U.S. patent application number 11/511569 was filed with the patent office on 2007-04-26 for therapy procedure for drug delivery for trigeminal pain.
Invention is credited to William H. II Frey, Daniel I. Jacobs, David C. Yeomans.
Application Number | 20070093420 11/511569 |
Document ID | / |
Family ID | 37654909 |
Filed Date | 2007-04-26 |
United States Patent
Application |
20070093420 |
Kind Code |
A1 |
Yeomans; David C. ; et
al. |
April 26, 2007 |
Therapy procedure for drug delivery for trigeminal pain
Abstract
The present invention relates to methods for the treatment or
prevention of trigeminal nerve-associated pain, in particular
chronic, acute and procedural-related pain. The methods comprise
administration of analgesic agents to the trigeminal nerve system
which results in analgesia to the facial or head region.
Inventors: |
Yeomans; David C.;
(Sunnyvale, CA) ; Frey; William H. II; (White Bear
Lake, MN) ; Jacobs; Daniel I.; (Mountain View,
CA) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
755 PAGE MILL RD
PALO ALTO
CA
94304-1018
US
|
Family ID: |
37654909 |
Appl. No.: |
11/511569 |
Filed: |
August 28, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60711950 |
Aug 26, 2005 |
|
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60794004 |
Apr 21, 2006 |
|
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Current U.S.
Class: |
424/130.1 ;
514/17.3; 514/17.4; 514/17.6; 514/18.5; 514/19.3; 514/2.4;
514/20.3 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 25/06 20180101; A61K 38/095 20190101; A61P 25/04 20180101;
A61K 9/0056 20130101; A61K 38/33 20130101; A61P 43/00 20180101;
A61K 38/31 20130101; A61K 45/06 20130101; A61K 9/0043 20130101;
A61P 5/10 20180101; A61K 31/00 20130101; A61P 29/00 20180101; A61K
31/196 20130101; A61K 9/0048 20130101; A61K 31/196 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/012 |
International
Class: |
A61K 38/33 20060101
A61K038/33 |
Claims
1. A method for treating an individual for trigeminal
nerve-associated pain, comprising: administering to the individual
an effective amount of an analgesic agent wherein the
administration is targeted to the trigeminal nerve system and
results predominantly in analgesia to the facial or head region as
compared to analgesic effects in other parts of the body.
2. A method according to claim 1, wherein the administration
results in minimal CNS or systemic side effects.
3. A method according to claim 1, wherein the administration
results in reduction of a pain rating on the VAS of 30% or
more.
4. A method according to claim 1, wherein the analgesic agent is
administered via mucosal administration, wherein mucosal
administration comprises intranasal administration, buccal
administration, sublingual administration and conjunctival
administration.
5. A method according to claim 1, wherein the analgesic agent is
administered via transdermal administration, wherein transdermal
administration comprises administering the agent to the skin of the
face, forehead, eyelids, nose, cheek, chin, scalp, temple region or
a combination thereof.
6. A method according to claim 1, wherein the analgesic agent is
administered via intranasal administration.
7. A method according to claim 1, wherein the analgesic agent is
administered via buccal or sublingual administration.
8. A method according to claim 1, wherein the analgesic agent is
administered via conjunctival administration or via other tissues
around the eye.
9. A method according to claim 1, wherein the analgesic agent
comprises a peptide.
10. A method according to claim 9, wherein the peptide is
administered in combination with at least one additional agent.
11. A method according to claim 9, wherein the peptide is selected
from the group comprising enkephalins, endorphins, dynorphins,
endomorphins, casomorphins, dermorphin, oxytocin, octreotide, and
analogues and derivatives thereof.
12. A method according to claim 1, wherein the analgesic agent
comprises an agent selected from the group comprising peptidergic
channel modulators, peptidergic enzyme inhibitors, analgesic
enzymes, trophic factors, peptidergic receptor agonists,
peptidergic receptor antagonists, amino acid receptor agonists,
N-methyl-D-aspartate receptor blockers, NSAIDs, steroid
anti-inflammatory drugs, ion channel blockers, antidepressants,
anti-seizure medications, nicotinic agonists, opioids, antibodies
directed toward proalgesic antigens and antibodies directed to
other neuropeptides.
13. A method according to claim 12, comprising administering at
least two analgesic agents.
14. A method according to claim 1, wherein the trigeminal
nerve-associated pain is selected from the group consisting of
chronic, acute and procedural-related pain and combinations
thereof.
15. A method according to claim 14, wherein the chronic pain is
selected from the group consisting of trigeminal neuralgia,
atypical facial pain, anesthesia dolorosa, post-herpetic neuralgia,
cancer of the head and neck, migraine headaches, and
temporomandibular joint pain.
16. A method according to claim 14, wherein the procedural-related
pain is pain arising from dental, medical, surgical or cosmetic
procedures.
17. A method according to claim 14, wherein the acute pain is pain
arising from a laceration, a bum, a broken bone, a headache, a
dental disease, a bacterial infection, an abscessed tooth, or a
sinus infection.
18. A method according to claim 1, wherein the analgesic agent is
administered as a pharmaceutical composition.
19. A method according to claim 18, wherein the pharmaceutical
composition is administered as a powder, a gel, an ointment, a
liquid, a suspension, a cream or a bioadhesive.
20. A method according to claim 18, wherein the pharmaceutical
composition further comprises at least one protease inhibitor or at
least one absorption enhancer.
21. A method according to claim 18, wherein the pharmaceutical
composition further comprises at least one protease inhibitor and
at least one absorption enhancer.
22. A method according to claim 1, wherein the method further
comprises administration of a vasoconstrictor.
23. A method according to claim 22, wherein the vasoconstrictor is
administered prior to the analgesic agent.
24. A method according to claim 22, wherein the vasoconstrictor is
co-administered with the analgesic agent.
25. A method according to claim 22, wherein administration of the
vasoconstrictor reduces systemic distribution of the analgesic
agent.
26. A method according to claim 25, wherein reduced systemic
distribution allows for a decreased effective dosage of the
analgesic agent to achieve analgesia.
27. A method according to claim 1, wherein the method further
comprises administration of at least one protease inhibitor and at
least one absorption enhancer.
28. A method according to claim 1, wherein the method further
comprises administration of at least one protease inhibitor, at
least one absorption enhancer and a vasoconstrictor.
29. A method according to claim 20, wherein the protease inhibitor
is selected from a group comprising antipain, arphamenine A and B,
benzamidine HCl, AEBSF, CA-074, calpain inhibitor I and II,
calpeptin, pepstatin A, actinonin, amastatin, bestatin,
chloroacetyl-HOLeu-Ala-Gly-NH.sub.2, DAPT, diprotin A and B,
ebelactone A and B, foroxymithine, leupeptin, pepstatin A,
phosphoramidon, aprotinin, BBI, soybean trypsin inhibitor,
phenylmethylsulfonyl fluoride, E-64, chymostatin,
1,10-phenanthroline, EDTA and EGTA.
30. A method according to claim 20, wherein the absorption enhancer
is selected from a group comprising surfactants, bile salts,
bioadhesive agents, phospholipid additives, mixed micelles,
liposomes, or carriers, alcohols, enamines, cationic polymers, NO
donor compounds, long-chain amphipathic molecules, small
hydrophobic penetration enhancers; sodium or a salicylic acid
derivatives, glycerol esters of acetoacetic acid, cyclodextrin or
beta-cyclodextrin derivatives, medium-chain fatty acids, chelating
agents, amino acids or salts thereof, N-acetylamino acids or salts
thereof, mucolytic agents, enzymes specifically targeted to a
selected membrane component, inhibitors of fatty acid synthesis and
inhibitors of cholesterol synthesis.
31. A method according to claim 22, wherein the vasoconstrictor is
selected from a group comprising phenylephrine hydrochloride,
tetrahydrozoline hydrochloride, naphazoline nitrate, oxymetazoline
hydrochloride, tramazoline hydrochloride, endothelin-1,
endothelin-2, epinephrine, norepinephrine and angiotensin.
32. A method for treating an individual for trigeminal
nerve-associated pain, comprising: administering to an individual
an effective amount of an analgesic agent wherein the agent is
administered by transmucosal or transdermal administration and
results predominantly in analgesia to the facial or head region as
compared to analgesic effects in other parts of the body.
33. A method for treating an individual for trigeminal
nerve-associated pain, comprising: administering to an individual
an effective amount of an analgesic agent wherein the
administration is targeted to the trigeminal nerve system and
results predominantly in localized analgesia to the facial or head
region with minimal central nervous system effects or systemic side
effects.
34. A method for treating an individual for trigeminal
nerve-associated pain, comprising: administering to an individual
an effective amount of an analgesic agent to the nasal cavity of
the individual wherein the administration is targeted to the
trigeminal nerve system and results predominantly in analgesia
localized to the facial or head region as compared to analgesic
effects in other parts of the body.
35. A method according to claim 34, further comprising the
administration of a vasoconstrictor.
36. A method according to claim 34, wherein the administration is
directed to the inferior two-thirds of the nasal cavity.
37. A method according to claim 34, wherein the administration is
directed to the inferior two-thirds of the nasal cavity and away
from the olfactory region.
38. A kit comprising at least one analgesic agent, suitable
packaging and instructions for treatment of trigeminal
nerve-associated pain.
39. A kit according to claim 36, further comprising a delivery
device.
40. A kit according to claim 36, further comprising a
vasoconstrictor.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The application is related to and claims the benefit of U.S.
Provisional Patent Application Ser. No. 60/711,950, filed Aug. 26,
2005, and U.S. Provisional Patent Application Ser. No. 60/794,004,
filed Apr. 21, 2006, the entire contents of which are hereby
incorporated by reference herein in their entirety.
TECHNICAL FIELD
[0002] The present invention relates generally to methods and
compositions for the treatment of pain. More specifically, the
present invention relates to methods for the treatment or
prevention of trigeminal nerve-associated procedural, acute and
chronic pain by administration and targeted delivery of analgesic
agents to the trigeminal nerve system resulting in localized pain
relief with minimal untoward central nervous system effects or
systemic side effects.
BACKGROUND OF THE INVENTION
[0003] Pain is experienced when the free nerve endings which
constitute the pain receptors in the skin as well as in certain
internal tissues are subjected to mechanical, thermal, chemical or
other noxious stimuli. The pain receptors (nociceptors) can
transmit signals along afferent neurons into the central nervous
system and then to the brain. The causes of pain can include
inflammation, injury, disease, muscle spasm and the onset of a
neuropathic event or syndrome. Ineffectively treated pain can be
devastating to the person experiencing it by limiting function,
reducing mobility, complicating sleep, and dramatically interfering
with the quality of life.
[0004] The trigeminal sensory nerves (afferents) innervate and
transmit to the brain most of the sensory signals from the face and
anterior head. Pain involving the trigeminal nerve and ganglion
arises in many different medical situations and presents unique
problems to pain therapists and doctors. Chronic pain due to
syndromes such as trigeminal neuralgia, atypical facial pain,
anesthesia dolorosa, post-herpetic neuralgia, cancer of the head
and neck, migraine headaches, and temporomandibular joint pain are
examples of very different pain syndromes that all involve the
trigeminal system and which present clinical challenges that are
peculiar to this nerve distribution. In addition to chronic pain
states, there are clinical situations where facial and head pain is
associated with acute trauma such as an abscessed tooth, a headache
or a direct injury to the face and/or head such as a laceration or
a bum. Further, medical procedures such as common dental work and
facial plastic and/or cosmetic surgery may elicit considerable
pain, as well as discomfort and anxiety.
[0005] Among syndromes associated with facial pain is trigeminal
neuralgia, also called "tic duloreaux" which is among the most
debilitating facial pain syndromes. Trigeminal neuralgia usually
begins after the age of 40, is slightly more common in women and
has an incidence of approximately 4-5 per 100,000 persons (Khorami
and Totah (2001) eMedicine Journal, Vol. 2). The primary symptom of
trigeminal neuralgia is the sudden onset of severe, sharp facial
pain, usually without warning. The quick bursts of pain are
described as "lightening bolt-like", "machine gun-like" or
"electric shock-like". The pain is generally on one side of the
face and is spasmodic, coming in short bursts lasting a few seconds
which may repeat many times over the course of a day. Trigeminal
neuralgia can involve one or more branches of the trigeminal nerve
and the causes are varied. Pharmacologic treatments include
anti-seizure medications such as carbamazepine (Tegretol,
Carbatrol), phenytoin (Dilantin), clonazepam (Klonopin), gabapentin
(Neurontin), and lamtrignine (Lamictal), tricyclic antidepressants
such as amitriptyline (Elavil) and muscle relaxants such as
baclofen. The treatments generally have limited efficacy and many
patients eventually undergo an invasive procedure. The procedural
interventions often involve the direct manipulation of the
trigeminal ganglion and include microvascular decompression,
alcohol injection aimed at destroying pain fibers, glycerol
injection aimed at selectively destroying pain-transmitting fibers,
percutaneous radiofrequency rhizotomy, pulse radio frequency and
gamma-knife. The pain relief from these procedures can be
successful in a percentage of these patients, but the relief can be
short-lived and often facial pain returns. Significant procedural
pain and long term morbidity may also be associated with such
treatments.
[0006] Atypical Facial Pain (ATFP) is a syndrome encompassing a
wide group of facial pain problems. ATFP can have many different
causes but the symptoms are all similar. Facial pain, often
described as burning, aching or cramping, occurs on one side of the
face, often in the region of the trigeminal nerve and can extend
into the upper neck or back of the scalp. Although rarely as severe
as trigeminal neuralgia, facial pain is continuous for ATFP
patients, with few, if any periods of remission. Some studies
propose that ATFP is an early form of trigeminal neuralgia, but
there is no agreement at this time. Drug treatments for ATFP are
similar to what is prescribed for trigeminal neuralgia including
anti-seizure medications and tricyclic antidepressants with limited
effectiveness.
[0007] Anesthesia dolorosa is one of the most dreaded complications
of neurosurgery and is considered to be non-reversible. The two
main symptoms of anesthesia dolorosa are facial numbness (much like
the numbness from a dental anesthetic injection) and constant pain.
The pain is usually burning, pulling or stabbing but can also
include a sharp, stinging, shooting or electrical component.
Pressure and "heaviness" can also be part of the pain symptoms and
often there is eye pain. Cold can increase the feeling of numbness
sometimes making the face feel frozen. Anesthesia dolorosa occurs
when the trigeminal nerve is damaged by surgery, physical trauma or
as a complication of surgery to correct a condition such as
trigeminal neuralgia. Topical treatments with capsaicin are used to
help manage the pain and discomfort, while topical clonidine has
been tested in a few cases but no single treatment has been found
that resolves all of the pain of this condition.
