Note: Descriptions are shown in the official language in which they were submitted.
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ADMINISTRATION OF KETAIVIINE
TO MANAGE PAIN AND TO REDUCE DRUIG DEPENDENCY
FIELD OF THE INVENTION
The present invention relates to the management of chronic pain without
requiring
administration of narcotics, or by synergizing with narcotics to allow for a
lower
effective narcotic dose. The invention also relates to self-management of pain
on an
outpatient basis.
BACKGROUND OF THE INVEN'TION
Ketamine ((2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone) is a general
anesthetic
used by anesthesiologists, veterinarians, and researchers. Usually, ketamine
is
administered intramuscularly (i.m.) or intravenously (i.v.) for induction of
anesthesia.
Presently, only ketamine for injection is available for admiriistration
(Physician's Desk
Reference). Nasal administration of ketamine, in one instance with midazolam,
for an
ophthalmic procedure, and prior to elective surgery in healthy children, has
been
reported (Louon et al., 1993, Br. J. Ophthalmol. 77:529-530; Weksler et al.,
1993,
Can. J. Anaesthesia 40:119-121).
Ketamine has also been known to have analgesic properties (Domino et al.,
1965, Clin.
Pharmacol. Ther. 6:279); analgesia can be achieved with subanesthetic doses of
ketamine (Bovill, 1971, Br. J. Anaesth. 43:496; Sadove et al., 1971, Anesth.
Analg.
50:452-457). The drug is administered by various routes, irlcluding i.v.,
i.m., caudal,
intrathecal, and subcutaneous (s.c.). Subcutaneous administration of ketamine
has
been used to treat pain following surgery and associated Nnrith terminal
cancer (see, e.g.,
Oshima et al., 1990, Can. J. Anaesth. 37:385-386). Ketamine hydrochloride
administered via a subcutaneous cannula was reported to successfully treat
phantom
limb pain (Stannard and Porter, 1993, Pain 54:227-230).
Management of pain, and particularly chronic pain, is complex and frequently
unsuccessful. The first line of treatment usually involves ,administration
of,u-opioid
agonists, e.g., narcotics such as morphine (see, e.g., Anderson and Brill,
1992, Semin.
Anesth. 11:158-171). However, rarely do physicians engage in aggressive pain
management. Undertreatment for pain frequently leads to conditions where
patients are
forced to suffer pain up to the point of tolerability before receiving
medication, and the
medication is usually only partially effective. Ineffective pain management is
a
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consequence of lack of training, and of fear of narcotics on the part of
patients, the
medical personnel, and society in general. Children, because of their natural
reticence
and budding communication skills combined with a greater fear of over-
administering
"dangerous" narcotics particularly suffer from under treatment for pain.
Moreover, rapid tolerance and marked resistance to narcotics frequently
develop, thus
rendering these agents ineffective (see, e.g., Abram, 1993, Reg. Anesth.
18(SUPPL):406-413). Non-competitive N-methyl-D-aspartate (NMDA) receptor
antagonists, including ketamine, have been reported to interfere with the
development
of tolerance to the analgesic effects of morphine, possibly through blockade
of the
NMDA receptor rather than from "side-effects" of the antagonist, since the
antagonists
were not found to reverse tolerance (Trujillo and Akil, 1994, Brain Res.
633:178-188).
Often, pain management involves administration of a plethora of drugs, such as
narcotics, agonist-antagonist agents, butorphanols, benzodiazepines, GABA
stimulators,
barbiturates, barbiturate-like drugs, orally, e.g., in a pill or liquid
formulation, or by i.v. or
i.m. injection. Opioid agonists and antagonists may be combined. Thus, a
combination
of drugs can have offsetting effects. More problematic is the possibility of
adverse side
effects, particularly gastric distress that accompanies oral administration,
or the fear
that injections can inspire.
Frequently, a patient suffering from chronic pain will require medication to
control
stomach and other gastric problems as a result of oral administration of
drugs.
Alternatives to oral self-administration for most of the analgesic and
sedative
medications for the treatment of chronic pain are not common, can be
cumbersome
(e.g., i.v. or s.c. administration requires use of a cannula or needle), and
generally
require medical training.
U.S. Patent No. 4,671,953 describes the administration of sedative, analgesic
or
sedative drugs in a candy matrix, such that the drug enters the bloodstream
through the
oral mucosal membranes. However, this method suffers from the disadvantage
that a
sedated patient may fall asleep with the candy remaining in his or her mouth,
which can
result in choking. Furthermore, because the total dose of the drug in the
candy may =
exceed the desired dose, administration of the candy must be medically
supervised.
Finally, the candy is simpiy unsuitable for everyday use, as sucking on a
lollipop is an
unseemly practice for an employee or business person.
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Moreover, when administration is under the control of the patient suffering
from pain,
i.e., on an outpatient basis, the potential for overdosing or abuse exists,
particularly
with respect to narcotics.
