam.
[0163] The indole derivatives include, but are not limited to
indomethacin, sulindac, and etodolac.
[0164] The pyrazolon derivatives include, but are not limited to
phenylbutazone, oxyphenbutazone, antipyrine, amonopyrine,
azapropazone, remifenzone and dipyrone.
[0165] Other nonsteroidal anti-inflammatory agents known as COX-II
inhibitors include flosulide, nimesulidde, rofecoxib, celecoxib
valdecoxib and parecoxib.
[0166] Non-steroidal, anti-inflammatory agents (NSAIDs) exert most
of their anti-inflammatory, analgesic and antipyretic activity and
inhibit hormone-induced uterine contractions and certain types of
cancer growth through inhibition of prostaglandin G/H synthase,
also known as cyclooxygenase.
[0167] Fatty acid cyclooxygenase (COX) was described as the source
of prostaglandins, thromboxanes, and a variety of other arachidonic
acid-, and higher desaturated fatty acid-derived biologically
active hydroxylated metabolites beginning in the late 1960's. Bengt
Sammuelsson, Sune Bergstrom and their colleagues discovered the
biological activity and elucidated the structures of the products
of cyclooxygenase in the late 1960's and early 1970's and John Vane
discovered that aspirin and other NSAIDs exert their major
biological activities by inhibiting cyclooxygenase. COX is directly
responsible for the formation of PGG and PGH and these serve as the
intermediates in the synthesis of PGD, PGE, PGF, PGI, and TXA. By
the late 1970's and early 1980's, it was appreciated that many
hormones and other biologically active agents could regulate the
cellular activity of COX. At first, it was assumed that COX
induction was the simple result of oxidative inactivation of COX,
which happens after only a few substrate turnovers. This is common
among enzymes that incorporate molecular oxygen into their
substrates--the oxygen rapidly degrades the enzyme. Such enzymes
are sometimes referred to as suicide enzymes. In response to the
rapid (within seconds) inactivation of cyclooxygenase, its message
is transcribed, and the enzyme is rapidly induced to replace that
lost due to catalysis. It was noticed by several groups that
cyclooxygenase was induced to a much greater degree than necessary
to replace the lost enzyme. Using an oligonucleotide directed to
the cloned COX-1 enzyme, a second band was identified on Northern
blots under low stringency. This gene was cloned and identified as
a second COX enzyme, named COX-2, and was found to be largely
absent from many cells under basal conditions but rapidly induced
by several cytokines and neurotransmitters. The expression of this
enzyme was found to be largely responsible for the
previously-observed excess COX activity in activated cells. The
genes for COX-1 and COX-2 are distinct, with the gene for COX-1
being 22 kb and the message size 2.8 kb whereas the gene for COX-2
is 8.3 kb and the message size 4.1 kb. Whereas the COX-1 promoter
does not contain recognized transcription factor binding sites, the
COX-2 promoter contains sites for NT-B, AP-2, NF-IL-6 and
glucocorticoids (H. R. Herschman, Canc. Metas. Rev. 13: 256, 1994).
There are some differences in the active sites of the enzymes.
Aspirin inhibits the cyclooxygenase activity of COX-1 but leaves
intact its peroxidase activity, whereas aspirin converts COX-2 from
a cyclooxygenase to a 15-lipoxygenase (E. A. Meade et al, J. Biol.
Chem. 268: 6610, 1993).
[0168] It has been proposed that the COX-1 enzyme is responsible,
in many cells for endogenous basal release of prostaglandins and is
important in the physiological functions of prostaglandins which
include the maintenance of gastrointestinal integrity and renal
blood flow. Inhibition of COX-1 causes a number of side effects
including inhibition of platelet aggregation associated with
disorders of coagulation, and gastrointestinal toxicity with the
possibility of ulcerations and of hemorrhage. It is believed that
the gastrointestinal toxicity is due to a decrease in the
biosynthesis of prostaglandins which are cytoprotective of the
gastric mucosa. Thus a high incidence of side effects has
historically been associated with chronic use of classic
cyclooxygenase inhibitors, all of which are about equipotent for
COX-1 or COX-2, or which are COX-1-selective. While renal toxicity
occurs, it usually becomes evident in patients who already exhibit
renal insufficiency (D. Kleinknecht, Sem. Nephrol. 15: 228, 1995).
By far, the most prevalent and morbid toxicity is gastrointestinal.
Even with relatively nontoxic drugs such as piroxicam, up to 4% of
patients experience gross bleeding and ulcertaion (M. J. S. Langman
et al, Lancet 343: 1075, 1994). In the United States, it is
estimated that some 2000 patients with rheumatoid arthritis and
20,000 patients with osteoarthritis die each year due to
gastrointestinal side effects related to the use of COX inhibitors.
In the UK, about 30% of the annual 4000 peptic ulcer-related deaths
are attributable to COX inhibitors (Scrip 2162, p. 17). COX
inhibitors cause gastrointestinal and renal toxicity due to the
inhibition of synthesis of homeostatic prostaglandins responsible
for epithelial mucus production and renal blood flow,
respectively.