[0008] Post-herpetic neuralgia is pain that remains after the rash
from shingles (herpes zoster) has healed. Shingles is an infection
of the nerves caused by the varicella-zoster virus, which is the
same virus that causes chickenpox. About one-third of the people
who get shingles will get post herpetic neuralgia. The pain of post
herpetic neuralgia may be constant, stabbing, aching, or burning
and can last for months to years after the shingles outbreak.
[0009] It is predicted that approximately 65,000 Americans will be
diagnosed with head and neck cancers this year, this represents
about 3% of all cancers diagnosed in the United States (American
Cancer Society). Close to 60% of head and neck cancer patients
report long-term pain with up to 25% claiming moderate or severe
pain (List and Stracks (2000) Curr. Opin. Oncol., 12:215-20). The
trigeminal nerves and ganglion are likely to mediate most of the
head and facial pain in these patients and sometimes are directly
affected by the cancerous growth. The recommended treatment for
most cancer patients with mild to severe pain is opioid therapy
such as hydrocodone, codeine, oxycodone, morphine, fentanyl and
hydromorphone. Opioid therapy has a multitude of problems including
systemic effects away from the site of pain stimulation.
Furthermore, opioids are highly addictive and patients build up
tolerance to the drugs quickly resulting in higher and higher doses
being administered.
[0010] Migraine headaches affect more than 29.5 million people in
the United States. The typical migraine headache is throbbing or
pulsatile, it builds up over a period of 1-2 hours and lasts from
several hours to a whole day. Pain intensity is moderate to severe
and can be debilitating and often causes nausea and vomiting. Of
particular interest to clinicians who study migraine headaches is
the superior trigeminal division (the ophthalmic division). This
division innervates the forehead, eyebrow, eyelid, anterior scalp,
nose and contents of the orbit thus giving an explanation for the
pain localization along with the visual aura that is common with
migraine headaches. Common treatments for migraine headaches
include beta-blockers such as propranolol (Inderal) and Atenolol,
tricyclic antidepressants, triptans, ergotamines, anti-seizure
drugs and calcium channel blockers. Many of these drugs have
systemic side effects and limited effectiveness.
[0011] Acute facial pain can arise in patients undergoing common
dental procedures such as tooth extraction, root canal surgery and
surgery for dental implants and dental prostheses. Acute dental
pain can also arise from dental/gingival disease, other conditions
such as an abscessed tooth or a bacterial infection or injury, that
arise separately from planned dental procedures. Most dentists use
topical anesthetics such as benzocaine, eugenol and forms of
xylocaine to numb various areas for minor procedures or before
injection of a local anesthetic. For most procedures a dentist will
inject a local anesthetic such as lidocaine, xylocaine and marcaine
to create a nerve block at or around the site where dental work
needs to be done. Local anesthetics numb the area where they are
injected and eliminate the acute pain of most procedures. In
addition to the pain of administration, another main disadvantage
of local anesthetics, especially for routine dental procedures, is
that numbness and loss of sensation in the facial region will
usually last for several hours after the dental procedure is
finished.
[0012] Facial plastic surgery is becoming a very common procedure
with several million procedures done in the United States each
year. The procedures range from necessary repair of damage such as
lacerations or broken bones to elective cosmetic surgeries such as
face lifts, rhinoplasties, skin rejuvenation, etc. For many of
these procedures local anesthetics are used (the patients are not
under general anesthetic) and as with dental procedures, the local
anesthetics can be painful to administer and include the problem of
lingering numbness lasting for hours after the procedure is
finished. In addition, depending on the surgery performed, patients
experience varying levels of post-operative pain after the
anesthetic wears off.
[0013] Pain treatment of almost any type usually includes some form
of analgesic agent or drug. Analgesic drugs are usually classified
into three groups: non-opioid drugs, opioid drugs, and co-analgesic
drugs, also known as adjuvants. Non-opioid analgesic drugs include
acetaminophen and non-steroidal anti-inflammatory drugs or NSAIDs.
Opioid drugs, sometimes referred to as "narcotics", include natural
substances such as morphine, and semi-synthetic and synthetic
substances. Co-analgesic medications are drugs that have a primary
use other than pain relief, but also help produce analgesia for
some painful conditions.
[0014] Opioid drugs are commonly used to relieve pain. However,
their usefulness is limited by the tolerance and dependence that
normally develops on chronic treatment. Opioid drugs such as
morphine can be addictive and can have central nervous
system-mediated side effects such as respiratory and cardiac
depressions and drowsiness. Additionally, opioid drugs suffer from
frequent side effects such as nausea, vomiting and
constipation.
[0015] Therapeutic drugs are delivered by a number of routes
including, for example, oral administration, intravenous injection,
intramuscular injection and subcutaneous injection. For patients
suffering procedural, acute or chronic pain associated with the
trigeminal nerve, one of the main problems with conventional drug
delivery with analgesic agents is the lack of localized pain relief
due to systemic distribution of the agent. Often larger dosages
need to be administered to achieve an effective concentration of
the drug at a desired site. With higher doses of an analgesic
agent, there is the additional problem of limited efficacy relative
to the increase in undesired side effects due to the systemic
distribution of the agent. Treatments consisting of localized but
invasive interventions directly to the trigeminal nerve have a
significant disadvantage due to the lack of selectivity and/or
reversibility of the intervention and the fact that these
procedures can, by themselves, cause additional facial nerve
problems including anesthesia doloroso, persistent numbness and
nerve deafferentation. An additional problem with conventional
treatments for trigeminal nerve-associated pain, especially with
invasive procedures, is the high level of skill, training and
equipment required by the medical team which can make treatment
expensive and impractical for widespread use.
[0016] Intranasal administration has been used for systemic
delivery of several therapeutic agents, for example, insulin,
thryrotropin-releasing hormone, and vasopressin. Using an
intranasal or other mucosal route for systemic delivery of a
therapeutic agent allows for ease of administration and the ability
to bypass intestinal degradation and first pass hepatic metabolism
of the therapeutic agent. There are times when it is desirable to
not have systemic distribution of a therapeutic agent or to have a
therapeutic agent targeted to a localized or regional area. For
example, intranasal drug delivery has been used to bypass the
blood-brain barrier and deliver substances to the central nervous
system (CNS) and the brain. It has been demonstrated that large
molecules such as polypeptides, peptides, oligonucleotides or DNA
plasmids can be delivered directly to the CNS via specific uptake
routes within the nose such as the axonal and perineural
vascular/lymphatic pathways of the olfactory and trigeminal nerves
(Frey II (2002) Drug Delivery Technology, 2:46-49; Thorne et al.
(2004) Neuroscience, 127:481-496). However, while there is evidence
that various therapeutic agents can be delivered to the brain by an
intranasal route and that the agents may travel along perineural
pathways, there is no known method utilizing these pathways to
specifically target the trigeminal nerve system for localized or
regional analgesia in individuals suffering from trigeminal
nerve-associated pain.
[0017] Despite a wide range of medical treatments, trigeminal
nerve-associated pain, in many different forms and situations,
continues to affect millions of people. Thus new methods for
treating an individual for trigeminal nerve-associated pain are
needed to directly target the trigeminal nerve system with
analgesic agents and deliver analgesia to facial or head regions
with minimal central nervous system effects or systemic side
effects.
BRIEF SUMMARY OF THE INVENTION
[0018] Provided herein are methods for treating an individual for
trigeminal nerve-associated pain, comprising: administering to the
individual an effective amount of an analgesic agent wherein the
administration is targeted to the trigeminal nerve system and
results predominantly in analgesia to the facial or head region,
particularly as compared to analgesic effects in other parts of the
body. Some aspects of the invention include methods wherein the
trigeminal nerve-associated pain is selected from the group
consisting of chronic, acute and procedural-related pain and
combinations thereof. In some examples, the chronic pain is
selected from the group consisting of trigeminal neuralgia,
atypical facial pain, anesthesia dolorosa, post-herpetic neuralgia,
cancer of the head and neck, migraine headaches, and
temporomandibular joint pain. In some examples, the
procedural-related pain is pain arising from dental, medical,
surgical or cosmetic procedures. In yet other examples, the acute
pain is pain arising from a laceration, a burn, a broken bone, an
injury, a headache, an abscessed tooth, dental disease, a bacterial
infection or a sinus infection.
[0019] Provided herein are methods for treating an individual for
trigeminal nerve-associated pain, comprising: administering to the
individual an effective amount of an analgesic agent wherein the
administration is targeted to the trigeminal nerve system and
results predominantly in analgesia to the facial or head region and
wherein the analgesic agent is administered via mucosal and/or
dermal administration. In some examples the analgesic agent is
administered intranasally. In other examples the analgesic agent is
administered via buccal or sublingual administration. In other
examples the analgesic agent is administered to conjunctiva or
other mucosal tissues around the eye. In yet other examples the
analgesic agent is administered to the skin or dermal surface. In
some examples, the analgesic agent is administered by more than one
route.
[0020] Provided herein are methods for treating an individual for
trigeminal nerve-associated pain, comprising: administering to the
individual an effective amount of an analgesic agent wherein the
administration is targeted to the trigeminal nerve system and
results predominantly in analgesia to the facial or head region.
Some aspects of the invention include methods wherein the analgesic
agent includes, but is not limited to, a peptide, an amino acid, a
polypeptide, an opiate or a small molecule compound which has
analgesic properties. In some examples the analgesic agent is an
opioid peptide selected from a group comprising enkephalins,
endorphins, dynorphins, endomorphins, casomorphins, dermorphin,
oxytocin and analogues and derivatives thereof. In some examples
the analgesic agent is a peptide which inhibits peptidergic
enzymes. In other examples the analgesic agent is a peptidergic
receptor agonist. In yet other examples the analgesic agent is a
peptidergic receptor antagonist. In further examples the analgesic
agent is an antibody directed against proalgesic antigens such as
endothelin, nerve growth factor, vasoactive intestinal polypeptide
(VIP) or pituitary adenylate cyclase-activating polypeptide
(PACAP). In some examples the analgesic agent is an antibody
directed against calcitonin gene-related peptide (CGRP),
cholecystokinin (CCK), Substance P or galanin. In other examples
the analgesic agent is a N-methyl-D-aspartate receptor blocker, a
non-steroidal anti-inflammatory drug, a steroid anti-inflammatory
drug, an ion channel blocker, an antidepressant or an anti-seizure
medication. In some examples the analgesic agent is an opioid.
[0021] Some aspects of the invention include methods wherein the
analgesic agent is administered as a pharmaceutical composition.
Accordingly, provided herein are methods for treating an individual
for trigeminal nerve-associated pain, comprising: administering to
the individual an effective amount of a pharmaceutical composition
comprising an analgesic agent wherein the administration is
targeted to the trigeminal nerve system and results predominantly
in analgesia to the facial or head region. Some aspects of the
invention include methods wherein the pharmaceutical composition is
administered in a formulation selected from a group comprising a
powder, a liquid, a gel, an ointment, a suspension, a film, a foil,
a cream or a bioadhesive. Some aspects of the invention include
methods wherein the pharmaceutical composition further comprises a
protease inhibitor, an absorption enhancer, a vasoconstrictor or
combinations thereof. In some examples, the protease inhibitor is
selected from a group comprising antipain, arphamenine A and B,
benzamidine HCl, AEBSF, CA-074, calpain inhibitor I and II,
calpeptin, pepstatin A, actinonin, amastatin, bestatin,
chloroacetyl-HOLeu-Ala-Gly-NH.sub.2, DAPT, diprotin A and B,
ebelactone A and B, foroxymithine, leupeptin, pepstatin A,
phosphoramidon, aprotinin, BBI, soybean trypsin inhibitor,
phenylmethylsulfonyl fluoride, E-64, chymostatin,
1,10-phenanthroline, EDTA and EGTA. In other examples the
absorption enhancer is selected from a group comprising
surfactants, bile salts, bioadhesive agents, phospholipid
additives, mixed micelles, liposomes, or carriers, alcohols,
enamines, cationic polymers, NO donor compounds, long-chain
amphipathic molecules, small hydrophobic penetration enhancers;
sodium or a salicylic acid derivatives, glycerol esters of
acetoacetic acid, cyclodextrin or beta-cyclodextrin derivatives,
medium-chain fatty acids, chelating agents, amino acids or salts
thereof, N-acetylamino acids or salts thereof, mucolytic agents,
enzymes specifically targeted to a selected membrane component,
inhibitors of fatty acid synthesis and inhibitors of cholesterol
synthesis.
[0022] Provided herein are methods for treating an individual for
trigeminal nerve-associated pain, comprising: administering to the
individual i) an effective amount of a pharmaceutical composition
comprising an analgesic agent wherein the administration is
targeted to the trigeminal nerve system and results predominantly
in analgesia to the facial or head region and ii) a vasoconstrictor
wherein administration of the vasoconstrictor reduces systemic
distribution of the analgesic agent. In some examples the
vasoconstrictor is selected from the group comprising phenylephrine
hydrochloride, tetrahydrozoline hydrochloride, naphazoline nitrate,
oxymetazoline hydrochloride, tramazoline hydrochloride,
endothelin-1, endothelin-2, epinephrine, norepinephrine and
angiotensin. In some examples the vasoconstrictor is administered
prior to the administration of the pharmaceutical composition. In
other examples the vasoconstrictor is co-administered with the
pharmaceutical composition. In some examples administration of the
vasoconstrictor results in a decreased effective dosage of the
analgesic agent.
[0023] Provided herein are methods for treating an individual for
trigeminal nerve-associated pain, comprising: administering to the
individual an effective amount of a pharmaceutical composition
comprising an analgesic agent wherein the peptide is administered
by buccal or sublingual administration to the oral cavity and
wherein the agent preferentially binds to opioid receptors within
the trigeminal nerve system and results predominantly in analgesia
to the facial or head region. Some aspects provide methods for
treating an individual for trigeminal nerve-associated pain,
comprising: administering to the individual an effective amount of
a pharmaceutical composition comprising an analgesic agent wherein
the peptide is administered by transdermal administration to the
skin and wherein the agent preferentially binds to opioid receptors
within the trigeminal nerve system and results predominantly in
analgesia to the facial or head region.
[0024] Provided herein are methods for treating an individual for
trigeminal nerve-associated pain, comprising: administering to the
individual an effective amount of a pharmaceutical composition
comprising an analgesic agent wherein the agent is administered by
intranasal administration to the nasal cavity and wherein the agent
preferentially binds to opioid receptors within the trigeminal
nerve system and results predominantly in analgesia to the facial
or head region. In some examples the administration is directed to
the inferior two-thirds of the nasal cavity. In other examples the
administration is directed to the inferior two-thirds of the nasal
cavity and is directed away from the olfactory region.