Thus, there is a need in the art for self-management of pain using non-opioid
drugs.
= There is a further need in the art for a rapid method for reducing or
eliminating
breakthrough pain that is refractory to standard treatmenl: regimens.
There is a further need in the art to avoid injection administration of pain
medication.
There is a need in the art for a fast, convenient, and socially acceptable
method for
patient self-administration of medication to manage or coritrol pain.
There is yet a further need in the art to avoid overdose and abuse of self-
administered
medication, and to enhance the effectiveness of pain medications, particularly
narcotic
pain medication.
These and other needs in the art have been addressed by the instant invention,
which is
based on the inventor's discovery that ketamine can surprisingly be
administered nasally
to alleviate pain safely and effectively, in conjunction with or independently
of other
pain management regimens.
The citation or identification of any reference in this application shall not
be construed
as an admission that such reference is available as prior art to the present
invention.
SUMMARY OF THE INVENTION
The present invention is broadly directed to a method for treating pain in a
subject
comprising administering via a transmucosal route a dose of ketamine effective
to
alleviate pain to a subject suffering from pain. In specific embodiments,
administration
of ketamine can be via transbuccal, sublingual, vaginal, and rectal routes.
Alternatively,
the pain-relieving effects of the present invention can be accomplished by
administration
via oral administration (via the gastrointestinal tract, rather than the oral-
pharyngeal
mucosa). In a further embodiment, the present invention provides for pulmonary
administration of ketamine by inhalation. In a specific aspect, the invention
provides an
effective pain-relieving dose of ketamine by transdermal administration.
Administration
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of an analgesic dose of ketamine advantageously allows for patient self
administration
of the drug, which provides for pain management on an outpatient basis.
Moreover,
ketamine administration via transmucosal and transdermal delivery are
generally socially
acceptable. 5
Transmucosal administration of ketamine is rapid, allowing for fast action of
the drug.
In addition, both transmucosal and transdermal administration are easily
accomplished
by a non-medically trained patient. The present invention is based, in part,
on the
discovery that high levels of analgesia can be achieved with small doses of
ketamine,
particularly ketamine administered by a transmucosal route (e.g., transbuccal,
sublingual, vaginal, and rectal), or by a transdermal route. It has further
been
discovered that effective pain treatment is better achieved by establishing
small doses
via transdermal or transmucosal delivery, and that these routes of
administration avoid
side effects associated with a bolus dose of ketamine delivered i.v. or i.m.
administration. Furthermore, a small transmucosal or transdermal dose of
ketamine can
be administered more frequently, which achieves a virtual steady state level
of the drug
that can be modulated as needed by the subject.
The present invention further advantageously provides for outpatient treatment
of
episodic and breakthrough pain conditions, which are not amenable to treatment
with
i.v. or i.m. bolus administration of the drug because of the need for medical
intervention
for these procedures.
In another embodiment, the present invention contemplates using ketamine
synergistically with a traditional pain relief medication, preferably a
narcotic pain
reliever. Preferably, ketamine can be administered in combination with a lower
dose of
a second pain relief drug, preferably a narcotic, than would otherwise be
indicated for
the condition if used alone. As pointed out above, the invention contemplates
administration of ketamine transmucosally, more preferably, nasally. In a
further
embodiment, the present invention provides for pulmonary administration of
ketamine
by inhalation. Where a patient's condition prevents nasal administration of
ketamine,
ocular administration, using, e.g., ketamine drops, can be substituted. The
invention
contemplates transdermal administration as well. In addition to transmucosal
administration of ketamine, e.g., nasal, transbuccal, sublingual, vaginal, and
rectal, the
invention contemplates oral administration (via the gastrointestinal tract,
rather than the =
oral-pharyngeal mucosa), and parenteral administration, e.g., intravenous,
intraarterial,
intraperitoneal, intradermal, intramuscular, intraventricular, or
subcutaneous. In each
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case, the second pain medication can be administered via the same route as
ketamine,
where appropriate, or via a different route, e.g., orally while the ketamine
is
administered transdermally or transbucally.
5 It has been a surprising discovery in the context of the present invention
that ketamine
administration to manage pain on top of an ongoing pain management regimen
involving
other medications, notably narcotics, allows for reduction over time of the
other
analgesic, particularly a narcotic analgesic. Generally, experience has shown
that the
effects of different analgesics are additive, and additional analgesics are
added to a
dosage regimen to supplement it, e.g., when tolerance to a first analgesic
builds up.
In this regard, ketamine administration provides the added benefit of reducing
drug,
particularly narcotic, dependency of individuals who are suffering from a pain
condition.
In other words, the present invention advantageously provides for treatment of
drug
dependency developed as a result of medical treatment (rather than drug abuse,
for
example).