[0169] The second form of cyclooxygenase, COX-2, is rapidly and
readily inducible by a number of agents including mitogens,
endotoxins, hormones, cytokines and growth factors.
[0170] It has been proposed that COX-2 is mainly responsible for
the pathological effects of prostaglandins, which arise when rapid
induction of COX-2 occurs in response to such agents as
inflammatory agents, hormones, growth factors, and cytokines. A
selective inhibitor of COX-2 therefore would have
anti-inflammatory, antipyretic and analgesic properties similar to
those of a conventional non-steroidal anti-inflammatory drug
(NSAID). Additionally, a COX-2 inhibitor would inhibit
hormone-induced uterine contractions and have potential anti-cancer
effects. A COX-2 inhibitor would have advantages over NSAIDS such
as a diminished ability to induce some of the mechanism-based side
effects. Moreover, it is believed that COX-2 inhibitors have a
reduced potential for gastrointestinal toxicity, a reduced
potential for renal side effects, a reduced effect on bleeding
times and a lessened ability to induce asthma attacks in
aspirin-sensitive asthmatic subjects.
[0171] Thus, compounds with high specificity for COX-2 over COX-1,
may be useful as alternatives to conventional NSAIDS. This is
particularly the case when NSAID use is contra-indicated, such as
in patients with peptic ulcers, gastritis, regional enteritis,
ulcerative colitis, diverticulitis or with a recurrent history of
gastrointestinal lesions; GI bleeding, coagulation disorders
including anemia, hypoprothrombinemia, haemophelia or other
bleeding problems; kidney disease, and patients about to undergo
surgery or taking anticoagulants.
[0172] Once it became clear that COX-1 but not COX-2 is responsible
for gastrointestinal epithelial prostaglandin production and a
major contributor to renal prostaglandin synthesis, the search for
selective COX-2 inhibitors became extremely active. This led very
quickly to the recognition that several COX inhibitors, including
rofecoxib (Vioxx), celecoxib (Celebrex), DUP-697, flosulide,
meloxicam, 6-MNA, L-745337, nabumetone, nimesulide, NS-398,
SC-5766, T-614, L-768277, GR-253035, JTE-522, RS-57067-000,
SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367, SC-5766,
PD-164387, etoricoxib, valdecoxib and parecoxib or pharmaceutically
acceptable salts, enantiomers or tautomers thereof.
[0173] In certain embodiments, the amount of COX 2 selective
inhibitor that is used in accordance with the present invention
preferably ranges from about 0.001 to about 100 milligrams per day
per kilogram of body weight of the subject (mg/day kg), more
preferably from about 0.05 to about 50 mg/day kg, even more
preferably from about 1 to about 20 mg/day kg.
[0174] Administration of capsaicinoid alone or with a local
anesthetic sometimes times results in the patient experiencing a
dull aching pain at and around the site of local anesthetic
administration. To prevent or reduce the occurrence of this dull
aching pain, the non-steroidal antiinflammatory adjunctive agent is
preferably administered prior to capsaicinoid and local anesthetic
administration. Preferably, the non-steroidal antiinflammatory
adjunctive agent is administered orally, which also helps to avoid
the discomfort of the patient receiving another injection.
Alternatively, in certain embodiments, a selective Cox-2 inhibitor
can be administered peripherally by injection or infiltration.
[0175] Suitable doses of the non-steroidal antiinflammatory
adjunctive agents vary due to the wide variations in potency among
the various NSAIDs and there respective selectivity for COX-1 or
COX-2 inhibition. The dose is also dependant on the severity of the
pain which must be prevented or alleviated, the physical condition
of the patient, the relative severity and importance of adverse
side effects, and other factors within the judgment of the
physician. Examples of suitable doses and routes of administration
for non-steroidal anti-inflammatory adjunctive agents are listed in
Tables IV-X below:
TABLE-US-00001 TABLE IV SALICYLATES and PARA-AMINOPHENOL
DERIVATIVES NSAID Dose Aspirin 325-650 mg orally every 4-6 hours
Diflunisal 500-1000 mg/day orally in 2 divided doses Salsalate 3
gm/day orally in 2-3 divided doses Olsalazine 1 gm/day orally in 2
divided doses Sulfasalazine 1 gm every 6-8 hours Salicylic Acid 10%
or 60%; gel 6%, 12%, 17% or 26%; oint. 3%, 25% or 60% applied
topically. Acetaminophen 325-650 mg orally every 4-6 hours; 1000 mg
orally every 6-8 hours
TABLE-US-00002 TABLE V PROPRIONIC ACID DERIVATIVES NSAID Dose
Ibuprofen 400-800 mg orally every 6-8 hours Naproxen 500-1000
mg/day orally in 2 divided doses Flurbiprofen 200-300 mg/day orally
in 2, 3 or 4 divided doses Fenoprofen 300-600 mg orally every 6-8
hours or 200 mg orally every 4-6 hours Ketoprofen 25-75 mg orally
every 6-8 hours Oxaprozin 600-1200 mg/day orally
TABLE-US-00003 TABLE VI FENAMATES NSAID Dose Meclofenamate 50 mg
orally every 4-6 hours Mefenamic acid 250 mg orally every 4 hours
Diclofnac 50 mg orally every 8 hours; 150-200 mg/day orally in 2-4
divided doses or 100-125 mg/day orally in 4-5 divided doses
Tolmentin 400 mg orally every 8 hours or 600 mg-1.8 gm/day orally
Ketorolac 10 mg orally every 4-6 hours for 5 days 30-60 mg
intramuscular X1, then 15-30 intramuscularly every 6 hours for max.