[0025] Provided herein are methods for treating an individual for
trigeminal nerve-associated pain, comprising: administering to the
individual an effective amount of an analgesic agent wherein the
administration is targeted to the trigeminal nerve system and
results predominantly in analgesia to the facial or head region,
particularly as compared to analgesic effects in other parts of the
body. In some examples, administration of an analgesic agent or a
composition comprising an analgesic agent results in reduction of a
pain rating on the VAS of 30% or more. In other examples,
administration of an analgesic agent or a composition comprising an
analgesic agent results in reduction of a pain rating on the VAS of
50% or more.
[0026] Provided are kits for carrying out any of the methods
described herein. Kits are provided for use in treatment of
trigeminal nerve-associated pain. Kits of the invention may
comprise at least one analgesic agent in suitable packaging. Kits
may further comprise a vasoconstrictor, at least one protease
inhibitor, and/or at least one absorption enhancer. Kits may
further comprise a delivery device, including but not limited to, a
device for intranasal administration. Kits may further comprise
instructions providing information to the user and/or health care
provider for carrying out any of the methods described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 depicts data demonstrating withdrawal latencies after
noxious thermal stimulation to the ears or hindpaws in a rat model
after intranasal administration of met-enkephalin. Panel A shows
baseline and treated withdrawal latencies after thermal stimulation
to the ear. Panel B shows baseline and treated withdrawal latencies
after thermal stimulation to the hindpaw. After taking baseline
withdrawal latencies, rats were intranasally administered 10
nmoles/kg met-enkephalin and withdrawal latencies were retested.
Each bar represents the average, across 4 animals, of latencies in
response to stimulation at a particular time after the beginning of
the set. Thus, the first white bar in each graph represents
responses at the beginning of the baseline testing set; the first
black bar represents responses at approximately five minutes after
administering met-enkephalin. Each successive bar represents
responses at approximately 15 minutes after the previous bar.
[0028] FIG. 2 depicts the effect of intranasal administration of
oxytocin on trigeminal nerve impulses in response to noxious laser
pulses to the face in a rat model. Data demonstrating average nerve
impulses after noxious laser pulses to the face pre- and
post-treatment are shown.
[0029] FIG. 3 depicts the effect of intranasal administration of
oxytocin on electrical stimulus-induced responses of trigeminal
nucleus caudalis wide dynamic range neurons. FIG. 3A shows
responses (action potentials per 30 stimuli) to repeated
stimulation of a rat's face before and after oxytocin
administration. FIG. 3B shows the approximate site (black spot) of
administration on the rat's face of the electrical administration.
FIG. 3C shows raw data recorded during electrical stimulation
before oxytocin administration. FIG. 3D. shows raw data recorded
during electrical stimulation 30 minutes after intranasal oxytocin
administration.
[0030] FIG. 4 depicts the effect of intranasal administration of
octreotide on long-pulse laser-induced responses of trigeminal
nucleus caudalis wide dynamic range neurons. FIG. 4A shows a
baseline response before administration with octreotide. FIG. 4B
shows responses 5 minutes after octreotide administration. FIG. 4C
shows responses 10 minutes after octreotide administration. FIG. 4D
shows responses 25 minutes after octreotide administration. FIG. 4E
shows the approximate site (black spot) of administration on the
rat's face of the electrical administration
[0031] FIG. 5 depicts the effect of intranasal administration of
octreotide on electrical stimulus-induced windup. FIG. 5A shows the
approximate site (black spot) of administration on the rat's face
of the electrical administration. FIG. 5B shows responses before
(solid squares) and 10 minutes after (open triangles) an intranasal
administration of octreotide. FIGS. 5C and 5D show the responses to
the 1.sup.st and 15.sup.th stimuli before octreotide
administration. FIGS. 5E and 5F show the responses to the 1.sup.st
and 15.sup.th stimuli 10 minutes after octreotide
administration.
DETAILED DESCRIPTION OF THE INVENTION
[0032] Described herein are methods for treating an individual for
trigeminal nerve-associated pain. In general, the methods are based
on the finding that molecules can travel along perineural pathways
to the trigeminal nerve and to the brain. Without wishing to be
bound by theory, it is believed that analgesic agents can be
targeted to the trigeminal nerve system and that administration of
the agents can result in analgesia and pain relief to an individual
suffering acute, chronic or procedural facial or head pain.
Furthermore, it is believed that targeted drug delivery to the
trigeminal nerve system can limit systemic distribution of an
analgesic agent which may decrease or eliminate undesirable central
nervous system (CNS) effects or systemic side effects. In
particular, it is believed that higher concentrations of an
analgesic agent at a targeted site will allow for administration of
lower dosages of the analgesic agent to the individual.
[0033] The methods described herein involve administration of a
variety of different analgesic agents to a individual for treatment
of trigeminal nerve-associated pain. In general, the methods can
administer to the trigeminal nerve an analgesic agent for
prevention or treatment of facial or head pain. Administration of
analgesic agents targeted for a predominantly regional analgesic
effect can result in prevention or alleviation of pain without
numbness as compared to local anesthetics. Since the trigeminal
nerve transmits most of the sensory signals of the face and head,
administration of analgesic agents targeted to the trigeminal nerve
can localize the analgesic effect to the face and head region,
particularly as compared to analgesic effects in other parts of the
body.
[0034] Targeted delivery can decrease the amount of agent
administered to an individual to achieve an analgesic effect, and
can decrease the undesirable CNS effects or systemic side effects
of many analgesic agents. More effective or efficient delivery of
an analgesic agent to the trigeminal nerve can decrease the total
dose of an agent administered to a subject suffering from
trigeminal nerve-associated pain. Effective targeted delivery of an
analgesic agent to the trigeminal nerve can decrease the systemic
distribution of the agent wherein CNS effects or systemic side
effects are minimized or eliminated.
[0035] In some aspects of the invention are included methods for
treating an individual for trigeminal nerve-associated pain
comprising administering to the individual an analgesic agent
wherein the administration is targeted to the trigeminal nerve
system and results predominantly in analgesia to the facial or head
region. In some examples, the analgesic agent can be a peptide, in
particular an opioid peptide. The opioid peptide can be selected
from a group comprising enkephalins, endorphins, a-neoendorphins,
dynorphins, endomorphins, casomorphins, deltorphins, dermorphin,
oxytocin and analogues and derivatives thereof. In some examples,
the peptide can be targeted to opioid receptors on the trigeminal
nerves. In other examples, more than one opioid peptide can be
administered. In some examples, the analgesic agent can be a
non-peptide, such as an amino acid, a polypeptide, an opiate, or a
small molecule compound.
Definitions
[0036] As used herein, unless otherwise specified, the term
"treatment" or "treating pain" refers to administration to an
individual an agent of interest wherein the agent alleviates or
prevents a pathology for which the subject is being treated.
Treatment for trigeminal nerve-associated pain refers to the
alleviation or prevention of trigeminal nerve-associated pain.
[0037] As used herein, "central nervous system" or "CNS" refers to
that part of the nervous system that consists of the brain and
spinal cord. The CNS is one of the two major divisions of the
nervous system. The other is the peripheral nervous system which is
outside of the brain and spinal cord and includes the cranial
nerves--of which the trigeminal nerve is a member.
[0038] Although analgesia in the strictest sense is an absence of
pain, as used herein, "analgesia" refers to reduction in the
intensity of the pain perceived by an individual without causing
general numbness.
[0039] As used herein, "analgesia agent", "analgesic agent" or
"analgesic" refers to any biomolecule that alleviates or prevents
pain.
[0040] As used here, "analgesic peptide" refers to any peptide
molecule that alleviates or prevents pain.
[0041] As used herein, "opioid peptide" refers to a peptide having
a opioid receptor binding moiety and the capacity to bind to an
opioid receptor. An opioid peptide can be a naturally occurring
endogenous peptide, fragments, analogues or derivatives thereof. An
opioid peptide can also be a non-endogenous peptide, fragments,
analogues or derivatives thereof.
[0042] As used herein, "analogues and derivatives" refers to any
peptide analogous to naturally occurring opioid peptides wherein
one or more amino acids within the peptide have been substituted,
deleted, or inserted. The term also refers to any peptide wherein
one or more amino acids have been modified, for example by chemical
modification. In general, the term covers all peptides which bind
to an opioid receptor and exhibit an opioid activity but which may,
if desired, have a different potency or pharmacological
profile.
[0043] As used herein, "acute pain" refers to sudden, severe pain
from a specific cause (injury, infection, inflammation, etc) that
lasts a limited period of time (as opposed to chronic pain). As
used herein "chronic pain" refers to a persistent state of pain
whereby the cause of the pain cannot be easily removed. Chronic
pain is often associated with long-term incurable or intractable
medical conditions or diseases. As used herein "procedural pain"
refers to pain arising from a medical, dental or surgical procedure
wherein the procedure is usually planned or associated with acute
trauma.
[0044] As used herein "systemic side effects" include, but are not
limited to, cardiovascular including peripheral vasodilation,
reduced peripheral resistance, and inhibition of baroreceptors;
dermatologic including pruritus (itching), flushing and red eyes;
gastrointestinal including nausea and vomiting, decreased gastric
motility in stomach, decreased biliary, pancreatic and intestinal
secretions and delays in food digestion in small intestine,
diminished peristaltic waves in large intestine contributing to
constipation, epigastric distress or biliary colic in biliary
tract; respiratory including depressed respiratory rate; and
urinary including urinary urgency and difficulty with urination,
and peripheral limb heaviness.
[0045] As used herein, "central nervous system effects" or "CNS
effects" include, but are not limited to, narcosis, euphoria,
drowsiness, apathy, psychotic ideation, mental confusion,
alteration in mood, reduction in body temperature, feelings of
relaxation, dysphoria (an emotional state characterized by anxiety,
depression, or unease), nausea and vomiting (caused by direct
stimulation of chemoreceptors in the medulla).
[0046] As used herein, "mucosal administration" or "administered
transmucosally" refers to delivery to the mucosal surfaces of the
nose, nasal passageways, nasal cavity; the mucosal surfaces of the
oral cavity including the gingiva (gums), the floor of the oral
cavity, the cheeks, the lips, the tongue, the teeth; and the
mucosal surfaces of or around the eye including the conjunctiva,
the lacrimal gland, the nasolacrimal ducts, the mucosa of the upper
or lower eyelid and the eye.
[0047] As used herein, "intranasal administration" or "administered
intranasally" refers to delivery to the nose, nasal passageways or
nasal cavity by spray, drops, powder, gel, inhalant or other
means.
[0048] The nasal cavity contains turbinate bones which protrude in
to the nasal cavity and generally separate it into three regions.
As used herein, the "inferior two-thirds of the nasal cavity"
refers to the portion of the nasal cavity where the middle and
inferior turbinate bones protrude and is the region of the nasal
cavity that is innervated by the trigeminal nerve system. The
superior third of the nasal cavity is defined by the superior
turbinate bone wherein the olfactory region is located.
[0049] As used herein, "transdermal administration" or "dermal
administration" refers to delivery to the skin of the face, neck,
scalp or combinations thereof.
[0050] As used herein, "pharmaceutically acceptable carrier" or
"suitable carrier" refers to a carrier that is conventionally used
in the art to facilitate the storage, administration, and/or the
healing effect of the agent.
[0051] As used herein, "therapeutically effective dose",
"therapeutically effective amount" or "an effective amount" refers
to an amount of an analgesic agent that is useful for treating
pain.
[0052] As used herein, "visual analogue scale" (VAS) refers to a
commonly used scale in pain assessment. It is a 10 cm horizontal or
vertical line with word anchors at each end, such as "no pain" and
"pain as bad as it could be". A subject or patient is asked to make
a mark on the line to represent pain intensity. This mark is
converted to distance in either centimeters or millimeters from the
"no pain" anchor to give a pain score that can range from 0-10 cm
or 0-100 mm. The VAS may refer to an 11 point numerical pain rating
scale wherein 0 equals "no pain" and 10 equals the "worst pain
imaginable".
[0053] It should be noted that, as used herein, the singular form
"a", "an", and "the" includes plural references unless indicated
otherwise. Additionally, as used herein, the term "comprising" and
its cognates are used in their inclusive sense; that is, equivalent
to the term "including" and its corresponding cognates.
Analgesic Agents
[0054] Many different classes of molecules are potentially useful
for targeted administration to the trigeminal nerve system for the
treatment of pain. Certain molecular and biological characteristics
make some therapeutic agents particularly unattractive for systemic
administration and good candidates for targeted delivery by
transdermal and/or transmucosal administration. One characteristic
is poor bioavailability of some systemically applied molecules and
their lack of ability to reach the target of choice, i.e. the
trigeminal nerve system. A second characteristic is the short
half-life of some molecules in the systemic circulation and the
resulting lack of bioavailability at the desired target, i.e.
trigeminal nerve system. Brief half-lives are generally due to
rapid degradation of the molecule by enzymes, rapid uptake and
turnover in the kidney and/or liver, or excretion via the lung.
Targeted delivery by transdermal and/or transmucosal administration
can bypass some of these problems. However, targeted delivery is
not limited to molecules with these characteristics, rather, these
characteristics allow targeted delivery to the trigeminal nerve
system, and limit the usefulness of the compounds through other
(e.g., systemic) routes of administration.
[0055] Opioids are one of the classes of analgesic drugs commonly
used for treatment of moderate to severe pain. These compounds
include both plant-derived and synthetic alkaloids and also include
endogenous peptides found in mammals as well as in lower animals.
Examples of opioid analgesics include, but are not limited to,
codeine, opium, oxycodone, loperimide, meperidine (Demerol),
diphenoxylate, propoxyphene (Darvon), fentanyl, 4-methyl fentanyl,
hydrocodone, morphine, diacetylmorphine, dihydrocodeine,
hydromorphone (Dilaudid), methadone, levorphanol (Levo-Dromoran),
dextromethorphan, oxymorphone (Numorphan), heroin, remifentanil,
butorphanol (Torbugesic), phenazocine, pentazocine, piminodine,
anileridine, buprenorphine (Suboxone), sufentanil, carfentanil,
alfentanil and the atypical opiates, tramadol and tapentadol.
[0056] Naturally occurring endogenous opioid peptides can generally
be referred to as "endorphins" (endogenous morphines) and include,
but are not limited to, beta-endorphin, endomorphins, enkephalins,
dynorphins, deltorphins, casomorphins, dermorphin and oxytocin.
[0057] Analgesic activity may be mediated by opiate receptors found
within the central nervous system and on peripheral neurons
throughout the body. Opioid peptides bind to the same opiate
receptors as narcotic opioid drugs. Both endogenous peptide opioids
and narcotic morphine-like analgesics can alter the central release
of neurotransmitters from afferent nerves sensitive to noxious,
i.e. painful, stimuli. After binding with a receptor, opioid drugs
or peptides may act to initiate or block various biochemical and
physiological sequences.