Pain therapy on an outpatient basis advantageously reduces the demands on
hospital
services, results in a substantial decrease in the cost of tneatment, and
provides the
patient with a more normal living and working environment, which can
positively affect
treatment outcome. Similarly, reduction in dependency ori other pain
medications,
particularly narcotics, can further reduce the need for medical intervention
and the cost
of treatment.
Another advantage of the invention is that it avoids or reduces the need to
administer
narcotic agents for the treatment of chronic pain. Although effective
analgesics,
narcotics can lose effectiveness due to tolerance or resistance. Narcotics are
also
highly addictive. In addition, narcotics induce side effects such as nausea,
constipation,
dizziness, etc., in proportion to dosage. Thus, another advantage of the
present
invention is that it helps avoid adverse side effects of administration of
narcotics.
Yet a further advantage of the invention is that ketamine is an inexpensive,
readily
available drug, with minor adverse side effects, especially when administered
in small
doses transmucosally, transdermally, or orally. Thus, the invention
contemplates
additional savings to the overburdened health care systemo
In one aspect, the pain-alleviating dose of ketamine is approximately 0.01 to
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approximately 1 mg/kg of body weight. In a more preferred aspect, the dose of
ketamine is approximately 0.05 to approximately 0.7 mg/kg of body weight. In
another
embodiment, the total dose of ketamine per nasal administration ranges from
about 1 to
about 30 mg.
In a specific aspect of the invention, the dose of ketamine is effective to
alleviate
breakthrough pain in a patient suffering from a chronic pain condition.
In another specific aspect of the invention, the dose of ketamine is effective
to alleviate
breakthrough pain associated with labor, particularly transition labor.
In another embodiment, which has proved clinically with great success, nasal
administration of ketamine is effective for treating migraine headache pain.
In a particular aspect, administration of ketamine can be a supplemental
therapy in a
pain management regimen that includes administration of one or more of
narcotics,
analgesics, and sedatives, e.g., as described above.
It should be noted that a further advantage of the instant invention is that
it avoids
dosing a patient with dysphoric or hallucinogenic amounts of ketamine by
providing only
an analgesic dose, which is well below the level associated with dysphoria or
hallucination. Thus, it avoids the need to administer a dysphoria-suppressive
drug, such
as a benzodiazepine.
In yet a further embodiment, the present invention contemplates administering
a lower
dose of a narcotic analgesic than would be effective taken alone to alleviate
pain with
the ketamine; preferably the narcotic analgesic is administered via the
mucosal or
transdermal route with the ketamine.
Accordingly, the invention provides various pharmaceutical carriers for
patient self-
administration of ketamine. Examples of such carriers include, but are not
limited to, a
suppository, a gum, a candy or lozenge; other carriers include a transbuccal
patch and a
transdermal patch. .
Thus, it is an object of the invention to provide for self administration of a
safe, non-
narcotic drug for outpatient treatment of pain.
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Yet a further object of the invention is to provide a device that can be used
outside a
hospital or medical office by non-medical personnel for nasal self
administration of
ketamine.
These and other objects of the present invention will become more readily
apparent by
reference to the following detailed description.
DETAILED DESCRIPTION OF THE INVENTOON
One aspect of the invention provides for transmucosal, transdermal, or oral
administration of ketamine for the treatment of pain. In a more preferred
aspect, the
invention provides a method and device for patient self administration of
ketamine for
pain management.
The invention can alleviate pain from many causes, inclu(iing but not limited
to shock;
limb amputation; severe chemical or thermal burn injury; sprains, ligament
tears,
fractures, wounds and other tissue injuries; dental surgery, procedures and
maladies;
labor and delivery; migraine; during physical therapy; post operative pain;
radiation
poisoning; cancer; acquired immunodeficiency syndrome (AIDS); epidural (or
peridural)
fibrosis; failed back surgery and failed laminectomy; sciatica; painful sickle
cell crisis;
arthritis; autoimmune disease; intractable bladder pain; arid the like.
Mucosal
administration of ketamine is also amenable to hospice use, particularly
hospices that
specialize in the care of cancer and AIDS patients. The present invention is
particularly
effective for the treatment of intractibie pain, whatever its cause.
In one embodiment, transmucosal, transdermal, or oral administration of
ketamine can
relieve or alleviate episodes of acute breakthrough pain that can occur in a
chronic pain
condition. In a further embodiment, administration of ketamine via any route
can be
used as an adjunct therapy to a conventional treatment regimen for a chronic
pain
condition to alleviate breakthrough pain. In a specific embodiment, infra,
nasal
(transmucosal) administration of ketamine is effective for treating
intractable bladder
pain.
A particular advantage of the present invention for reducing labor and
delivery pain is
that ketamine in low doses is not known to have significant adverse effects on
the
fetus.