5 days
TABLE-US-00004 TABLE VII OXICAMS NSAID Dose Piroxicam 10-20 mg/day
orally Meloxicam 7.5-15 mg/day orally Nabumetone 1000 mg/day
orally, additional 500-1000 mg orally if necessary
TABLE-US-00005 TABLE VIII INDOLE DERIVATIVES NSAID Dose
Indomethacin 25-50 mg orally or rectally every 8-12 hours Sulindac
150-200 mg orally every 12 hours Etodolac 200-400 mg orally every
6-8 hours
TABLE-US-00006 TABLE IX PYRAZOLON DERIVATIVES NSAID Dose
Phenylbutazone 100-200 mg orally every 6-8 hours
TABLE-US-00007 TABLE X COX-II INHIBITORS NSAID Dose Nimesulide
.sup. 100 mg orally every 12.degree. Rofecoxib 12.5-25 mg/day
orally Celecoxib 100-200 mg orally every 12-24 hours
[0176] In certain embodiments, dosage levels of NSAIDs on the order
of about 0.05 mg/kg to about 75 mg/kg body weight per day are
effective for enhancing the desired effects of localized
capsaicinoid administration and decreasing the undesired effects,
or for minimizing diffusion of capsaicinoid from the site of
administration so as to amplify either of the preceding. Dosage
levels of NSAIDs on the order of about 5 mg/kg to about 40 mg/kg
body weight per day and dosage levels of NSAIDs on the order of
about 0.1 mg/kg to about 4 mg/kg body weight per day can also be
administered.
[0177] In embodiments where the present invention contemplates the
use of a non-anesthetic sodium channel blocker adjunctive agent,
suitable non-anesthetic sodium channel blocker adjunctive agents
may include, but are not limited to aminopyridines,
benzothialzoles, phenylbenzothialzoles, 5 amino-triazines,
pyrazinoylguanidines, derivatives thereof and mixtures thereof,
which include antiairhythmic agents, anticonvulsant agents,
diuretic agents, combinations thereof and mixtures thereof.
[0178] Suitable antiarrhythmic agents include, but are not limited
to disopyramide, encainide, flecainide, lorcainide, mexilitine,
moricizine, phenyloin, procainide, propafenone, quinidine,
tocainide, pharmaceutically acceptable salts thereof and mixtures
thereof.
[0179] Suitable anticonvulsant agents include, but are limited to
carbamezapine, lamotrigine, phenyloin, pharmaceutically acceptable
salts thereof and mixtures thereof.
[0180] Suitable diuretic agents include, but are not limited to
amiloride, triamterene, pharmaceutically acceptable salts thereof
and mixtures thereof.
[0181] In certain other embodiments of the present invention, the
non-anesthetic sodium channel blocker adjunctive agent can be
selected from the group consisting of phenyloin, carbamazepine,
lamotrigine, zonisamide, riluzole, lifarizine, ralitoline,
fluarizin, mexiletine, aprinidine, benzamil, phenamil, trimebutine,
GEA-968, azure A, pancuronium, N-methylstrychnine, CNS 1237,
BW1003C87, BW619C89, U54494A, PD85639, C1953, pharmaceutically
acceptable salts thereof and mixtures thereof.
[0182] The sodium channel blockers may be administered to mammals,
e.g. humans, orally at a dose of 0.1 to 10 mg/kg, or an equivalent
amount of the pharmaceutically acceptable salt thereof, per day of
the body weight of the mammal being treated. For carbamazepine,
from about 50 to about 1500 mg/day, preferably about to about 800
mg/day, more preferably about 100 to about 600 mg/day, and most
preferably about 100 to about 400 mg/day; can be orally
administered. For lamotrigine, from about 50 to about 1200 mg/day,
preferably 100 to about 600 mg/day, more preferably about 100 to
about 450 mg/day, and most preferably about 100 to about 300 mg/day
can be orally administered.
[0183] Many of the above contemplated non-anesthetic sodium channel
blocker adjunctive agents are described more fully in the
literature, such as in Goodman and Gilman, The Pharmacological
Basis of Therapeutics (9th Edition), McGraw-Hill, 1993, and Drug
Facts and Comparisons, Wolters Kluwer Co. (1999).
[0184] In another embodiment of the present invention, it is
preferable to administer the non-anesthetic sodium channel blocker
adjunctive agent peripherally by injection.
[0185] In preferred embodiments, carbamazepine is the adjunctive
agent and is administered by injection or by infiltration.