[0058] Several major categories of opioid receptors are known: mu
(.mu.), kappa (.kappa.), delta (.delta.), and epsilon (.epsilon.).
In general, mu-receptors mediate analgesia, euphoria, respiratory
and physical depression, miosis, and reduced GI motility,
delta-receptors mediate analgesia, dysphoria, psychotomimetic and
respiratory effects and kappa-receptors mediate analgesia,
sedation, miosis, respiratory depression and dysphoria. There is a
differential distribution of these opiate receptors on nerves
throughout the CNS and the peripheral neural system. In particular,
mu and delta opioid receptors are found on the nociceptors in the
trigeminal nerve but not on the olfactory nerve fibers within the
nasal cavity. The differential distribution of opioid receptors can
allow for targeted administration of opioid peptides to receptors
within the trigeminal nerve while delivery to the olfactory nerve
and the brain is minimized.
[0059] The peptides for use in the herein described methods can be
natural or synthetic, therapeutically or prophylactically active,
peptide fragments, peptide analogues, and chemically modified
derivatives or salts of active peptides. A variety of peptide
analogues and derivatives are available and others can be
contemplated for use within the invention and can be produced and
tested for biological activity according to known methods. Peptides
for use within the invention can be peptides that are obtainable by
partial substitution, addition, or deletion of amino acids within a
naturally occurring or native peptide sequence. Peptides can be
chemically modified, for example, by amidation of the carboxyl
terminus (--NH.sub.2), the use of D amino acids in the peptide,
incorporation of small non-peptidyl moieties, as well as the
modification of the amino acids themselves (e.g. alkylation or
esterification of side chain R-groups). Such analogues, derivatives
and fragments should substantially retain or enhance the desired
biological activity of the native peptide.
[0060] All peptides described and/or contemplated herein can be
prepared by chemical synthesis using either automated or manual
solid phase synthetic technologies, generally known in the art. The
peptides can also be prepared recombinantly, using techniques known
in the art.
[0061] A list of peptides is included in Table I, however one
skilled in the art would know this list is not complete and one
could contemplate and produce additional peptides, analogues and
derivatives. Enkephalin was isolated from mammalian brains and
found to be a mixture of two pentapeptides which differ only in the
amino acid present at the 5-position. The two pentapeptides are
methionine enkephalin (also known as met-enk or met-enkephalin) and
leucine enkephalin (also known as leu-enk or leu-enkephalin).
Met-enkephalin has an amino acid sequence of Tyr-Gly-Gly-Phe-Met
and leu-enkephalin has an amino acid sequence of
Tyr-Gly-Gly-Phe-Leu wherein the Tyr, Met and Leu residues are all
L-amino acids. The tyrosine moiety is important for activity and
probably corresponds to the 3-hydroxyl group on the morphine
molecule. Proenkephalin A is the precursor for met-enkephalin,
leu-enkephalin and several other larger peptides. The structure of
proenkephalin A contains four copies of met-enkephalin and one copy
of leu-enkephalin, along with a heptapeptide (met-enk-Arg-Phe) and
an octapeptide (met-enk-Arg-Gly-Leu). A series of peptides
containing met-enkephalin at the N-terminus also possess opioid
activity, and include peptide F and peptide E. Peptide F contains
two met-enkephalin sequences one at each end, while peptide E
contains met-enkephalin at the N-terminus and leu-enkephalin at the
C-terminus.
[0062] In addition to naturally occurring enkephalins, enkephalin
analogues and derivatives are known in the art, including, for
example, derivatives and analogues which are specific for different
types of opiate receptors. (Hruby and Gehrig (1989) Medicinal
Research Reviews 9:343-401). Furthermore, enkephalin peptides can
be modified by replacement and/or modification of specific amino
acids, as it is known in the art that these modifications decrease
the rate of hydrolysis and degradation of enkephalins by
proteases.
[0063] .beta.-endorphin is a 31-amino acid peptide formed from a
larger precursor, pro-opio-melanocortin. .beta.-endorphin contains
a tetrapeptide sequence (Tyr-Gly-Gly-Phe) which is common to the
enkephalin peptides and this tetrapeptide sequence appears to be
essential to the function of these peptides. .alpha.-endorphin is a
16-amino acid peptide that is also formed from precursor
pro-opiomelanocortin.
[0064] Dynorphins are another class of endogenous opioids that
exist in multiple forms in the central nervous system. Dynorphins
derive from precursor prodynorphin (proenkephalin B). Dynorphin,
also known as Dynorphin A1-17, is a well-known opioid peptide that
has the sequence
Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln.
Smaller peptides such as dynorphin A1-8 and three leu-enkephalins
are also contained within proenkephalin B and are abundant in the
neural lobe of the pituitary gland. Dynorphin A1-13 has been found
in the striatonigral pathway and may provide a feedback mechanism
for regulating dopaminergic activity in the striatum.
[0065] Endomorphins are amidated tetrapeptides and are structurally
unrelated to the other endogenous opioid peptides. Two peptides,
endomorphin-1 and endomorphin-2 have been isolated from mammalian
brain. Both peptides have similar characteristics including
analgesia against heat stimuli, mechanical stimuli and inflammatory
and neuropathic pain. (Zadina et al. (1997) Nature 386:499-502;
Hackler et al. (1997) Peptides 18:1635-1639)
[0066] Casomorphin peptides are novel opioid peptides derived from
casein. Beta-casomorphins are the more extensively studied opioid
peptides arising from the proteolytic breakdown of food proteins.
The .beta.-casomorphin peptide, Tyr-Pro-Phe-Pro-Gly-Pro-Ile was
originally isolated from bovine beta-casein, and subsequently
peptides with the same sequence were identified originating from
ovine and buffalo beta-caseins. A human beta-casomorphin has been
identified and has two amino acid differences from the bovine
sequence, Tyr-Pro-Phe-Val-Glu-Pro-Ile. Several other casomorphin
peptides have been isolated including .beta.-casomorphin 1-3,
.beta.-casomorphin 1-4, .beta.-casomorphin 1-5 and
.beta.-casomorphin 1-8.
[0067] Dermorphin is a seven amino acid peptide, originally
isolated from Phylomedusa sauvagei frog skin. It is a ligand which
binds with high affinity to the mu opioid receptor and has many
biological roles including analgesia, endocrine modulation,
immunomodulation, increased K+ conductance and inhibition of action
potentials.
[0068] Oxytocin is a nine amino acid cyclic peptide hormone that is
released from the posterior lobe of the pituitary gland and
stimulates the contraction of smooth muscle of the uterus during
labor and facilitates release of milk from the breast during
nursing. Studies have shown that oxytocin can also play an
important role in nociceptive modulation. The mu receptors as well
as oxytocin receptors appear to be the predominant receptor bound
by oxytocin and that they both are involved in oxytocin's
physiological effects. (Wang et al. (2003) Regul. Pept.,
115:153-159; Zubrzycka et al. (2005) Brain Res. 1035:67-72).
[0069] Accordingly, in some aspects of the invention, the analgesic
agent can be an opioid peptide selected from the group comprising
leu-enkephalin, met-enkephalin, met-enk-Arg-Phe,
met-enk-Arg-Gly-Leu, peptide E, peptide F, .beta.-endorphin,
.alpha.-endorphin, dynorphin A1-17, dynorphin B, beta-neoendorphin,
.alpha.-neoendorphin, dynorphin A1-8, dynorphin A1-13,
endomorphin-1, endomorphin-2, .beta.-casomorphin,
.beta.-casomorphin 1-3, .beta.-casomorphin 1-4, .beta.-casomorphin
1-5, .beta.-casomorphin 1-8, dermorphin, deltorphin I, deltorphin
II, dermenkephalin, morphiceptin, oxytocin and analogues and
derivatives thereof. In some examples more than one peptide is
administered. In other examples, an opioid peptide is administered
in combination with a second agent. In some examples, the opioid
peptide is administered in combination with more than one
additional agent. TABLE-US-00001 TABLE I Name Amino Acid Sequence
Leu-enkephalin Tyr-Gly-Gly-Phe-Leu SEQ ID NO:1 Met-enkephalin
Tyr-Gly-Gly-Phe-Met SEQ ID NO:2 Peptide F Tyr-Gly-Gly-Phe-Met- SEQ
ID NO:3 Lys-Lys-Met-Asp-Glu- Leu-Tyr-Pro-Leu-Glu-
Val-Glu-Glu-Glu-Ala- Asn-Gly-Gly-Phe-Val- Leu-Gly-Lys-Arg-Try-
Gly-Gly-Phe-Met .beta.-endorphin Tyr-Gly-Gly-Phe-Met- SEQ ID NO:4
(human) Thr-Ser-Glu-Lys-Ser- GenBank Gln-Thr-Pro-Leu-Val- 764134
Thr-Leu-Phe-Lys-Asn- Ala-Ile-Ile-Lys-Asn- Ala-Tyr-Lys-Lys-Gly- Glu
.alpha.-endorphin Tyr-Gly-Gly-Phe-Met- SEQ ID NO:5
Thr-Ser-Glu-Ser-Gln- Thr-Pro-Leu-Val-Thr- NH.sub.2 Dynorphin A
Tyr-Gly-Gly-Phe-Leu- SEQ ID NO:6 Arg-Arg-Ile-Arg-Pro-
Lys-Leu-Lys-Trp-Asp- Asn-Gln Dynorphin B Tyr-Gly-Gly-Phe-Leu- SEQ
ID NO:7 Arg-Arg-Gln-Phe-Lys- Val-Val-Thr .alpha.-neoendorphin
Tyr-Gly-Gly-Phe-Leu- SEQ ID NO:8 Arg-Lys-Tyr-Pro-Lys
.beta.-neoendorphin Tyr-Gly-Gly-Phe-Leu- SEQ ID NO:9
Arg-Lys-Tyr-Pro Dynorphin A1-8 Tyr-Gly-Gly-Phe-Leu- SEQ ID NO:10
Arg-Arg-Ile Dynorphin Tyr-Gly-Gly-Phe-Leu- SEQ ID NO:11 A1-13
Arg-Arg-Ile-Arg-Pro- Lys-Leu-Lys Endomorphin-1
Tyr-Pro-Trp-Phe-NH.sub.2 SEQ ID NO:12 Endomorphin-2
Tyr-Pro-Phe-Phe-NH.sub.2 SEQ ID NO:13 Dermorphin
Tyr-(D)Ala-Phe-Gly- SEQ ID NO:14 Tyr-Pro-Ser-NH.sub.2
.beta.-casomorphin Tyr-Pro-Phe-Pro-Gly- SEQ ID NO:15 (bovine)
Pro-Ile .beta.-casomorphin Tyr-Pro-Phe-Val-Glu- SEQ ID NO:16
(human) Pro-Ile .beta.-Casomorphin Tyr-Pro-Phe SEQ ID NO:17 1-3
.beta.-Casomorphin Tyr-Pro-Phe-Pro SEQ ID NO:18 1-4
.beta.-Casomorphin Tyr-Pro-Phe-Pro-NH.sub.2 SEQ ID NO:19 1-4, amide
.beta.-Casomorphin Tyr-Pro-Phe-Pro-Gly SEQ ID NO:20 1-5
.beta.-Casomorphin Tyr-Pro-Phe-Pro-Gly- SEQ ID NO:21 1-8
Pro-Ile-Pro Deltorphin I Tyr-(D)Ala-Phe-Asp- SEQ ID NO:22
Val-Val-Gly-NH.sub.2 Deltorphin II Tyr-(D)Ala-Phe-Glu- SEQ ID NO:23
Val-Val-Gly-NH.sub.2 Dermenkephalin Tyr-(D)Met-Phe-His- SEQ ID
NO:24 Leu-Met-Asp-NH.sub.2 Dermorphin Tyr-(D)Ala-Phe-Gly- SEQ ID
NO:25 Tyr-Pro-Ser Morphiceptin Tyr-Pro-Phe-Pro-NH.sub.2 SEQ ID
NO:26 Oxytocin Cys-Tyr-Ile-Gln-Asn- SEQ ID NO:27
Cys-Pro-Leu-Gly
[0070] Other analgesic or potentially analgesic agents can include
opioids, amino acids, non-opioid peptides, polypeptides,
non-peptidic compounds and small molecule compounds. These agents
may have an analgesic effect by interacting with opiate receptors,
non-opiate receptors and/or ion channels. These agents can include,
but are not limited to, peptidergic channel modulators, peptidergic
enzyme inhibitors, analgesic enzymes, trophic factors, peptidergic
receptor agonists, peptidergic receptor antagonists, amino acid
receptor agonists, N-methyl-D-aspartate receptor blockers,
nicotinic agonists, non-steroidal anti-inflammatory drugs (NSAIDs),
steroid anti-inflammatory drugs, ion channel blockers,
antidepressants, anti-seizure medications, antibodies directed
toward proalgesic antigens and antibodies directed to other
neuropeptides. Channel modulators may include snail toxins, such as
omega-conotoxin MVIIA, and their derivatives, saxitoxin and
tetrodotoxin. Enzyme inhibitors may include cyclosporin A,
bestatin, bestatin analogue Z4212 (N-[(2S,
3R)-3-Amino-2-hydroxy-4-(4-3.
methylsulphonyl-phenyl)-1-oxobutyl]-1-aminocyclopentanecarboxylic)
and bestatin analogue Z 1796
((2S)-N-[(2S,3R)-3-Amino-2-hydroxy-4-(4-methylsulphonyl-phenyl)-1-oxobuty-
l]-L-leucine). Analgesic enzymes may include endothelin-1
peptidase. Trophic factors may include glial-derived neurotrophic
factor (GDNF) and brain-derived neurotrophic factor (BDNF).
Peptidergic receptor agonists may include somatostatin and its
synthetic analogue octreotide, nocistatin, galanin and neuropeptide
Y. Peptidergic receptor antagonists may include calcitonin
gene-related peptide receptor antagonist CGRP(8-37),
cholecystokinin (CCK) receptor antagonists such as
Tyr-(D)Phe-Gly-(D)Trp-NMeNle-Asp-Phe-NH.sub.2 or PD134308,
neurokinin-1 receptor (substance P receptor) antagonists such as
spantide II ((D)-NicLys1, 3-Pal3, D-Cl2Phe5, Asn6, D-Trp7.9,
Nle11-substance P), vasoactive intestinal peptide (VIP) receptor
antagonists such as (Ac-Try1, D-Phe2)-GRF-(1-29) (where GRF is
growth hormone releasing factor) and galanin receptor antagonists
such as RWJ-57408). Amino acid receptor agonists may include
gamma-amino butyric acid (GABA) and glycine. N-methyl-D-asparate
(NMDA) receptor blockers may include ketamine and dextromethorphan.