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In a related embodiment, transmucosal, transdermal, or oral administration can
be used
as an adjunct or directly to treat an acute asthma attack. Since unrelated
pain
conditions can induce asthma, the present invention advantageously provides
for
alleviating pain, thus blocking the cause of the attack. Furthermore, ketamine
(in
contrast to narcotic pain medications) is a bronchodilator.
In yet another related embodiment, transmucosal, transdermal, or oral
administration of
ketamine can be used in the treatment of acute nausea. Rectal or transdermal
ketamine
is particularly suitable for this condition, as nausea precludes the use of
oral
medications. In particular, rectal or transdermal ketamine can alleviate pain
that may be
causing the nausea, and can alleviate the abdominal pain that frequently
accompanies
sever nausea, without stimulating gag responses or involving oral or nasal
passages.
In yet a further related embodiment, transmucosal, transdermal, or oral
administration of
ketamine can be used to treat acute agitation, for example, agitation
exhibited by an
alcohol or drug intoxicated individual, or by a person placed under arrest by
the police.
Similarly, transmucosal, transdermal, or oral ketamine may be useful in the
treatment of
shock resulting from severe injuries. Thus, even if a patient fails to sense
pain because
of severe shock, the extreme pain associated with a severe injury contributes
to shock.
The present invention is based on the surprising and unexpected discovery that
transmucosal administration of ketamine can alleviate symptoms of chronic
pain. Thus,
in a specific Example, infra, a patient suffering from intractable bladder
pain, and taking
a variety of narcotics, analgesics, and sedatives in an unsuccessful attempt
to control
the pain, was able to achieve more satisfactory pain management by nasal
administration of 16-32 mg of ketamine, corresponding to about 0.2-0.6 mg/kg
of body
weight. (in the specific Example, infra, a dosage of 16-32 mg corresponds to
0.27-
0.53 mg/kg of body weight.) The dosage was effective for about 15 minutes to
about
1 hour for alleviating pain. The patient was able to reduce the amount of a
oral pain
medications, which had caused gastric distress.
It has further been found that dozens of patients suffering from intractable
pain, =
migraine headache, chronic fatigue syndrome, or other pain-associated
afflictions, have
benefitted from the methods and devices of the invention.
Accordingly, the present invention is directed to methods for alleviating
chronic or
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~
breakthrough pain on an outpatient basis by transmucosal, transdermai, or oral
administration of ketarnine, and to devices usable by non-medical personnel
for
transmucosal, transdermal, or oral self-administration of ketamine.
Ketamine will preferably be prepared in a formulation or pharmaceutical
composition
appropriate for transmucosal, transdermal, or oral administration. Suitable
formulations
are discussed In detail, infra. In a further embodiment, ketamine can be
formulated with
a mucosal or dermal penetration enhancer to facilitate delivery of the drug.
The
formulation can also be prepared with pH optimized for solubility, drug
stability,
absorption through mucosa or skin, and other considerations.
The invention provides for administration of a therapeutically effective dose
of
ketamine, i.e., a dose effective to alleviate pain, or to facilitate reduction
in dependence
on other pain medications, particularly narcotic medications. The actual dose
will vary,
depending on the body weight of the patient, the severity of the pain, the
route of
administration, the nature of medications administered concurrently, the
number of
doses to be administered per day, and other factors generally considered by
the ordinary
skilled physician in the administration of drugs. In a specific embodiment,
the amount
of ketamine administered to a patient suffering from chronic pain is about 10%
to about
20% of the amount used to induce anesthesia. In another specific embodiment,
the
dose of ketamine is about 0.01 mg per kg of body weight (0.01 mg/kg) to about
1
mg/kg; preferably about 0.05 mg/kg to about 0.7 mg/kg. In yet another
embodiment,
the dose ranges trom about i mg to about 30 mg. Preferably, the effective dose
is
titrated under the supervision of a physician or medical care provider, so
that the
optimum dose for the particular application is accurately determined. Thus,
the present
invention provides a dose suited to each individual patient.
Once the dosage range is established, a further advantage of the invention is
that the
patient can administer ketamine on an as-needed, dose-to-effect basis. Thus,
the
frequency of administration is under control of the patient. However, the
relatively low
dose with each administration will reduce the possibilities for abuse.
Yet another particular advantage of the present invention is that
transmucosal,
transdermal, or oral administration of ketamine is non-invasive, and provides
for
introduction into the bloodstream aimost as fast as i.v. administration.
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9a
In accordance with one aspect of the present invention there is provided a use
of ketamine
in the manufacture of a medicament dosage for transmucosal administration for
treating
pain.
In accordance with another aspect of the present invention there is provided a
ketamine for
use in treating pain in a subject by transmucosal administration.
In accordance with yet another aspect of the present invention there is
provided a ketamine
for use in treating pain in a subject by transdermal administration.
In accordance with still another aspect of the present invention there is
provided a ketamine
for use in treating pain in a subject by oral administration.