[0186] Suitable doses of the non-anesthetic sodium channel blocker
adjunctive agents may vary due to the wide variations in potency
among the particular agents and there respective mechanism for
decreasing propagation and/or generation of action potentials. The
dose administered may also be dependant on the severity of the pain
which must be prevented or alleviated, the physical condition of
the patient, the relative severity and importance of adverse side
effects, and other factors within the judgment of the physician.
Examples of suitable doses and routes of administration for the
various non-anesthetic sodium channel blocker adjunctive agents are
listed in Tables XI-XIII below:
TABLE-US-00008 TABLE XI Antiarrhythmic Sodium Channel Blocking
Agents Antiarrhythmic Dose Disopyramide 100-1600 mg/day orally
Encainaide 25-300 mg/day orally Flecainaide 50-400 mg/day orally
Mexiletine 200-1200 mg/day orally Moricizine 600-900 mg/day orally
every 8 hours Phenytoin 50-600 mg/day orally; intravenous injection
5 mg/kg/day Propafenone 150-900 mg/day orally Procainamide 50
mg/kg/day intramuscularly or orally Quinidine 200-1800 mg/day
orally; 200 mg-600 mg intramuscular Tocainide 400-1800 mg/day
orally
TABLE-US-00009 TABLE XII Anticonvulsant Sodium Channel Blocking
Agents Anticonvulsant Dose Carbamazepine 5 mg/kg/day orally
Lamotrigine 1-15 mg/kg/day orally Phenytoin 50-600 mg/day orally; 5
mg/kg/day intravenous injection
TABLE-US-00010 TABLE XIII Diuretic Sodium Channel Blocking Agents
Diuretic Dose Amiloride 5-30 gm/day orally or intravenously
Triamterene 50-300 mg/day orally
[0187] In embodiments where the present invention contemplates the
use of a vasoconstrictor adjunctive agent, vasoconstrictors
suitable for use in the present invention include, but are not
limited to catecholamines, alpha-1 and alpha-2 adrenergic agonists,
analogs thereof, active metabolites thereof, and mixtures thereof.
Catecholamines include, but are not limited to epinephrine,
norepinephrine, and dopamine. Alpha-1 adrenergic agonists include,
but are not limited to methoxamine, phenylephrine, mephentermine,
metaraminol, mitodrine, ethysergide, ergotamine, ergotoxine,
dihydroergotamine, sumatriptan, and mixtures thereof. Alpha-2
adrenergic agonists include, but are not limited to clonidine,
guanfacine, guanabenz, methyldopa, ephedrine, amphetamine,
methamphetamine, methylphenidate, ethylnorepinephrine ritalin,
pemoline and other sympathomimetic agents including active
metabolites, and mixtures thereof.
[0188] Each of the above-contemplated vasoconstricting agents is
described more fully in the literature, such as in Goodman and
Gilman, The Pharmacological Basis of Therapeutics (9th Edition),
McGraw-Hill, 1993, Pgs. 199-225. For example, the catecholamine
epinephrine is a potent stimulant of both .alpha.- and
.beta.-adrenergic receptors. It is considered as one of the most
potent vasopressor drugs known. Epinephrine's chief vascular action
is exerted on the smaller arterioles and precapillary sphincters,
although, veins and large arteries also respond to epinephrine
administration. Administration of epinephrine via injection
produces a marked decrease in cutaneous blood flow, constricting
precapillary vessels and small venules. Cutaneous vasoconstriction
produces a significant decrease in blood flow in the hands and
feet. The marked decrease in cutaneous blood flow after intravenous
administration of epinephrine contributes to epinephrine's slow
absorption from subcutaneous tissues. However, absorption of
epinephrine is more rapid after intramuscular administration.
[0189] Compounds, formulations, and dosages of the vasoconstrictors
described in this method are known in the art. In certain
embodiments, for example, vasoconstrictive compositions may be used
at art-recognized effective doses, such as, about 0.001 milligram
per milliliter to about 0.01 milligram per milliliter of
epinephrine.
[0190] In certain embodiments, when epinephrine is administered
with an anesthetic, preferably the epinephrine is added in an
amount of 0.5 to 1 ml (1:1000) per 100 ml of anesthetic solution
for a vasoconstrictive effect. Preferably epinephrine 1:100,000 or
1:200,000 dilution is used.
[0191] Norepinephrine, like epinephrine, is a potent agonist at
.alpha.-receptors; but it is somewhat less potent than epinephrine.
Dopamine, the immediate metabolic precursor of norepinephrine and
epinephrine, produces vasoconstriction at high concentrations,
whereas, total peripheral resistance due to vasoconstriction is
practically unchanged at low to intermediate doses due to
dopamine's ability to reduce regional arterial resistance in the
mesentary and kidneys while causing only minor increases in other
vascular beds.
[0192] The existence of more than one adrenergic receptor was first
proposed in 1948 by Ahlquist. H is hypothesis was based on a study
of the abilities of epinephrine, norepinephrine and other related
agonists to regulate various physiological processes. As a result
of his studies, the alpha (.alpha.) and beta (.beta.) designations
were established.