Anti-seizure medications that decrease pain may include gabapentin,
lamotrigine, tiagabine, topiramate, carbamazepine, oxcarbazepine,
clonazepam, valproic acid, and phenytoin. Nicotinic agonists may
include nicotine and epibatidine. Typical and atypical
non-steroidal anti-inflammatory drugs may include aspirin,
acetaminophen, choline and magnesium salicylates, choline
salicylate, celecoxib, diclofenac potassium, diclofenac sodium,
diclofenac sodium with misoprostol, diflunisal, etodolac,
fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin,
ketorolac, ketoprofen, magnesium salicylate, meclofenamate sodium,
mefenamic acid, meloxicam, nabumetone, naproxen, naproxen sodium,
oxaprozin, piroxicam, rofecoxib, salsalate, sodium salicylate,
sulindac, tolmetin sodium, valdecoxib. Steroid anti-inflammatory
drugs may include prednisone and dexamethasone. Ion channel
blockers may include selective blockers of TrpV1, TrpV2, Nav1.3,
Nav1.7, Nav1.8, Nav1.9 and ASICs (acid sensing ion channels), as
well as P, Q, and N type calcium channels, such as ziconotide, and
non-specific sodium channel blockers, such as mexiletine,
lidocaine, cocaine, mepivacaine, prilocaine, bupivacaine and
eidocaine. Antidepressants may include amitriptyline,
nortryptiline, desipramine, paroxetine, citralopram, venlafaxine,
clomipramine, and bupropion. Antibodies directed toward proalgesic
antigens may include antibodies to endothelin, nerve growth factor,
vasoactive intestinal peptide (VIP) and pituitary adenylate
cyclase-activating polypeptide (PACAP). Antibodies directed toward
other neuropeptides may include antibodies to CGRP, CCK, substance
P and galanin. Other compounds may include, but are not limited to,
SNC 80, DPI-125, clonidine, dexmedetomidine, calcitonin, baclofen,
d-cycloserine, ergotamine, serotonin agonists and 5HT drugs. One
skilled in the art would know this list is not complete and it is
believed that one could contemplate and produce additional
peptides, polypeptides, non-peptidic compounds, small molecule
compounds, analogues and derivatives thereof which have analgesic
properties.
[0071] Accordingly, in some aspects of the invention, the analgesic
agent is an amino acid, a non-opioid peptide, a polypeptide, a
non-peptidic compound or a small molecule compound. In some
examples, two agents are administered in combination. In other
examples, more than two agents are administered in combination. The
agents may be administered at the same time or may be administered
at different times.
Administration
[0072] Chronic, acute or procedural pain associated with the
trigeminal nerve system is experienced in many syndromes and
diseases including, but not limited to, trigeminal neuralgia,
atypical facial pain, anesthesia dolorosa, post-herpetic neuralgia,
cancer of the head and neck, migraine headaches, other types of
headaches, temporomandibular joint pain, injuries to the face
and/or head, injuries or infections of the teeth, common dental
procedures and facial surgeries such as cosmetic plastic surgery.
It is believed that analgesic agents can be targeted to the
trigeminal nerve system and that this directed administration can
result in analgesia and pain relief for a individual suffering
acute, chronic or procedural facial or head pain.
[0073] The trigeminal nerve (fifth cranial nerve or CN V) is the
largest of the 12 cranial nerves and it is the principal general
sensory nerve to the head, particularly the face and is the motor
nerve to the muscles of mastication. The trigeminal nerve
innervates tissues of a mammal's (e.g. human) head including skin
of the face and scalp, oral tissues and tissues of and surrounding
the eye. The trigeminal nerve has three major branches or
divisions: the ophthalmic, the maxillary, and the mandibular
divisions. Thus, some aspects of the present invention include
methods for treating an individual for trigeminal nerve-associated
pain comprising administering to the individual an analgesic agent
wherein the administration of the analgesic agent is targeted to
one or more of the three major branches of the trigeminal nerve
including the ophthalmic, maxillary, and mandibular divisions.
[0074] The ophthalmic division is the superior division of the
trigeminal nerve, it is the smallest of the three branches and is
wholly sensory. The ophthalmic nerve has three branches known as
the nasociliary nerve, the frontal nerve, and the lacrimal nerve
which participate in the sensory supply to the skin of the
forehead, upper eyelid and nose. The nasociliary nerve further
divides into the anterior ethmoidal nerve and the infratrochlear
nerve, while the frontal nerve divides into the supratrochlear and
supraorbital nerves. The supratrochlear nerve supplies the middle
part of the forehead, and the supraorbital nerve supplies the
lateral part and the front of the scalp. The lacrimal nerve,
supplies the lacrimal gland and the lateral part of the upper
eyelid. Thus, in some aspects, methods of the invention involve
administration of an analgesic agent to the one or more of the
nerves branching from the ophthalmic nerve including the
nasociliary nerve, frontal nerve, lacrimal nerve, anterior
ethmoidal nerve, infratrochlear nerve, supratrochlear nerve and
supraorbital nerve.
[0075] The maxillary division is the intermediate division of the
trigeminal nerve. It has three cutaneous branches: the infraorbital
nerve which participates in the sensory supply to the skin on the
lateral aspect of the nose, upper lip, and lower eyelid; the
zygomaticofacial nerve, which supplies the skin of the face over
the zygomatic bone; and the zygomaticotemporal nerve which supplies
the skin over the temporal region. Thus, in some aspects, methods
of the invention involve administration of an analgesic agent to
the one or more of the nerves branching from the maxillary nerve
including infraorbital, zygomaticofacial and
zygomaticotemporal.
[0076] The mandibular division is the inferior division of the
trigeminal nerve. It has three sensory branches: the buccal nerve
supplies the skin of the cheek over the buccinator muscle. It also
supplies the mucous membrane lining of the cheek and the posterior
part of the buccal surface of the gingiva (gum). The
auriculotemporal nerve supplies parts of the auricle, the external
acoustic meatus, the tympanic membrane (eardrum) and the skin in
the temporal region. The inferior alveolar nerve further divides
into the incisive nerve and the mental nerve. The incisive nerve
supplies the incisor teeth, the adjacent gingiva, and the mucosa of
the lower lip and the mental nerve supplies the skin of the chin,
the skin and mucosa membrane of the lower lip and gingiva. The
lingual nerve supplies general sensory fibers to the anterior
two-thirds of the tongue, the floor of the mouth, and the gingiva
of the mandibular teeth. Thus, in some aspects, methods of the
invention involve administration of an analgesic agent to one or
more of the nerves branching from the mandibular nerve including
buccal, auriculotemporal, inferior alveolar, incisive, mental and
lingual.
[0077] Accordingly, some aspects of the invention include methods
for treating an individual for trigeminal nerve-associated pain
comprising administering to the individual an analgesic agent to
mucosa tissue or epithelium within the oral cavity, within or
around the eye or to the skin. The methods can include
administering an agent to oral tissues wherein the analgesic agent
is targeted to mucosal tissue innervated by a trigeminal division,
for example the mandibular division. The oral mucosal tissues
include, but are not limited to, the gingiva (gums), the floor of
the oral cavity, the cheeks, the lips, the tongue, the teeth or a
combination thereof. The methods can include administering an agent
to conjunctiva or other mucosal tissues around the eye wherein the
analgesic agent is targeted to mucosal tissue or epithelium
innervated by a trigeminal division, for example the ophthalmic or
maxillary division. The tissues or epithelium include, but are not
limited to, the conjunctiva, the lacrimal gland, the nasolacrimal
ducts, the mucosa of the upper or lower eyelid, the eye, or a
combination thereof. An agent that is administered to the
conjunctiva but not absorbed completely through the conjunctival
mucosa can drain through the nasolacrimal ducts into the nose
wherein it can be absorbed by mucosal tissue innervated by the
trigeminal nerve within the nasal cavity. The methods can include
administering an agent to skin of the face or head wherein the
analgesic agent is targeted to tissue innervated by one of the
trigeminal divisions. The agent can be administered to the skin of
the face, scalp or temporal region. Suitable skin of the face
includes skin of the chin, the upper lip, the lower lip, the
forehead, the nose, the cheek, the skin around the eyes, the upper
eyelid, the lower eyelid or combinations thereof. Suitable skin of
the scalp includes the front of the scalp, the scalp over the
temporal region, the lateral part of the scalp, or combinations
thereof. Suitable skin of the temporal region includes the temple
and the scalp over the temporal region and combinations
thereof.
[0078] Within the nasal cavity, the trigeminal nerve innervates
mainly the inferior two-thirds of the nasal mucosa, while the
olfactory nerve innervates the superior upper third of the nasal
mucosa. There are primary afferent somotosensory neuronal fibers in
the trigeminal nerve which allows for craniofacial somatosensory
information including touch, temperature, proprioception (position
sense) and pain. Those that are involved in pain (nociception) are
termed "nociceptors". In contrast, there are no nociceptors or
other somatosensory primary afferents in the olfactory nerve which
is essentially devoted to the sense of smell and pheromone
detection. The anterior ethmoidal nerve, a branch of the
nasociliary nerve, innervates, among other tissues, the ethmoidal
sinus and regions of the inferior two-thirds of the nasal mucosa,
including the anterior portion of the nasal septum and the lateral
wall of the nasal cavity. The maxillary division has several
branches that innervate the nasal cavity and sinuses, including the
nasopalatine nerve, the greater palatine nerve, the posterior
superior alveolar nerves, the middle superior alveolar nerve and
the anterior superior alveolar nerve. The maxillary sinus is
innervated by the posterior, middle and anterior superior alveolar
nerves. The mucous membrane of the nasal septum is supplied chiefly
by the nasopalatine nerve and the lateral wall of the nasal cavity
is supplied by the greater palatine nerve.
[0079] Accordingly, some aspects of the invention include methods
for treating an individual for trigeminal nerve-associated pain
comprising administering to the individual an analgesic agent to
mucosa tissue within the nasal cavity. In some examples, the
methods include administration of an analgesic agent to the
inferior two-thirds of the nasal cavity wherein the analgesic agent
is targeted to mucosal tissue innervated by the trigeminal nerve
and away from the olfactory nerve. In some examples, the methods
include administration of an analgesic agent to the inferior
two-thirds of the nasal cavity wherein the analgesic agent
preferentially binds to opioid receptors within the trigeminal
nerves. In some examples, the methods also include administration
of an analgesic agent to the inferior two-thirds of the nasal
cavity wherein the analgesic agent preferentially binds to
non-opioid receptors within the trigeminal nerve system. Thus, in
some aspects of the invention, methods involve administration of an
analgesic agent to one or more of the nerves branching from the
maxillary division that innervate the nasal cavity including
nasopalatine, greater palatine, posterior superior alveolar, middle
superior alveolar and anterior superior alveolar.
[0080] Intranasal drug delivery has been a topic of research and
development for many years, although it has been only within the
past decade that carrier systems have been devised which make
delivery of substances effective. (Sayani and Chien (1996) Critical
Reviews in Therapeutic Drug Carrier Systems, 13:85-184.)
[0081] Intranasal delivery of analgesic agents has a number of
advantageous features including comparatively high bioavailability,
rapid kinetics of absorption and avoidance of liver first-pass
effect. In regard to patient compliance and ease of use, intranasal
administration provides a simple, rapid and non-invasive mode of
application. In particular, intranasal delivery can allow for
targeted delivery of an analgesic agent to the nasal cavity and to
the trigeminal nerve system to treat or prevent trigeminal
nerve-associated pain. Furthermore, targeted delivery to the
trigeminal nerve system and preferably not the olfactory region can
reduce the amount of drug entering the CNS or systemic circulation
thereby reducing or eliminating CNS effects or systemic side
effects. Targeted delivery to the trigeminal nerve system can
reduce the effective dosage necessary to achieve-analgesia in the
facial or head regions wherein lower effective dosages will further
reduce CNS or systemic side effects.
[0082] Accordingly, some aspects of the present invention include
methods for treating an individual for trigeminal nerve-associated
pain comprising administering to the individual an analgesic agent
by intranasal administration wherein the administration is targeted
to the trigeminal nerve system and results predominantly in
analgesia to the facial or head region, particularly as compared to
analgesic effects in other parts of the body. The methods can
administer an analgesic agent to the nasal cavity of an individual,
in particular to the inferior two-thirds of the nasal cavity, to
promote delivery to the trigeminal nerve system with minimal
delivery to the olfactory nerve.
[0083] Within the oral cavity, the buccal or sublingual delivery
routes are convenient choices for drug delivery as they are
user-friendly and non-invasive. Some of the advantages include i)
less proteolytic activity in the oral cavity as compared to some
other routes thereby avoiding the problems of enzymatic degradation
of peptide and protein drugs and ii) bypassing the liver first pass
effect. In particular, buccal or sublingual delivery can allow for
targeted delivery of an analgesic agent to the oral mucosa and to
the trigeminal divisions that innervate the oral mucosa to treat or
prevent trigeminal nerve-associated pain. Targeted delivery to a
trigeminal division can reduce the effective dosage necessary to
achieve analgesia in the facial or head regions wherein lower
effective dosages will further reduce CNS effects or systemic side
effects.
[0084] Accordingly, some aspects of the present invention include
methods for treating an individual for trigeminal nerve-associated
pain comprising administering to the individual an analgesic agent
by buccal or sublingual administration wherein the administration
is targeted to a trigeminal division and results predominantly in
analgesia to the facial or head region. The methods involve
administration of an analgesic agent to the oral cavity of an
individual to promote delivery to the trigeminal nerve with minimal
systemic distribution.
[0085] Drug delivery to the mucosal tissue around the eye or to the
conjunctiva is another convenient choice for drug delivery that is
non-invasive. In particular, administration to the mucosa or
epithelium of the eyelids, the conjunctiva or the lacrimal system
can allow for targeted delivery of an analgesic agent to the mucosa
and tissues innervated by trigeminal divisions to treat or prevent
trigeminal nerve-associated pain. Targeted delivery to a trigeminal
division can reduce the effective dosage necessary to achieve
analgesia in the facial or head regions wherein lower effective
dosages will further reduce CNS effects or systemic side
effects.
[0086] Accordingly, some aspects of the present invention include
methods for treating an individual for trigeminal nerve-associated
pain comprising administering to the individual an effective amount
of an analgesic agent to the conjunctiva or other mucosal tissues
around the eye wherein the administration is targeted to a
trigeminal division and results predominantly in analgesia to the
facial or head region.