In accordance with yet still another aspect of the present invention there is
provided a
pharmaceutical composition for treating pain in a subject comprising ketamine
in an amount
effective to alleviate pain in a subject suffering from pain, in association
with a
pharmaceutically acceptable carrier, said composition being in a form for
transmucosal
administration.
In accordance with a further aspect of the present invention there is provided
a
pharmaceutical composition for treating pain in a subject comprising ketamine
in an amount
effective to alleviate pain in a subject suffering from pain, in association
with a
pharmaceutically acceptable carrier, said composition being in a form for
transdermal
administration.
In accordance with yet a further aspect of the present invention there is
provided a
pharmaceutical composition for treating pain in a subject comprising ketamine
in an amount
effective to alleviate pain in a subject suffering from pain, in association
with a
pharmaceutically acceptable carrier, said composition being in a form for oral
administration.
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9b
In accordance with still a further aspect of the present invention there is
provided a
pharmaceutical composition for treating pain in a subject comprising ketamine
in a dose,
adapted for incremental administration transmucosally, effective to provide
about 0.01
mg/kg of body weight to about 1 mg/kg of ketamine to alleviate pain in a
subject
suffering from pain while avoiding dysphoria.
In accordance with yet still a further aspect of the present invention there
is provided a
pharmaceutical composition for treating pain in a subject comprising ketamine
in a dose,
adapted for administration transdermally, effective to alleviate pain in a
subject suffering
from pain, wherein the composition is in a form for transdermal administration
consisting
of absorption of the ketamine non-invasively through the skin to the
bloodstream for
systemic delivery of the ketamine.
In accordance with one embodiment of the present invention there is provided a
pharmaceutical composition for treating pain in a subject comprising ketamine
in a dose,
adapted for incremental administration orally, effective to provide about 0.01
mg/kg of
body weight to about 1 mg/kg of ketamine to alleviate pain in a subject
suffering from
pain while avoiding dysphoria.
More importantly, a patient can control administration of the pain medication,
because
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transmucosal, transdermal, or oral administration provides for precise control
over the
dosage and effect of the drug used to offset changes in activity and pain
levels
throughout a day. Transmucosal, transdermal, or oral administration of
ketamine
optimally provides for dose-to-effect administration of the drug.
5
Thus, according to the invention, the patient can safely administer an amount
of drug
effective to alleviate pain by controlling the amount and frequency of
administration of a
formulation according to the invention. Safe patient regulated control of pain
medication is an important advantage because pain is such a subjective
condition. The
10 advantage is two-fold here, as the patient can effectively alleviate pain,
and the power
to alleviate the pain will have significant psychological benefits. A positive
psychological attitude can significantly improve the course and outcome of a
treatment
regimen, as well as making the entire process more bearable to the patient.
Similarly, ketamine, which is not itself addictive, surprisingly acts
synergistically with
other pain therapies, particularly pain medications, and especially narcotics.
Thus,
administration of ketamine allows for reduction of the levels of other pain
medications,
particularly narcotics, with associated savings in cost and avoidance of
addiction.
Various terms are used throughout the specification, which are defined herein:
As can be readily appreciated by one of skill in the art, the term "ketamine"
refers to
ketamine [(2-o-chlorophenyl)-2-(methylamino)-cyclohexanonel, pharmaceutically
acceptable salts thereof, and biologically equivalent derivatives and analogs
thereof,
e.g., ketamine aspartate, ketamine succinate, etc. In specific embodiments,
ketamine
refers to ketamine hydrochloride. Other names for ketamine include ketaject,
ketalar,
ketanest, ketaset, ketalar, calypos, and feldeross. Also included within the
scope of the
term "ketamine," as one of ordinary skill would presume, are isomers and
enantiomers
thereof that demonstrate analgesic properties, e.g., with greater potency or
fewer side
effects, or both.
The term "mucosal" refers to a tissue comprising a mucous membranes, such as
the
nasal mucosa pulmonary mucosa, oral-pharyngeal mucosa, stomach and intestines,
rectal mucosa, and vaginal mucosa.
The term "transmucosal" in all its grammatical forms refers to administration
of a drug
through the mucous membrane to the bloodstream for systemic delivery of the
drug.
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The term "transdermal" in all its grammatical forms refers to administration
of a drug
through the skin to the bloodstream for systemic delivery of the drug.
The term "oral" refers to administration of a drug through the mouth and into
the
stomach or intestines, or both.
The advantages of transmucosal, transdermal, and oral administration for drug
delivery
are that they do not require injection using a syringe and rieedle, they avoid
necrosis
that can accompany i.m. administration of drugs, and all 'three are highly
amenable to
self administration.