[0193] Alpha adrenergic receptors are present in many organs
throughout the human body. However, vasoconstriction is not
produced in all organs. In fact, adrenergic vasoconstriction is
produced in veins and the following arterioles: coronary, skin and
mucousa, skeletal muscle, cerebral, pulmonary, abdominal viscera,
salivary glands, and renal artertioles. Only alpha-1 receptors are
found in skeletal muscle, cerebral, pulmonary, and abdominal
viscera and both alpha-1 and alpha-2 receptors are found in
coronary, skin and mucousa, salivary glands, and renal
arterioles.
[0194] When the vasoconstrictor adjunctive agents used in the
present invention are co-administered with the capsaicinoids and/or
local anesthetic of the present invention, the vasoconstrictor
adjunctive agent produces a decrease in cutaneous blood flow to the
area surrounding the injection site, thus prolonging the activity
of the capsaicinoid and/or local anesthetic at the injection
site.
[0195] Suitable doses of vasoconstrictor adjunctive agents may vary
due to the wide variations in potency among the particular
catecholamines and adrenergic agonist and there respective
selectivity for alpha-1 or alpha-2 adrenergic receptors. The dose
administered may also be dependant on the severity of the pain
which must be prevented or alleviated, the physical condition of
the patient, the relative severity and importance of adverse side
effects, and other factors within the judgment of the physician.
Examples of suitable doses and routes of administration for the
various vasoconstrictor adjunctive agents are listed in Tables
XIV-XV below:
TABLE-US-00011 TABLE XIV ENDOGENOUS CATECHOLAMINES Catecholamine
Dose Epinephrine 0.3-5 mg by intravenous or subcutaneously
TABLE-US-00012 TABLE XV .alpha.-1 ADRENERGIC AGONISTS .alpha.-1
Agonist Dose Methoxamine 3-5 mg intravenously or 10-20 mg
intamuscularly (during spinal anesthesia); DOA-1-1.5 hrs.
Phenylephrine 2-5 mg/dose intramuscularly every 1-2 hours as
needed; intravenous bolus 0.1-0.5 mg/dose every 1-15 min as needed;
100-180 mcg/min intravenous drip Mephentermine 30-45 mg
intravenousl, 30 mg doses repeated as required; 30-45 mg
intramuscularly 1-20 min prior anesthesia. Metaraminol 2-10 mg
intramusculary or intravnously Dihydroergotamine 1-3 mg
intramuscularly; 1-2 mg intravenous push sumatriptan 1-6 mg
subcutaneously
[0196] In embodiments where the present invention contemplates the
use of a tricyclic antidepressant adjunctive agent, the term
tricyclic antidepressant adjunctive agent ("TCA" adjunctive agent),
as used herein, represents a tricyclic antidepressant agent which
can be identified as such by the skilled artisan. Tricyclic
antidepressants are known for their use in the treatment of
depression. For example, Goodman and Gilman's "The Pharmacological
Basis of Therapeutics," 9th edition, Macmillan Publishing Co.,
1996, pp 413-423, provides well known examples of tricyclic
antidepressant agents. Specific tricyclic antidepressant agents
useful in the present invention are also disclosed in detail in The
Merck Index, 12.sup.th Edition, Merck.& Co., Inc.
[0197] Tricyclic antidepressant agents useful in the present
invention include, but are not limited to adinazolam,
amitriptyline, amitriptylinoxide, amoxapine, butriptyline,
clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine,
dothiepin, doxepin, fluacizine, imipramine, imipramine-oxide,
iprindole, lofepramine, maprotiline, melitracen, metapramine,
nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,
protriptyline, quinupramine, tianeptine, trimipramine,
pharmaceutically acceptable salts thereof and mixtures thereof.
[0198] Systemically administered antidepressants offer an alternate
therapy in neuropathic and chronic pain states. Interactions with
biogenic amines; endogenous opioids, excitatory amino acid
receptors, substance P and calcium and sodium channels have been
considered in efforts to pinpoint the mechanism of systemically
administered antidepressants (reviewed by Eschalier A, Mestre C,
Dubray C, Ardid D (1994) CNS Drugs 2: 261). What is clear is that
antidepressants can act at both supraspinal (Spiegel, K., Kalb, R.
and Pasternak, G. W., Ann. Neurol. 13 (1983) 462-465, Eschalier A,
Mestre C, Dubray C, Ardid D (1994) CNS Drugs 2: 261) and spinal
(Hwang, A. S. and Wilcox, G. L., Pain 28 (1987) 343-355; Iwashita,
T. and Shimizu, T., Brain Research 581 (1992) 59-66; J. Eisenachand
G. F. Gebhart, Anesthesiology 83 (1995) 1046-1054) sites of
action.
[0199] This analgesic action is independent of antidepressant
effects as it occurs in non-depressed subjects and occurs
independently of mood changes in depressed subjects (Magni G (1991)
Drugs 42: 730; Onghena P, Van Houdenhove B (1992) Pain 49: 205; Max
M B (1994) In: Progress in Pain Research and Management (Ed. Fields
H L, Liebskind J C) IASP Press, Seattle, 229, McQuay H J, Tramer M,
Nye B A, Carroll D, Wiffen P J. Moore R A (1996) Pain 68: 217).