[0087] Transdermal drug delivery or administration of a therapeutic
agent to the skin has become a proven technology over the last 20
years. Transdermal drug delivery offers controlled release of a
drug to the patient and transdermal patches are user-friendly,
convenient, painless, and offer multi-day dosing which usually
results in improved patient compliance. Administration to the skin
by transdermal delivery can allow for targeted delivery of an
analgesic agent to the skin innervated by any one of the trigeminal
divisions or a combination thereof to treat or prevent trigeminal
nerve-associated pain in the facial or head regions.
[0088] Accordingly, some aspects of the present invention include
methods for treating an individual for trigeminal nerve-associated
pain comprising administering to the individual an effective amount
of an analgesic agent to the skin of the face, head or scalp
wherein the administration is targeted to the trigeminal nerve
system and results predominantly in analgesia to the facial or head
region. In some examples, the analgesic agent is administered to
particular sites on the face or scalp to promote delivery to
particular trigeminal divisions.
[0089] In some aspects of the invention a vasoconstrictor is used
to decrease systemic distribution of the analgesic agent. The
vasoconstrictor can be included in a pharmaceutical composition to
decrease systemic distribution of the analgesic agent.
Alternatively, the vasoconstrictor may be delivered to the mucosal
or dermal surface separately from the pharmaceutical composition.
Vasoconstrictors are compounds that constrict blood vessels and
capillaries and decrease blood flow. They can be used to increase
concentration of an agent at a desired site by inhibiting movement
of the analgesic agent into the bloodstream and thereby reducing
systemic distribution of the agent. Vasoconstrictors can be used to
decrease the effective dosage of agent needed to achieve analgesia
by limiting systemic distribution and concentrating the agent in
the trigeminal nerve. A vasoconstrictor can be administered before
administration of the analgesic agent or can be co-administered
with the analgesic agent. Vasoconstrictors may include, but are not
limited to, phenylephrine hydrochloride, tetrahydrozoline
hydrochloride, naphazoline nitrate, oxymetazoline hydrochloride,
tramazoline hydrochloride, endothelin-1, endothelin-2, epinephrine,
norepinephrine and angiotensin.
[0090] In some examples of the invention, methods involve
administration of a vasoconstrictor to the oral cavity of an
individual prior to administration of an analgesic agent to the
oral cavity, wherein administration of the vasoconstrictor
decreases systemic distribution of the analgesic agent thereby
minimizing undesirable CNS effects or systemic side effects. In
other examples, methods involve administration of a vasoconstrictor
and an analgesic agent to the oral cavity of an individual. A
vasoconstrictor may be administered to the oral cavity of an
individual prior to or at the same time as an analgesic agent,
wherein administration of the vasoconstrictor decreases systemic
distribution of the analgesic agent thereby decreasing the
effective dosage amount of analgesic agent necessary to achieve
analgesia to the facial or head region.
[0091] In some examples of the invention, methods involve
administration of a vasoconstrictor to the nasal cavity of an
individual prior to administration of an analgesic agent to the
nasal cavity, wherein administration of the vasoconstrictor
decreases systemic distribution of the analgesic agent thereby
minimizing undesirable CNS effects or systemic side effects. The
methods can co-administer a vasoconstrictot and an analgesic agent
to the nasal cavity of an individual, wherein administration of the
vasoconstrictor decreases systemic distribution of the analgesic
agent thereby minimizing undesirable CNS or systemic side effects.
The methods can administer a vasoconstrictor to the nasal cavity of
an individual prior to or co-administer with an analgesic agent,
wherein administration of the vasoconstrictor decreases systemic
distribution of the analgesic agent thereby decreasing the
effective dosage amount of analgesic agent necessary to achieve
analgesia to the facial or head region.
Pharmaceutical Composition
[0092] While it is possible to administer an analgesic agent alone,
there are situations wherein it is advantageous to present it as
part of a pharmaceutical composition. Thus, in some aspects of the
present invention, the analgesic agent is administered as a
pharmaceutical composition. The pharmaceutical composition can
comprise an analgesic agent at a therapeutically effective dose
together with one or more pharmaceutically acceptable carriers and
optionally other ingredients. A suitable carrier is one which does
not cause an intolerable side effect, but which allows the
analgesic agent to retain its pharmacological activity in the body.
A carrier may also reduce any undesirable side effects of the
agent. A suitable carrier should be stable, i.e., incapable of
reacting with other ingredients in the formulation. A suitable
carrier should have minimal odor or fragrance or fragrance or a
positive (pleasant) odor. A suitable carrier should not irritate
the mucosa, epithelium, underlying nerves or provide a health risk.
It may be an accepted transcutaneous or percutaneous carrier or
vehicle, because any carrier that can effectively penetrate the
stratum corneum of the skin should be highly efficacious in not
only penetrating mucosa, but also allowing rapid absorption of
substances into the submucosal tissues, nerve sheaths and
nerves.
[0093] Suitable nontoxic pharmaceutically acceptable carriers will
be apparent to those skilled in the art of pharmaceutical
formulations. Also see Remington: The Science and Practice of
Pharmacy, 20th Edition, Lippincott, Williams & Wilkins (2000).
Typical pharmaceutically acceptable carriers include, but are not
limited to, mannitol, urea, dextrans, lactose, potato and maize
starches, magnesium stearate, talc, vegetable oils, polyalkylene
glycols, ethyl cellulose, poly(vinylpyrrolidone), calcium
carbonate, chitosan, ethyl oleate, isopropyl myristate, benzyl
benzoate, sodium carbonate, gelatin, potassium carbonate, silicic
acid, and other conventionally employed acceptable carriers. Other
carriers include, but are not limited to, phosphatidylcholine,
phosphatidylserine, and sphingomyelins.
[0094] The choice of a suitable carrier will depend on the exact
nature of the particular formulation desired, e.g., whether the
drug is to be formulated into a liquid solution (e.g., for use as
drops, as a spray or impregnated in a nasal tampon, or other
agent-impregnated solid), a suspension, a ointment or a gel. If
desired, sustained-release compositions, e.g. sustained-release
gels, transdermal patches, etc. can be readily prepared. The
particular formulation will also depend on the route of
administration. The agent can be administered to the nasal cavity
as a powder, a granule, a solution, a film, a cream, a spray, a
gel, an ointment, an infusion, a drop or a sustained-release
composition. For buccal administration, the composition can take
the form of tablets or lozenges formulated in a convention manner.
For sublingual administration, the composition can take the form of
a bioadhesive, a spray, paint or a swab applied to or under the
tongue. For administration to the conjunctiva or other mucosal
tissues around the eye, the composition can be applied as an
ointment, a solution or a drop. For administration to the skin, the
composition can be applied as a topical ointment, a topical gel, a
cream, a lotion, a solution, a spray, a paint, a film, a foil, a
cosmetic, a patch or a bioadhesive.
[0095] Liquid carriers include, but are not limited to, water,
saline, aqueous dextrose, and glycols particularly (when isotonic)
for solutions. The carrier can be also be selected from various
oils, including those of petroleum, animal, vegetable or synthetic
origin, (e.g. peanut oil, soybean oil, mineral oil, sesame oil, and
the like). Suitable pharmaceutical excipients include, but are not
limited to, starch, cellulose, talc, glucose, lactose, sucrose,
gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate,
sodium stearate, glycerol monostearate, sodium chloride, dried skim
milk, glycerol, propylene glycol, water, ethanol, and the like. The
compositions can be subjected to conventional pharmaceutical
expedients, such as sterilization, and can contain conventional
pharmaceutical additives, such as preservatives, stabilizing
agents, reducing agents, anti-oxidants, chelating agents, wetting
agents, emulsifying agents, dispersing agents, jelling agents,
salts for adjusting osmotic pressure, buffers, and the like. Where
the carrier is a liquid, it is preferred that the carrier be
hypotonic or isotonic with body fluids and have a pH within the
range of 4.5-8.5. Where the carrier is in powdered form, it is
preferred that the carrier be within an acceptable non-toxic pH
range. The use of additives in the preparation of peptide and/or
protein-based compositions, particularly pharmaceutical
compositions, is well-known in the art.
[0096] These lists of carriers and additives are by no means
complete and a worker skilled in the art can choose excipients from
the GRAS (generally regarded as safe) list of chemicals allowed in
the pharmaceutical preparations and those that are currently
allowed in topical and parenteral formulations. (See also Wang et
al., (1980) J. Parent. Drug Assn., 34:452-462; Wang et al., (1988)
J. Parent. Sci. and Tech., 42:S4-S26.)
[0097] Other forms of compositions for administration include a
suspension of a particulate, such as an emulsion, a liposome, or in
a sustained-release form to prolong the presence of the
pharmaceutically active agent in an individual. The powder or
granular forms of the pharmaceutical composition may be combined
with a solution and with a diluting, dispersing or surface-active
agent. Additional compositions for administration include a
bioadhesive to retain the agent at the site of administration, for
example a spray, paint, or swab applied to the mucosa or
epithelium. A bioadhesive can refer to hydrophilic polymers,
natural or synthetic, which, by the hydrophilic designation, can be
either water soluble or swellable and which are compatible with the
pharmaceutical composition. Such adhesives function for adhering
the formulations to the mucosal tissues of the oral or nasal
cavity. Such adhesives can include, but are not limited to,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxy
ethylcellulose, ethylcellulose, carboxymethyl cellulose, dextran,
gaur gum, polyvinyl pyrrolidone, pectins, starches, gelatin,
casein, acrylic acid polymers, polymers of acrylic acid esters,
acrylic acid copolymers, vinyl polymers, vinyl copolymers, polymers
of vinyl alcohols, alkoxy polymers, polyethylene oxide polymers,
polyethers, and combinations thereof. The composition can also be
in the form of lyophilized powder, which can be converted into
solution, suspension, or emulsion before administration. The
pharmaceutical composition is preferably sterilized by membrane
filtration and is stored in unit-dose or multi-dose containers such
as sealed vials or ampoules.
[0098] The pharmaceutical composition can be formulated in a
sustained-release form to prolong the presence of the active agent
in the treated individual. Many methods of preparation of a
sustained-release formulation are known in the art and are
disclosed in Remington's Pharmaceutical Sciences (see above).
Generally, the agent can be entrapped in semi-permeable matrices of
solid hydrophobic polymers. The matrices can be shaped into films
or microcapsules. Matrices can include, but are not limited to,
polyesters, co-polymers of L-glutamic acid and gamma
ethyl-L-glutamate, polylactides, polylactate polyglycolate,
hydrogels, non-degradable ethylene-vinyl acetate, degradable lactic
acid-glycolic acid copolymers, hyaluronic acid gels, and alginic
acid suspensions. Suitable microcapsules can also include
hydroxymethylcellulose or gelatin and poly-methyl methacrylate.
Microemulsions or colloidal drug delivery systems such as liposomes
and albumin microspheres can also be used. Some sustained-release
compositions can use a bioadhesive to retain the agent at the site
of administration.
[0099] To further enhance the mucosal delivery of a pharmaceutical
composition comprising an analgesic agent, an enzyme inhibitor,
particularly proteases inhibitors, can be included in the
formulation. Protease inhibitors may include, but are limited to,
antipain, arphamenine A and B, benzamidine HCl, AEBSF, CA-074,
calpain inhibitor I and II, calpeptin, pepstatin A, actinonin,
amastatin, bestatin, boroleucine, captopril,
chloroacetyl-HOLeu-Ala-Gly-NH2, DAPT, diprotin A and B, ebelactone
A and B, foroxymithine, leupeptin, pepstatin A, phosphoramidon,
aprotinin, puromycin, BBI, soybean trypsin inhibitor,
phenylmethylsulfonyl fluoride, E-64, chymostatin,
1,10-phenanthroline, EDTA and EGTA.
[0100] To enhance delivery into or across a mucosal surface and/or
absorption of a pharmaceutical composition comprising an analgesic
agent, an absorption-enhancing agent can be included in the
formulation. These enhancing agents may enhance the release or
solubility (e.g., from a formulation delivery vehicle), diffusion
rate, penetration capacity and timing, uptake, residence time,
stability, effective half-life, peak or sustained concentration
levels, clearance and other desired mucosal delivery
characteristics (e.g., as measured at the site of delivery) of the
composition. Enhancement of mucosal delivery can thus occur by any
of a variety of mechanisms, for example by increasing the
diffusion, transport, persistence or stability of an analgesic
agent, increasing membrane fluidity, modulating the availability or
action of calcium and other ions that regulate intracellular or
paracellular permeation, solubilizing mucosal membrane components
(e.g., lipids), changing non-protein and protein sulfhydryl levels
in mucosal tissues, increasing water flux across the mucosal
surface, modulating epithelial junctional physiology, reducing the
viscosity of mucus overlying the mucosal epithelium, reducing
mucociliary clearance rates, and other mechanisms.
[0101] Mucosal absorption enhancing compounds may include, but are
not limited to, surfactants, bile salts, dihydrofusidates,
bioadhesive agents, phospholipid additives, mixed micelles,
liposomes, or carriers, alcohols, enamines, cationic polymers, NO
donor compounds, long-chain amphipathic molecules, small
hydrophobic penetration enhancers; sodium or a salicylic acid
derivatives, glycerol esters of acetoacetic acid, cyclodextrin or
beta-cyclodextrin derivatives, medium-chain fatty acids, chelating
agents, amino acids or salts thereof, N-acetylamino acids or salts
thereof, mucolytic agents, enzymes specifically targeted to a
selected membrane component, inhibitors of fatty acid synthesis and
inhibitors of cholesterol synthesis.
[0102] These additional agents and compounds can be coordinately
administered or combinatorially formulated with the analgesic
agents. Accordingly, some aspects of the present invention include
methods wherein the analgesic agent is administered as a
pharmaceutical composition that comprises protease inhibitors,
absorption enhancers, vasoconstrictors or combinations thereof. The
pharmaceutical composition can be administered to the nasal cavity,
oral cavity, to conjunctiva or other mucosal tissues around the eye
or to the skin. The pharmaceutical composition can be administered
by an intranasal route. The pharmaceutical composition can be
administered by a buccal or sublingual route. The pharmaceutical
composition can be administered by a transdermal route. The
pharmaceutical composition can include at least one protease
inhibitor, at least one absorption enhancer, at least one
vasoconstrictor or combinations thereof. The pharmaceutical
composition can be co-administered with a vasoconstrictor or
administered after the vasoconstrictor has been delivered.
Delivery Systems
[0103] An analgesic agent or pharmaceutical composition comprising
an analgesic agent may be dispensed to the buccal or sublingual
surfaces in a number of different formulations or dosage forms
including, but not limited to, fast-melting tablets, liquid-filled
capsules, liquid sprays or lozenges. Alternatively, the
pharmaceutical composition can be delivered to the mucosa of the
oral cavity by direct placement of the composition in the mouth,
for example, with a gel, an ointment, a dropper, or a bioadhesive
strip or patch.