The term "mucosal penetration enhancer" refers to a reagent that increases the
rate or
facility of transmucosal penetration of ketamine, such as but not limited to,
a bile salt,
fatty acid, surfactant, or alcohol. In specific embodiments, the permeation
enhancer
can be sodium cholate, sodium dodecyl sulphate, sodium deoxycholate,
taurodeoxycholate, sodium glycocholate, dimethylsulfoxicle or ethanol.
Suitable
penetration enhancers also include glycyrrhetinic acid (U.S. Patent No.
5,112,804 to
Kowarski) and polysorbate-80, the latter preferably in combination with an non-
ionic
surfactant such as nonoxynol-9, laureth-9, poloxamer-124, octoxynol-9, or
lauramide-
DEA (European Patent EP 0 242 643 B1 by Stoltz).
A "therapeutically effective amount" of a drug is an amount effective to
demonstrate a
desired activity of the drug. According to the instant invention, in one
embodiment a
therapeutically effective amount of ketamine is an amount effective to
alleviate, i.e.,
noticeably reduce, pain in a patient. In another embodiment, a therapeutically
effective
amount is an amount effective to act synergistically with another pain
therapy, e.g., a
pain medication such as a narcotic. Preferably the synergistic activity of
ketamine co-
administration is reflected by reduced dependency on the other pain therapy,
particularly
a narcotic analgesic, without reducing, and preferably entiancing, the level
of pain relief.
As used herein, the term "pharmaceutically acceptable" refers to a
biologically or
pharmacologically compatible for in vivo use, and preferably means approved by
a
regulatory agency of the Federal or a state government or listed in the U.S.
Pharmacopeia or other generally recognized pharmacopeia for use in animals,
and more
particularly in humans.
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The term "breakthrough pain" is used herein in accordance with its usual
meaning in
pain treatment. For example, breakthrough pain can refer to pain experienced
by a
subject receiving treatment for pain, but who experiences a level of pain that
is not
treatable by the current treatment regimen. "Spike pain" is an acute form of
breakthrough pain. Usually medications or therapies for chronic pain do not
provide
adequate relief for breakthrough pain, either because the maximum pain relief
effects of
these regimens have been achieved, because of tolerance to medications that
has
developed, or because the treatment is not fast enough.
A subject in whom administration of ketamine is an effective therapeutic
regimen for
management of pain, or for synergism with alternative pain therapy is
preferably a
human, but can be any animal. Thus, as can be readily appreciated by one of
ordinary
skill in the art, the methods and devices of the present invention are
particularly suited
to administration of ketamine to any animal, particularly a mammal, and
including, but
by no means limited to, domestic animals, such as feline or canine subjects,
farm
animals, such as but not limited to bovine, equine, caprine, ovine, and
porcine subjects,
wild animals (whether in the wild or in a zoological garden), research
animals, such as
mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., i.e., for
veterinary medical use.
For veterinary use, rectal administration or transdermal administration are
convenient
and allow for minimal aggravation or irritation of the animal.
Transmucosal Administration of Ketamine
As noted above, the present invention is directed inter a/ia to transmucosal
administration of ketamine. Initial studies have demonstrated that nasal
administration
of ketamine, either via the nasal mucosa or pulmonary inhalation and
absorption via
pulmonary mucosa, is higly effective for the treatment of pain. Subsequently,
it has
been discovered that other routes of transmucosal administration of ketamine
are also
effective for treatment of pain, as set forth above. In particular, it has
surprisingly been
discovered that transmucosal administration of ketamine allows for effective
pharmacokinetics with low doses of the drug, thus avoiding dysphoria or other
side
effects associated with bolus i.v. or i.m. dosing. Transmucosal ketamine is
particularly
indicated for breakthrough and spike pain, e.g., as described in greater
detail above.
According to the invention, any transmucosal route of administration,
including but not
limited to rectal, oral, vaginal, buccal, etc. can be employed. In particular,
the present
invention is directed to the following transmucosal routes of administration.
It can be
readily appreciated that any of the transmucosal routes of administration may
be
CA 02230690 1998-02-27
WO 97/07750 PCT/US96/14095
13
enhanced by use of a mucosal penetration enhancer, e.g., as described supra.
The
selection of a particular mucosal penetration enhancer may depend on the
characteristics of the specific mucosa. These factors are addressed in greater
detail
below.
Administration Via Suppositories
In another aspect, ketamine is formulated in a matrix suitable for rectal (or
vaginal)
insertion, i.e., in a suppository. The invention is not limited to any
particular
suppository formulation. Indeed, many suppository formulations are known in
the art,
e.g, as described in Remington's Pharmaceutical Sciences, Physician's Desk
Reference,
and U.S. Pharmacopeia.
Administration via suppositories may be preferred in certain situations, e.g.,
because
convention and custom prefers it, or where nasal administration is deemed
unacceptable.
Administration Via a Buccal Patch
According to the invention, ketamine can be formulated in a buccal patch for
administration via the interior of the cheek. It may be appreciated that a
buccal patch
constitutes another form of transmucosal administration. The technology for
preparing
buccal patch formulations is known in the art, e.g., Remington's
Pharmaceutical
Sciences, supra.