Agents which block the uptake of both noradrenaline (NA) and
5-hydroxytryptamine (5-HT) such as amitriptyline, or which block NA
but not 57-HT, such as desipramine, are more effective than those
with selectivity for 5-HT, such as fluoxetine (Max M B (1994) In:
Progress in Pain Research and Management (Ed. Fields H L, Liebskind
J C) IASP Press, Seattle, 229). Pain relief is reported to be
apparent within one week of therapy (McQuay H J. Carroll D, Glynn C
J (1992) Anaesthesia 47: 646). This time course corresponds to the
time required to attain stable plasma levels (t[frac12] 17-36 hours
in humans, Ziegler V E, Biggs J T, Aardekani A B, Rosen S H (1978)
J Clin Pharmacol 18: 462). By contrast, the antidepressant activity
of these compounds takes 4-6 weeks to become apparent (Potter W Z,
Rudorfer M, Manji H (1991) New Eng J Med 325: 633). These
differences in profile of active drugs, time course, and
independent expression of effects suggest that mechanisms
underlying pain relief and alleviation of depression differ.
[0200] In animal tests, both the systemic and spinal administration
of antidepressants show intrinsic efficacy in a number of
nociceptive pain tests, and augment analgesia produced by opioids
(reviewed by Eschalier A, Mestre C, Dubray C, Ardid D (1994) CNS
Drugs 2: 261). However, this profile can be variable, and
inhibitory effects on the action of morphine have been observed in
some cases (reviewed by Eschalier et al., supra). Methodological
issues (e.g., test paradigm, intensity of stimulus, dose, regimen
of acute versus chronic administration) are reported to account for
many of these differences (Kellstein D E, Malseed R T, Goldstein F
J (1984) Pain 60: 275; Kellstein D E, Malseed R T, Ossipov M H,
Goldstein F J (1988) Neuropharmacology 27: 1; Fialip J, MartyH,
Makambila M C, CiViate M A, Eschalier A (1989) J Pharmacol Exp Ther
248: 747). Systemically administered antidepressants also exhibit
intrinsic actions in a number of neuropathic pain tests including
nerve transaction (Seltzer Z, Tal M, Sherav Y (1989) Pain, 37:
245), mononeuropathy (Ardid D, Gilbaud G (1992) Pain 49: 279) and
diabetic neuropathy models (C. Courteix et al. (1994) Pain
57:153-160). One study examined chronic versus acute dosing
regimens (Ardid D, Gilbaud G (1992) Pain 49: 279), and observed
that the activity seen following chronic paradigms appeared to be
accounted for by accumulating doses rather than being qualitatively
different.
[0201] The mechanism of action of the tricyclic antidepressant
agents used in the present invention is presumed to be due to the
anticholinergic action of the tricyclic antidepressant, whereby
they block the neurotransmitter acetylcholine to prevent
transmission of impulses in the A-delta and C pain fibers, thereby
resulting in pain relief.
[0202] Locally administered tricyclic, second generation, or third
generation antidepressant(s) produce a local antinociceptive
action, especially against inflammatory and neuropathic pain. When
administered locally in animal models of inflammatory (formalin
test) and neuropathic pain (spinal nerve ligation), amitriptyline,
a non selective noradrenaline (NA) and 5-hydroxytryptamine (5-HT)
reuptake inhibitor, and desipramine, a selective NA reuptake
inhibitor, produced local antinociceptive actions.
[0203] Suitable doses of the tricyclic antidepressant adjunctive
agents vary due to the wide variations in potency among the various
TCAs. The dose is also dependant on the severity of the pain which
must be prevented or alleviated, the physical condition of the
patient, the relative severity and importance of adverse side
effects, and other factors within the judgment of the physician.
Examples of suitable doses and routes of administration of
tricyclic antidepressant adjunctive agents are listed in Table XVI
below:
TABLE-US-00013 TABLE XVI TRICYCLIC ANTIDEPRESSANTS TCA Dose
Amitriptyline 25-300 mg/day orally or injection Clomipramine 25-250
mg/day orally Doxepin 25-300 mg/day orally Imipramine 25-300 mg/day
orally or injection Trimipramine 25-300 mg/day orally Amoxapine
50-600 mg/day orally Desipramine 25-300 mg/day orally Maprotiline
25-225 mg/day orally Nortriptyline 25-250 mg/day orally
Protriptyline 10-60 mg/day orally
[0204] In embodiments where the present invention contemplates the
use of a vasodilator, e.g., a nitrate vasodilator. Nitrate
vasodilators include, but are not limited to nitrites, organic
nitrates, nitroso compounds and any other nitrogen oxide-containing
substances. As capsaicinoids are highly protein bound, vasodilators
are useful as adjunctive agents as they facilitate the capsaicinoid
being diffused throughout the desired site before it has a chance
to bind to the tissue.
[0205] Organic nitrates and nitrites act on almost all smooth
muscle structures, e.g., bronchial, biliary, gastrointestinal
tract, uterine and ureteral smooth muscles. Pain and other symptoms
associated with increased pressure can be transiently relieved. For
example, administration of a nitrate in a patient with T-tube
drainage can reduce biliary pressure and can induce rapid emptying
of biliary contents into the duodenum.