[0104] In some aspects of the present invention, the methods
comprise administering to an individual a pharmaceutical
composition wherein administration to the buccal and/or sublingual
mucosal surfaces of the oral cavity is by a delivery device. The
delivery device can include, but is not limited to, unit dose
containers, pump sprays, droppers, squeeze bottles, airless and
preservative-free sprays, nebulizers, dose inhalers and pressurized
dose inhalers. The delivery device can be metered to administer an
accurate effective dosage amount (as described below) to the oral
cavity. In some aspects, an accurate effective dosage amount is
contained within a capsule, tablet, lozenge, or bioadhesive patch
that is placed directly within the oral cavity.
[0105] An analgesic agent or pharmaceutical composition may be
dispensed to the conjunctiva or to other mucosal tissues around the
eye in a number of different formulations such as a liquid drop, a
gel, an ointment or a bioadhesive patch or strip. Thus, in some
aspects of the present invention the methods comprise administering
to an individual a pharmaceutical composition wherein
administration is directed to the conjunctiva or other mucosal
tissues around the eye. In some aspects, an accurate effective
dosage amount is contained within a drop, a gel, an ointment or a
bioadhesive patch that is placed directly onto the mucosal tissues
around the eye.
[0106] An analgesic agent or pharmaceutical composition may be
administered to the skin or scalp in a number of different
formulations such as a liquid, a spray, a gel, an ointment or a
bioadhesive patch or strip. Thus, in some aspects of the present
invention the methods comprise administering to an individual a
pharmaceutical composition wherein administration is directed to
the skin of the face or scalp. In some aspects, an accurate
effective dosage amount is contained within a drop, a gel, an
ointment or a bioadhesive transdermal patch that is placed directly
onto the skin.
[0107] An analgesic agent or pharmaceutical composition may be
dispensed intranasally as a powdered or liquid nasal spray,
suspension, nose drops, a gel or ointment, through a tube or
catheter, by syringe, by packtail, by pledget (a small flat
absorbent pad), by nasal tampon or by submucosal infusion. Nasal
drug delivery can be carried out using devices including, but not
limited to, unit dose containers, pump sprays, droppers, squeeze
bottles, airless and preservative-free sprays, nebulizers (devices
used to change liquid medication to an aerosol particulate form),
metered dose inhalers, and pressurized metered dose inhalers. It is
important that the delivery device protect the drug from
contamination and chemical degradation. The device should also
avoid leaching or absorption as well as provide an appropriate
environment for storage. Each drug needs to be evaluated to
determine which nasal drug delivery system is most appropriate.
Nasal drug delivery systems are known in the art and several are
commercially available.
[0108] The composition may be conveniently delivered in the form of
an aerosol spray using a pressurized pack or a nebulizer and a
suitable propellant including, but not limited to,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, hydrocarbons, compressed air, nitrogen
or carbon dioxide. An aerosol system requires the propellant to be
inert towards the pharmaceutical composition. In the case of a
pressurized aerosol, the dosage unit may be controlled by providing
a valve to deliver an accurately metered amount.
[0109] The means to deliver the analgesic agent to the nasal cavity
as a powder can be in a form such as microspheres delivered by a
nasal insufflator device (a device to blow a gas, powder, or vapor
into a cavity of the body) or pressurized aerosol canister. The
insufflator produces a finely divided cloud of the dry powder or
microspheres. The insufflator may be provided with means to ensure
administration of a substantially metered amount of the
pharmaceutical composition. The powder or microspheres should be
administered in a dry, air-dispensable form. The powder or
microspheres may be used directly with an insufflator which is
provided with a bottle or container for the powder or microspheres.
Alternatively the powder or microspheres may be filled into a
capsule such as a gelatin capsule, or other single dose device
adapted for nasal administration. The insufflator can have means
such as a needle to break open the capsule or other device to
provide holes through which jets of the powdery composition can be
delivered to the nasal cavity.
[0110] Nasal delivery devices can be constructed or modified to
dispense the pharmaceutical composition wherein the composition is
delivered predominantly to the inferior two-thirds of the nasal
cavity. For example, the angle of dispersion from a delivery device
such as a nebulizer or an insufflator can be set so that the
pharmaceutical composition is mechanically directed to the inferior
two-thirds of the nasal cavity, and preferably away from the
superior region of the nasal cavity. Alternatively, the
pharmaceutical composition can be delivered to the inferior
two-thirds of the nasal cavity by direct placement of the
composition in the nasal cavity, for example, with a gel, an
ointment, a nasal tampon, a dropper, or a bioadhesive strip.
[0111] Thus in some aspects of the present invention, the methods
comprise administering to an individual a pharmaceutical
composition wherein administration to the nasal cavity is by a
nasal delivery device. The nasal delivery device can include, but
is not limited to, unit dose containers, pump sprays, droppers,
squeeze bottles, airless and preservative-free sprays, nebulizers,
dose inhalers, pressurized dose inhalers, insufflators, and
bi-directional devices. The nasal delivery device can be metered to
administer an accurate effective dosage amount (as described below)
to the nasal cavity. The nasal delivery device can be for single
unit delivery or multiple unit delivery. In some aspects of the
present invention, the nasal delivery device can be constructed
whereby the angle of dispersion of a pharmaceutical composition is
mechanically directed towards the inferior two-thirds of the nasal
cavity thereby minimizing delivery to the olfactory region. The
nasal delivery device can be constructed whereby the angle of
dispersion of a pharmaceutical composition is mechanically directed
towards the inferior two-thirds of the nasal cavity thereby
maximizing delivery of the agent to opioid receptors in the
trigeminal nerve. In some aspects of the present invention, the
pharmaceutical composition is a gel, cream, ointment, impregnated
in a nasal tampon or bioadhesive strip whereby the composition is
placed in the inferior two-thirds of the nasal cavity. In some
aspects of the present invention, the methods include intranasal
administration of an analgesia agent wherein the administration
uses a nasal delivery device with an angle of dispersion that
mechanically directs the agent to the inferior two-thirds of the
nasal cavity wherein the analgesic agent is administered after a
vasoconstrictor. In some aspects of the present invention, the
methods include intranasal administration of an analgesia agent
wherein the administration uses a nasal delivery device with an
angle of dispersion that mechanically directs the agent to the
inferior two-thirds of the nasal cavity wherein the analgesic agent
is co-administered with a vasoconstrictor.
Dosages
[0112] An analgesic agent is administered in a dose sufficient to
provide a therapeutically effective amount to the trigeminal nerve
system that results predominantly in analgesia to the facial or
head region of an individual suffering from trigeminal
nerve-associated pain. In particular, the analgesic agent can be
administered in a dose that results in analgesia to the facial or
head regions with minimal CNS effects or systemic side effects. The
analgesic agent can be administered in a dose that results in
analgesia predominantly to the facial or head regions as compared
to analgesic effects in other parts of the body. A therapeutically
effective dose of an analgesic agent can be determined empirically
and depends on the analgesic agent, the type and severity of the
pain, the route of administration, the state of disease
progression, and the size/weight and overall health of the patient.
In particular, a therapeutically effective dose of an analgesic
agent which results in regional analgesia with minimal CNS effects
or systemic side effects can be determined empirically and will
depend on the same described parameters.
[0113] The amount of an analgesic agent administered as a unit dose
will depend upon the type of pharmaceutical composition being
administered, for example, a solution, a suspension, a gel, an
emulsion, a powder, or a sustained-release formulation. Generally
the effective dosage will be lower than dose amounts needed for
oral, intravenous, intramuscular or subcutaneous administration of
the analgesic agent involved, since targeted delivery will allow
for a more concentrated level of the analgesic agent in the
trigeminal nerve. The effective dosage will be lower than dosage
amounts generally used for other common analgesic opioid drugs, for
example, morphine. The quantity of dosage form needed to deliver
the desired dose will depend on the concentration of the analgesic
agent in the composition. Such determinations are within the skill
of one in the art.
[0114] The therapeutic dosage of an analgesic agent in the
pharmaceutical compositions used in the methods of the present
invention will depend on a number of factors such as the particular
analgesic agent chosen, its bioavailability by the chosen route of
administration, its efficacy, and the desired frequency of
administration combined with the desired single dosage of the
formulation. Particularly, dosage of the analgesic agent will be
chosen to maximize analgesia to the facial and head regions and
minimize CNS effects or systemic side effects. Such pharmacological
data can be obtained from animal models and clinical trials with
normal human volunteers or patients experiencing trigeminal
nerve-associated pain by one with skill in the art.
[0115] Experimental models to test for analgesic activity of agents
are known in the art. Animal models comprise tests which include,
but are not limited to, acetic acid writhing, phenylquinone
writhing, tail-flick, paw withdrawal and ear or face withdrawal
wherein the pain receptor activation is induced by such compounds
as acetic acid, phenylquinone, formalin or capsaicin, or by thermal
activators such as a hot plate or a laser. In particular, models
for facial or head pain utilizing tests such as orofacial delivery
of capsaicin, orofacial delivery of formalin, or delivery of
thermal heat to the trigeminally innervated tissue, such as the
face or part of the ear are available. Models can be used to
determine optimal dosage ranges wherein an analgesic agent
delivered to the trigeminal nerve results in analgesia in the
facial or head region with minimal analgesia at a systemic site,
i.e. the paw. Further, models can be used to administer an
analgesic agent by a particular delivery route, e.g. intranasally,
and test for analgesic effect at the ears and at the hindpaws.
Thus, one model can be used to test for analgesic activity of an
analgesic agent after administration of a pharmaceutical
composition to the trigeminal nerve. Withdrawal latencies at the
ear or face will determine localized analgesia while withdrawal
latencies at the hindpaw will determine systemic distribution and
analgesia.
[0116] As stated above, an effective amount of an analgesic agent
will depend on the analgesic agent being used in the method.
Preferably the effective amount of an analgesic agent administered
transmucosally or transdermally to the trigeminal nerve is lower
than dosages used when the agent is delivered by other routes (e.g.
oral, intravenous, intramuscular or subcutaneous). For example,
dosages used for administration of an enkephalin peptide can
include, but are not limited to, an effective amount within the
dosage range of about 0.01 ng per kg body weight to about 50 .mu.g
per kg body weight, or within 0.1 ng per kg body weight to about 50
.mu.g per kg body weight, or within 1 ng per kg body weight to
about 50 .mu.g per kg body weight, or within about 10 ng per kg
body weight to about 50 .mu.g per kg body weight, or within about
0.1 .mu.g per kg body weight to about 50 .mu.g per kg body weight,
or within about 1 .mu.g per kg body weight to about 50 .mu.g per kg
body weight.
[0117] Dosages used for administration of an endophorin peptide can
include, but are not limited to, an effective amount within the
dosage range of about 0.4 .mu.g per kg body weight to about 4 mg
per kg body weight, or within 4 .mu.g per kg body weight to about
400 .mu.g per kg body weight, or within 4 .mu.g per kg body weight
to about 200 .mu.g per kg body weight, or within 10 .mu.g per kg
body weight to about 100 .mu.g per kg body weight.
[0118] Dosages used for administration of an endomorphin peptide
can include, but are not limited to, an effective amount within the
dosage range of about 0.15 nmol per kg body weight to about 1.5
.mu.mol per kg body weight, or within 1.5 nmol per kg body weight
to about 150 nmol per kg body weight, or within 1 nmol per kg body
weight to about 100 nmol per kg body weight, or within 1 nmol per
kg body weight to about 50 nmol per kg body weight.
[0119] Dosages used for intranasal administration of a dynorphin
peptide can include, but are not limited to, an effective amount
within the dosage range of about 10 nmol per kg body weight to
about 100 .mu.mol per kg body weight, or within 100 nmol per kg
body weight to about 50 .mu.mol per kg body weight, or within 250
nmol per kg body weight to about 25 .mu.mol per kg body weight, or
within 0.5 .mu.mol per kg body weight to about 5 .mu.mol per kg
body weight.
[0120] Dosages used for administration of an oxytocin peptide can
include, but are not limited to, an effective amount within the
dosage range of about 0.1 IU to about 150 IU, or within 1 IU to
about 100 IU, or within 10 IU to about 80 IU, or within about 25 IU
to about 50 IU, or within about 1 IU to about 40 IU, or within
about 1 IU to about 30 IU, or within about 4 IU to about 16 IU, or
within about 4 IU to about 24 IU.
[0121] Dosages used for administration of octreotide can include,
but are not limited to, an effective amount within the dosage range
of about 0.1 mg to about 200 mg, or within 0.1 mg to about 100 mg,
or within 0.5 mg to about 100 mg, or within about 0.5 mg to about
75 mg, or within about 1 mg to about 50 mg, or within about 1 mg to
about 25 mg, or within about 1 mg to about 20 mg, or within about 1
mg to about 10 mg.
[0122] Dosages can be administered in a single dose or in multiple
doses, for example, dosages can be administered two, three, four,
up to ten times daily depending on the analgesic agent and the type
of pain being treated. Dosages can be administered in a sustained
release formulation which allows for the analgesic agent to be
administered less frequently such as six times a week, five times a
week, four times a week, three times a week, twice a week, or once
a week.
[0123] Thus some aspects of the present invention include methods
for treating an individual for trigeminal nerve-associated pain
comprising administering to the individual an effective amount of
an analgesic agent wherein the administration is targeted to the
trigeminal nerve system and results predominantly in analgesia to
the facial or head region with minimal CNS effects or systemic side
effects. The analgesic agent can be an enkephalin with a dosage
range of about 0.01 ng per kg body weight to about 50 .mu.g per kg
body weight, or within 0.1 ng per kg body weight to about 50 .mu.g
per kg body weight, or within 1 ng per kg body weight to about 50
.mu.g per kg body weight, or within about 10 ng per kg body weight
to about 50 .mu.g per kg body weight, or within about 0.1 .mu.g per
kg body weight to about 50 .mu.g per kg body weight, or within
about 1 .mu.g per kg body weight to about 50 .mu.g per kg body
weight. The analgesic agent can be an endorphin with a dosage range
of about 0.4 .mu.g per kg body weight to about 4 mg per kg body
weight, or within 4 .mu.g per kg body weight to about 400 .mu.g per
kg body weight, or within 4 .mu.g per kg body weight to about 200
.mu.g per kg body weight, or within 10 .mu.g per kg body weight to
about 100 .mu.g per kg body weight. The analgesic agent can be
oxytocin with a dosage range of about 0.1 IU to about 150 IU, or
within 1 IU to about 100 IU, or within 10 IU to about 80 IU, or
within about 25 IU to about 50 IU, or within about 1 IU to about 40
IU, or within about 1 IU to about 30 IU, or within about 4 IU to
about 16 IU, or within about 4 IU to about 24 IU.