Oral-Pharyncaeal Administration
In yet another embodiment, ketamine can be formulated for oral-pharyngeal,
including
sublingual and transbuccal, administration. For example, ketamine can be
incorporated
in a "candy" matrix, such as that described in U.S. Patent No. 4,671,953, in a
gum
base, or a lozenge. In another embodiment, the ketamine can be formulated in a
capsule or pill form for sublingual placement.
It is particularly contemplated that ketamine for oral-pharyngeal
administration may be
formulated with a flavor masking agent or coating. Many flavor masking agents
for use
with oral pharmaceuticals are known in the art, and can be selected for use
with the
present invention.
Oral Administration
In still a further embodiment, ketamine can be formulated for oral
administration via the
CA 02230690 2006-11-09
14
stomach and intestinal mucosa. For oral edministration, ketamine can be
administered
in a carrier designed for drug, release in either the stomach (an acidic
environment), or
the intestines, or both. Many capsules, pifls, and matrices for oral
administration of a
drug are known in the art, and can be selected on the basis of compatibility
with
ketamine, and the desired point and rate of drug release by the ordinary
skilled
physician. Oral administration of ketamine may require higher dosages than
other
routes of administration to overcome the effects of first pass metabolism by
the liver.
TMsdermal Administration
-n a further embodiment, as noted above, the present invention is directed to
transdermal administration of ketamine. It has been discovered that
transderrnal
administration of katamine is also effective for treatment of pain, as set
forth above, for
many of the same reasons transmucosal administrntion. is effective. in
particular, it has
scirprisingly been discovered that transdermal administration of ketamine
allows for
effective pharmacokinetics with low doses af the drug, thus avoiding dysphoria
or other
side effects associated with bolus i.v. or i.m. dosing. Transdermal ketamine
is
particularly indicated for breakthrough and spike pain, e.g., as described In
greater detail
above.
Various and numerous methods are known in the art for transdermal
administration of a
drug, e.g., via a transdermal patch. These methods and associated devices
provide for
control of the rate and quantity of administration of a drug, and some allow
for
continuous modulation of drug delivery. Transdermal patches are described in,
for
example, U.S. Patent No. 5,407,713, issued April 18, 1995 to Rolando et al.;
U.S.
Patent No. 5,352,456, issued October a, 1004 to Falton et 'al.; U.S. Patent
No.
5,332,213 issued August 9, 1994 to D'Angelo et al.; U.S. Patent No. 5,336,168,
issued August 9, 1994 to Sibalis; U.S. Patent No. 5,290,561, issued March 1,
1994 to
Farhadieh at al.; U.S. Patent No. 5,254,346, issued October 19, 1993 to Tucker
et al.;
U.S. Patent No. 5,164,189, issued November 17, 1992 to Berger et al.; U.S.
Patent
No. 5,163,899, issued November 17, 1992 to Sibalis; U.S. Patent Nos. 5,088,977
and
5,087,240, both issued February 18, 1992 to Sibalis; U.S. Patent No.
5,008,110,
issued April 16, 1991 to Benecke et al.; and U.S. Patent No. 4,921,475, issued
May 1,
1990 to Sibalis.
It can be readily appreciated that a transdermal route of administration may
be
enhanced by use of a dermal penetration enhancer, e.g., such as enhancers
described in
CA 02230690 1998-02-27
WO 97/07750 PC'H'/US96/14095
U.S. Patent No. 5,164,189 (supra), U.S. Patent No. 5,008,110 (supra), and U.S.
Patent
No. 4,879,119, issued November 7, 1989 to Aruga et al., the disclosure of each
of
which is incorporated herein by reference in its entirety.
5 Administration of Ketamine for Syneray With Other Pain Therapy
In addition to the effects of ketamine alone administered via a transmucosal,
transdermal, or oral route, which is particularly effective f'or breakthrough
or spike pain
conditions, the present invention is directed to administration of ketamine
via any route,
including parenteral administration in addition to transmucosal, transdermal,
and oral
10 administration. Thus, the present invention is not limited to any
particular mode or
route of administration of ketamine for its synergistic effects with other
pain therapies,
particularly drug administration, and most particularly, use of narcotic
analgesics.
Accordingly, where medical necessity or preference dictates, parenteral
administration
of ketamine can be effected to synergistically treat pain vvith other pain
therapies.
Alternate pain therapies include non-pharmaceutical treatrnents, such as but
not limited
to, chiropractic medicine, acupuncture, biofeedback, and other alternative
therapies.