[0206] Nitrates, organic nitrates, nitroso compounds, and a variety
of other nitrogen oxide-containing compounds work by activating
guanylate cyclase and increasing the synthesis of guanosine
3',5'-monophosphate (cyclic GMP) in smooth muscle and other
tissues. These agents all lead to the formation of nitric oxide
(NO). Nitric oxide is a reactive free radical that interacts with
and activates guanylate cyclase. The interaction of nitric oxide
and guanylate cyclase stimulates cyclic-GMP dependent protein
kinase, which results in the phosphorylation of various proteins in
smooth muscle, which further results in de-phosphorylation of the
light chain of myosin, a protein thought to play an important role
in the contractile process in its phosphorylated form. Analogs of
cyclic-GMP can also relax vascular and bronchial smooth muscle
(See: Goodman and Gilman's "The Pharmacological Basis of
Therapeutics," 9th edition, Macmillan Publishing Co., 1996, pp
798-799 and 806-816).
[0207] Specific nitrate vasodilator adjunctive agents useful in the
present invention are also disclosed in detail in The Merck Index,
12.sup.th Edition, Merk & Co., Inc nitrate vasodilator agents
useful in the present invention include, but are not limited to
clonitrate, erythrityl tetranitrate, isobutyl nitrate, isoidide
dinitrite or mononitrite, isomannide dinitrite or mononitrite,
isosorbide dinitrate or mononitrate, mononitrate, mannitol
hexanitrate, nitroglycerin, pentaeryhtritol tetranitrate,
pentaeryhtritol trinitrate or dinitrite or mononitrite,
pentrinitrol, propatyl nitrate, sodium nitroprusside, trolnitrate
phosphate, 1,3-propane dinitrite, 1,7-heptane dinitrite,
cyclohexylmethyl nitrite, 2-phenylethyl nitrite, 3-chloro-2,2
dimethylpropyl nitrite, tert-amyl nitrite, 2-methyl-2-hexyl
nitrite, hexyl nitrite, 2-methyl-1,3-propane dinitrite,
2,2,dimethyl-1,3-propane dinitrite, 2-methyl-2-propyl-1,3-propane
dinitrite, 3-hexyl nitrite, octyl nitrite, 4-methyl-2-pentyl
nitrite, 4-methyl-1-pentyl nitrite, 2-heptyl nitrite, 3-octyl
nitrite, 2-methyl-2-pentyl nitrite, 5-methyl-2-hexyl nitrite,
6-methyl-2-heptyl nitritepharmaceutically acceptable salts thereof
and mixtures thereof.
[0208] Suitable doses of the nitrate vasodilator adjunctive agents
vary due to the wide variations in potency among the various
nitrate vasodilators. The dose is also dependant on the severity of
the pain which must be prevented or alleviated, the physical
condition of the patient, the relative severity and importance of
adverse side effects, and other factors within the judgment of the
physician. In certain embodiments of the present invention suitable
doses of nitrate vasodilator adjunctive agents may range from about
0.0001 to 120 mg/kg of body weight per day, more preferably from
about 0.01 to about 75 mg/kg and most preferably from about 0.5 to
about 30 mg/kg.
[0209] in certain embodiments of the present invention, oral doses
of the vas dilator adjunctive agents range from about 2.5 to about
300 mg/day of nitrite, preferably from about 5 to about 160
mg/day.
[0210] In certain embodiments, a vasodilator and a vasoconstrictor
can be used as adjunctive therapy for capsaicinoid administration.
For example, the capsaicinoid can be administered with a
vasodilator at the intended site. To compliment the capsaicinoid
therapy, a local anesthetic can be administered at a distal site to
provide a regional block at the site of capsaicinoid
administration. The vasoconstrictor can be administered with the
local anesthetic to prolong the duration of effect of the local
anesthetic.
[0211] In certain other embodiments there is provided a composition
comprising a capsaicinoid and one or more adjunctive agents
disclosed herein.
Breakthrough Pain
[0212] 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 farther
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
[0213] 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.
[0214] 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.
[0215] 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-00014 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
[0216] 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.
[0217] Placebo vehicle for purified capsaicin was supplied in vials
containing 5 mL. Local anesthetic (Lignocaine 2%) was used for each
intra-articular infiltration.
[0218] 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.
[0219] Patients were treated randomly and in double-blind fashion
in four treatment groups, with each group 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 group. Gross and microscopic pathology analysis was
completed for each treatment group before the next treatment group
was treated.
[0220] 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.
[0221] 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.
[0222] 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.
[0223] 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.
[0224] 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.
[0225] 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. Tmax 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.
[0226] 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.
[0227] 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.
[0228] 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.
[0229] 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.
[0230] 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.
[0231] 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
[0232] The following clinical study evaluates 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.
[0233] The primary objective of the study is 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).