Preferably, the synergistic effects of ketamine administrai:ion are reflected
by reduced
dependency on other pain therapies, or by an reduction in the level of pain
experienced,
or both. This aspect of the invention is based on the surprising discovery
that ketamine
allows for a reduction over time of narcotic analgesics. Such a reduction over
time runs
counter to the normal course of pain treatment, where progressively larger
doses of
analgesics, particularly narcotic analgesics, are required to overcome
tolerance.
Usually, combinations of pain medications yield at best aciditive or
supplemental results.
Thus, it is a significant advantage of the present invention that it allows
for a reduction
in the level of a pain medication, without compromising the level of pain
relief.
Parenteral administration generally refers to intravenous irijection, and also
includes, but
is not limited to, intra-arteriole, intramuscular, intradermal, subcutaneous,
intraperitoneal, intraventricular, and intracranial administrrtion.
In another embodiment, the ketamine can be delivered in a vesicle, in
particular a
liposome (see Langer, 1990, Science 249:1527-1533; Treat et al., 1989, in
Liposomes
in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler
(eds.), Liss:
New York, pp. 353-365; Lopez-Berestein, ibid, pp. 317-327; see generally
ibid). To
CA 02230690 2006-11-09
16
reduce its systemic side effects, this may be a preferred, method for
introducing
ketamine.
-n yet another embodiment, ketamine may be delivered in a controlled release
system.
For example, ketamine may be administered using intravenous infusion, an
implantable
osmotic pump, a transdermal patch, liposomes, or other modes of sustained
release
administration. In one embodiment, a pump may be used (see (,anger, supra;
Sefton,
1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery
88:507;
Saudek et al., 1989, N. Eng(: J. Med. 321:574). In another-embodiment,
polymeric
materials can be used (see Medical Applications of Controlled Release, Langer
and Wise
(ads.), CRC Pres., Boca Raton, Florida (1974); Control%d Drug Bioavai/abi/ity,
Drug
Product Design and Performance, Smolen and Ba(I (eds.), Wiley, New York
(1984);
Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; see
also
Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351;
Howard
et al., 1989, J. Neurosurg. 71:105).
Other controlled release systems are discussed in the review by Langer (1990,
Science
249:1527-1333).
The invention can be better understood by referring to the following example,
which is
provided merely by way of exemplification and is not intended to limit the
invention.
EXAMPLE
26 A female patient, age 40, weighing approximately 80 kg, presented with
intractable
bladder pain (interstftial ceptitis), which had been diagnosed 4-5 months
previously.
TM
Pain management in this patient consisted of 100 mg Demoral every 3 hours;
Ditaudid
2-4 mg every 4 hours; Oalmane 30 mg per day; Duralgesic patches (fentanyl
transdermal patches); bladder washes with Pyridium (phenaropyridine HCI),
which is a
urinary tract analgesic; and belladonna and opiate suppositories. (n addition
to the pain
medication, the patient took Zanax and Tagamet to alleviate gastric distress,
and
Compazine (an anti-emetic) to counteract nausea. Gastric distress and nausea
in this
patient resulted from the pain medication.
Despite the dosages and range of pain medications used by this patient,
satisfactory
pain management was not achieved.
CA 02230690 2006-11-09
17
A diagnostic pre-sacral, or ilio-hypogastric, nerve block was performed on
this patient to
alleviate the pain. Unfortunately, the effect of the block was temporary, and
the block
was associated with significant motor weakness. After the block wore off, the
patient
stated that she was unable to function, as the most mundane activities were
exhausting.
Ketamine (10 mg/cc) drip was administered i.v. over one hour, for a total dose
of 40 mg
ketamine. This resulted in reduction of the pain level by a factor of 2 (from
#20 to
about #10-12) as subjectively evaluated by the patient. About 1 hour after
ketamine
infusion was discontinued, the patient reported that the level of pain had
increased to
about #15, and thereafter rapidly to its previous level. The patient continued
to take
the other pain medications without effect.
Four days after the ketamine i.v. challenge, a 5 mi bottle containing 100
mg/mI
ketamine solution was prepared. A single spray from the bottle delivered
approximately
116 ml of solution, i.e., 16 mg of ketamine. The patient was instructed to
self-
administer 1-2 sprays from the bottle for severe pain. The nasal spray bottle
was
prepared in order to provide sustainable pain medication on an outpatient
basis.
The patient has demonstrated remarkable pain management with nasal
administration of
ketamine. Nasal ketamine has been particularly effective for control of
breakthrough
pain. The patient has decreased the amount of the other pain medications.
To date, dozens of patients, including subjects suffering from intractable
pain, severe
migraine headaches, chronic fatigue syndrome, and other painfui afflictions,
have
successfully employed nasal administration of ketamine to treat these
problems.
The present invention is not to be limited in scope by the specific
embodiments describe
herein. Indeed, various modifications of the invention in addition to those
described
herein will become apparent to those skilled in the art from the foregoing
description
and the accompanying figures. Such modifications are intended to fall within
the scope
of the appended claims.