[0234] Purified capsaicin is supplied in vias 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 is used to dilute the
drug to final concentrations of purified capsaicin, as follows:
TABLE-US-00015 TABLE 2 Dose Level Concentration Total Volume of
Dose 1000 .mu.g 200 .mu.g/mL 5 mL
[0235] Each vial is used for one infiltration administration only
and appropriately labeled. The supplier of the purified capsaicin
is FormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810. The
vials are supplied in bulk to the study center with each vial
labeled according to the contents of the vial. The Pharmacist/Study
Nurse, who prepares the injection, maintains the investigational
product in a lockable cabinet at the required temperature,
15-25.degree. C. The study blind is maintained by the
Pharmacist/Study Nurse.
[0236] Placebo vehicle for purified capsaicin is supplied in vials
containing 5 mL. Local anesthetic (Lignocaine 2%) is used for each
subacromial bursa infiltration.
[0237] The study is 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 are scheduled to undergo total
knee replacement from three to six weeks post study drug
administration, wherein the primary endpoint is pain reduction at
three weeks following study drug administration.
[0238] The study is designed to include 12 evaluation subjects
(Patients suffering a defined pain: >40 mm on VAS). Six (6)
subjects will be treated with capsaicin 1000 .mu.g and 6 subjects
will be treated with placebo vehicle. Patients are treated randomly
and in double blind fashion. Gross and microscopic pathology
analysis are 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 is randomized, pre-treatment
evaluation is performed. The patient is brought into the procedure
room, and a VAS pain score is taken (0 mm--no pain, 100 mm--extreme
pain). Once the patient marks his or her pain on the card, he/she
is prepped for knee cannulation. Once the cannula is placed, the
patient receives, by intra-articular infiltration, 3mg/kg (maximum
dose of 200 mg) of 2% lignocaine into the knee scheduled to be
replaced. This infiltration of local anesthetic is 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.
[0239] VAS pain scores as well as verbal reports are taken
immediately following administration, as well as prior to knee
replacement surgery. On the Post-Treatment Day, a study evaluation
is 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 are excluded since
analgesia from remaining lignocaine or residual pain from the
actual procedure (large volume injection) and lysing c-fiber
endings is not capable of being excluded.
[0240] 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
[0241] 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).
[0242] 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.
[0243] 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-00016 TABLE 3 Dose Level Concentration Total Volume of
Dose 1000 .mu.g 250 .mu.g/mL 4 mL
[0244] 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.
[0245] Placebo vehicle for purified capsaicin was supplied in vials
containing 5 mL. Local anesthetic (Lignocaine 2%) was used for each
infiltration.
[0246] 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.
[0247] 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).
[0248] 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 of purified capsaicin concentration, and review
of concomitant medication; 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 be closed
according to normal practices and procedures.
Post-Operation:
[0249] 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
alfentanil 1 mg, repeated at 6 hourly intervals, if necessary.
After discharge from the hospital, alfentanil was substituted with
co-codamol 30/500 (codeine phosphate 30 mg+paracetamol 500 mg),
repeated at 4 hourly intervals when necessary. Amy 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:
[0250] 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.
[0251] 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.
[0252] 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.
[0253] 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-00017 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
[0254] Administration of 1000 .mu.g of capsaicin prior to wound
closure decreased opioid rescue. Only 45% 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
[0255] 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.
The study drug will be administered to the sternal edges, muscles
(e.g., muscle edges), bone (e.g., bone edges), and tissues. 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.
[0256] 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 win be
used following discharge for a two-week period.
[0257] 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
[0258] The primary objective of this study is to evaluate 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.
[0259] 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. Study subject will receive a dose of purified capsaicin
1000-3000 .mu.g divided over the 4 part wounds-infiltrated along
the cut muscle edges.
[0260] 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
[0261] 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.
[0262] 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 1.000 .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.
[0263] 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.
[0264] 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
[0265] 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 is to
determine the amount of opioid consumption and postoperative pain
scores following mastectomy for patients receiving capsaicin.
[0266] 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.
[0267] 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.
[0268] 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.
[0269] 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.
Example VIII
[0270] (i) Examples I to VII are repeated and ibuprofen is
administered orally in an amount of 10/mg/kg before, during or
after the administration of the capsaicinoid in order to decrease
the pain and inflammation at the site of capsaicinoid
administration.
[0271] (ii) Examples I to VII are repeated and carbamazepine is
administered orally in an amount of 800 mg/day, before, during or
after the administration of the capsaicinoid in order to decrease
propagation and/or generate action potentials.
[0272] (iii) Examples I to VII are repeated and amitriptyline is
administered orally in an amount of 100 mg/day either before,
during or after the administration of the capsaicinoid in order to
diffuse the capsaicinoid throughout the area.
[0273] (iv) Examples I to VII are repeated and epinephrine is
administered parenterally at the site of action either before,
during or after the administration of the capsaicinoid restrict the
capsaicinoid at the area.
[0274] (v) Examples I to VII are repeated and isosorbide dinitrite
is administered by injection at the site of administration of the
capsaicinoid either before, during or after the administration of
the capsaicinoid in order to diffuse the capsaicinoid throughout
the area.
[0275] 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.
* * * * *