[0124] To determine the therapeutic effect of an analgesic agent
the "visual analogue scale" (VAS) may be used to assess the
reduction or alleviation of pain. VAS is a 10 cm horizontal or
vertical line with word anchors at each end, such as "no pain" and
"pain as bad as it could be". A subject or patient is asked to make
a mark on the line to represent pain intensity. This mark is
converted to distance in either centimeters or millimeters from the
"no pain" anchor to give a pain score that can range from 0-10 cm
or 0-100 mm. The VAS may also be set up as an 11 point numerical
pain rating scale wherein 0 equals "no pain" and 10 equals the
"worst pain imaginable". Using the VAS, an agent is considered to
have an analgesic effect when there is a change of about 30% or
more, for example a change from 9 to 7 or from 5 to 3.5.
Therapeutic Uses
[0125] Chronic pain in the face and head region can arise from a
variety of medical conditions including but not limited to
neuropathic pain, headache pain, TMJ, pain from cancer and/or
cancer treatment. These pain syndromes are often not effectively
treated with current medications or invasive interventions and new
methods for localized pain relief in the face and head regions are
needed. Accordingly, some aspects of the present invention include
methods for treating an individual for trigeminal nerve-associated
chronic pain by administration of an analgesic agent wherein the
administration is targeted to the trigeminal nerve system and
results predominantly in analgesia to the facial or head region,
particularly as compared to analgesic effects in other parts of the
body. The analgesic agent can be administered to a patient with
neuropathic pain, including but not limited to, trigeminal
neuralgia, atypical facial neuralgia and post herpetic neuralgia.
The analgesic agent can be administered to an individual with
headache pain, for example, migraine headaches or cluster
headaches. The analgesic agent can be administered to an individual
with chronic pain arising from head or facial cancer or arising
from previous treatment of head or facial cancer.
[0126] Local anesthesia is used for most medical, dental or
cosmetic procedures wherein the procedures last a short period of
time and wherein the work is isolated to the teeth, face or head.
Anesthesia is generally defined as the total or partial loss of
sensation, especially tactile sensibility, usually induced by use
of an anesthetic compound. In addition to the pain of
administration, another main disadvantage of local anesthesia is
that loss of sensation results in numbness which often lasts
significantly longer than the procedure. Thus there are situations
wherein patients undergoing medical, dental or cosmetic procedures
would benefit from short-term regional analgesia of the teeth, face
or head regions. Some procedures potentially would require no other
pain relieving agents or any vasoconstrictors, and the length of
time of analgesia, in the absence of numbness, would be much less
important than the excessive length of time of facial numbness
resulting from an anesthetic. Such medical, dental and cosmetic
procedures can include, but are no limited to, microdermabrasion,
Botox injection, photodynamic therapy or other skin tumor
ablations, hair removal (including electrolysis, laser, waxing,
etc.), general facial laser treatments (including pigment removal,
vascular lesions), dermal and subdermal injectable fillers
(including collagen, hyaluronic acid, methylmethacrylate,
hydroxyapetite, etc), facial peels by chemical or laser
applications, photofacials, collagen shrinkage procedures
(including radiofrequency, HIFU, high intensity light, laser,
etc.), routine dental procedures, tattooing, tattoo removal,
piercing and treatment of scars, keloids, etc. by steroid
injection.
[0127] Thus some aspects of the present invention include methods
for treating an individual for trigeminal nerve-associated pain
arising from medical, dental or cosmetic procedures comprising
administration of an analgesic agent wherein the administration is
targeted to the trigeminal nerve system and results predominantly
in analgesia of the facial or head regions. The methods can include
an analgesic agent administered to an individual undergoing a
procedure selected from the group comprising medical, dental and
cosmetic. The methods can include medical, dental or cosmetic
procedures selected from the group comprising microdermabrasion,
Botox injection, photodynamic therapy or other skin tumor
ablations, hair removal (including electrolysis, laser, waxing,
etc.), general facial laser treatments (including pigment removal,
vascular lesions), dermal and subdermal injectable fillers
(including collagen, hyaluronic acid, methylmethacrylate,
hydroxyapetite, etc), facial peels by chemical or laser
applications, photofacials, collagen shrinkage procedures
(including radiofrequency, HIFU, high intensity light, laser,
etc.), dental procedures, tattooing, tattoo removal, piercing and
treatment of scars and keloids by steroid injection. The analgesic
agent can be administered to a patient undergoing a procedure
wherein the analgesic effect lasts the length of the procedure. The
analgesic agent can be administered to a patient undergoing a
procedure wherein the time requirement for the procedure and for
analgesia is less than 30 minutes, is less than 45 minutes, is less
than 60 minutes or is less than 90 minutes. The analgesic agent can
be administered to a patient undergoing a procedure wherein the
time requirement for the procedure and for analgesia is more than
90 minutes.
[0128] For medical, dental or cosmetic procedures that are more
extensive and will take a longer period of time, a local anesthetic
is used usually in combination with a sedative to make the patient
drowsy. In some cases, depending on the procedure, the patient is
put under a general anesthetic. The use of local or general
anesthesia does not effectively mitigate post-operative pain and
analgesics are almost always delivered to the patient after the
procedure is complete.
[0129] An evolving concept in operative pain management is the use
of preemptive analgesia. The pain and inflammation that result from
surgery normally causes increased prostaglandin production and
sensitization. If analgesic agents are administered before surgery
the amount of sensitization may be decreased or prevented and the
degree and persistence of post-operative pain may be diminished.
Therefore, there are situations wherein patients undergoing
medical, dental or cosmetic procedures would benefit from regional
trigeminal or facial analgesia prior to the procedure, during the
procedure and during the post-operative period. Some procedures
typically benefit by the use of vasoconstrictors, for example,
before plastic surgery to decrease the amount of bleeding at an
incision site. Therefore one level of benefit from facial analgesia
would be the elimination of pain associated with an injection of a
vasoconstrictor, wherein the time required for analgesia could be
less than 10 minutes. Another level of benefit exists if the facial
analgesia starts before the surgery starts, lasts throughout the
entire procedure and continues into the post-operative period,
wherein the post-operative period could represent hours or days.
Examples of dental procedures may include, but are not limited to,
major dental procedures such as periodontal, reconstructive,
palatal, tooth extraction, root canal surgery, etc. Examples of
cosmetic or medical surgical procedures may include, but are not
limited to, facelift, blepharoplasty, browlift, rhinoplasty, cheek
implant, chin implant, fat injections, lesion removal, excisional
biopsies, Mohs surgery (micrographic surgery for skin cancer), flap
reconstruction, orthognathic (correction of jaw deformities),
ophthalmic and oculoplastic (plastic surgery of the eye), hair
replacement surgery, extensive laser resurfacing, trauma such as
laceration repair, nasal fracture repair, facial bone fracture
repair, burn debridement and wound cleaning.
[0130] Accordingly, some aspects of the present invention include
methods for treating an individual for trigeminal nerve-associated
pain arising from medical, dental or cosmetic procedures comprising
administration of an analgesic agent wherein the administration is
targeted to the trigeminal nerve system and results in localized
analgesia of the face, head or teeth. The methods can include an
effective dosage amount wherein the localized analgesia lasts for
the length of the procedure and continues into a post-operative
period. The methods can include medical, dental or cosmetic
procedures selected from the group comprising periodontal surgery,
reconstructive tooth surgery, palatal surgery, tooth extraction,
root canal surgery, facelifts, blepharoplasties, browlifts,
rhinoplasties, cheek implants, chin implants, fat injections,
lesion removal, excisional biopsies, Mohs surgery, flap
reconstruction, orthognathic surgery, ophthalmic surgery,
oculoplastic surgery, hair replacement surgery, extensive laser
resurfacing, laceration repair, nasal fracture repair, facial bone
fracture repair, burn debridement and wound cleaning. The analgesic
agent can be administered to a patient undergoing a medical
procedure prior to injection of a vasoconstrictor into the facial
or head region. The analgesic agent can be administered to a
patient undergoing a medical procedure wherein the analgesia lasts
beyond the length of the procedure and into a post-operative time
period. The analgesic agent can be administered to a patient
undergoing a medical procedure wherein the analgesia lasts for
hours to days after the medical procedure is finished.
Kits
[0131] Provided herein are kits for use in carrying out any of the
methods described herein. Kits are provided for use in treatment of
trigeminal nerve-associated pain. Kits of the invention may
comprise at least one analgesic agent in suitable packaging. Kits
may further comprise a vasoconstrictor, at least one protease
inhibitor and/or at least one absorption enhancer. Kits may further
comprise a delivery device, including but not limited to, a device
for intranasal administration. Kits may further comprise
instructions providing information to the user and/or health care
provider for carrying out a method described herein.
[0132] Kits comprising a single component will generally have the
component enclosed in a container (e.g., a vial, ampoule, or other
suitable storage container). Likewise, kits including more than one
component may also have the additional reagents in containers
(separately or in a mixture).
[0133] The instructions relating to the use of the kit generally
describe how the contents of the kit are used to carry out the
methods of the invention. Instructions supplied in the kits of the
invention are typically written instructions on a label or package
insert (e.g., a paper sheet included in the kit), but
machine-readable instructions (e.g., instructions carried on a
magnetic or optical storage disk) are also acceptable.
EXAMPLES
Example 1
[0134] One way to test activity of an analgesic agent in a rat
model is by treatment-induced changes in latencies (times) of
withdrawal in response to noxious heating of the skin, typically
using an ear, the face or a hindpaw. Thus, application of coherent
or non-coherent (non-laser) radiant heat to the ear, the face or
hindpaw will elicit rapid withdrawal movements. Latencies of
withdrawal have been demonstrated to be sensitive to analgesic
treatments, such that analgesics increase the latency to
withdrawal. Transmucosal or transdermal administration of analgesic
agents to the trigeminal nerve to reduce trigeminal
nerve-associated pain can be tested for regional and/or systemic
analgesia. The rostral external part of a rat's ear is innervated
by a branch of the mandibular nerve, itself a branch of the
trigeminal nerve, thus after treatment an increase in latency to
withdrawal time would indicate regional analgesia. A change in the
latency to withdrawal time of the hindpaw would indicate whether
there was a systemic analgesic effect, i.e. no change in the
latency to withdrawal time indicates no systemic effect, while an
increase in latency to withdrawal time would indicate a systemic
effect.
[0135] Rats are housed in a 12/12-hour light/dark environment and
are provided food and water ad libitum. Efforts are made to
minimize discomfort and reduce the number of animals used. Rats are
lightly anesthetized with urethane and placed with minimal
restraint on a heating pad to maintain their body temperature at
37.degree. C. A laser beam is directed via a fiberoptic cable to
the rostral external part of both ears. Characteristic responses to
laser irradiation are a retraction or withdrawal of the stimulated
ear for 1-3 seconds after a thermal stimulus by the laser. Laser
stimulation is terminated rapidly after response of the stimulated
ear or after a maximal response (cut-off) latency of 30 seconds to
prevent tissue damage.
[0136] For baseline testing of latency withdrawal responses to the
ear, 3 pulses are applied to the portion of each ear that is
innervated by the trigeminal nerve. The stimulation site is changed
after each pulse allowing at least 2 minutes in between 2 stimuli
on the same ear. For baseline testing of latency withdrawal
responses to the hindpaw, 3 pulses are applied to the hindpaw. The
stimulation site is changed after each pulse allowing at least 2
minutes in between 2 stimuli on the same hindpaw. Testing sessions
are videotaped for off-line analysis of responses. The off-line
analysis is performed by an investigator who determines the latency
of withdrawal responses to the laser stimulation and who is blinded
to the treatment groups.
[0137] After measuring baseline latencies, analgesic agents are
administered intranasally. This involves 5 equal 10 .mu.l
applications to the nose by pipette for a total volume of 50 .mu.l
over 20 minutes. The effect of different doses of an agent (e.g. 10
nmoles/kg met-enkephalin) on latency responses is examined. To
assess the local analgesic effect, the latency responses of the ear
are tested at various time points after agent administration. To
assess the systemic analgesic effect, the latency responses of
hindpaws are tested at various timepoints after agent
administration.
Example 2
[0138] Sprague-Dawley rats (Charles River Laboratories) were
lightly anesthetized with urethane and placed with minimal
restraint on a heating pad to maintain their body temperature at
37.degree. C. A laser beam was directed via a fiberoptic cable to
the rostral external part of both ears or to the hindpaws as
described above. Baseline withdrawal latencies were measured by
delivering 4 separate stimuli with a resting period of
approximately 15 minutes between each stimulus. 50 .mu.l of
met-enkephalin in phosphate-buffered saline was intranasally
administered in 5 equal 10 .mu.l applications at a dosage of 10
nmoles/kg of body weight. Withdrawal latencies for both ears and
hindpaws were tested five minutes after the final application of
met-enkephalin. As described above, testing sessions were
videotaped and analyzed. Results demonstrated that intranasal
administration of met-enkephalin at this dosage achieved a regional
analgesic effect in the head region (FIG. 1A) without a systemic
analgesic effect at the hindpaw (FIG. 1B).
Example 3
Normal Human Volunteers.
[0139] Regional analgesia in the face region after administration
of analgesic agents by intranasal delivery can be tested in normal
subjects. Study participants are selected based on
inclusiori/exclusion criteria, history and physical exam,
laboratory tests, and other customary procedures. Thermal pain
responses are elicited on the face, in particular the cheek, and on
the hand of healthy normal volunteers, such that temperature
thresholds for evoking pain and/or the temperature of maximal pain
tolerance can be assessed and baselines established. Increasing
doses of an analgesic agent are administered to the subjects and a
dose-response curve is calculated for each stimulation site.
Changes in thermal pain threshold and tolerance at the two sites
can be compared so that the efficacy of an analgesic agent at a
given dose in affecting facial and whole-body pain can be
determined.
[0140] The analgesic agent is delivered intranasally to the
subjects by a metered dose nebulizer. For example, a dose of 0.01
.mu.g/kg of oxytocin in 0.1 ml of saline is administered with each
nasal puff application to the subjects. 0.1 ml of saline only with
each nasal puff application is administered to control subjects. It
is determined what doses of an analgesic agent administered to the
trigeminal nerve are effective for establishing regional analgesia
in the facial region (i.e. the cheek) with minimal systemic
distribution and minimal or no analgesic effect at the peripheral
site (i.e. the hand).
Example 4
Human Patients.
[0141] Patients undergoing cosmetic facial surgery normally
experience significant post-operative pain. The patients are
treated with an analgesic agent which is administered intranasally
by metered dose nebulizer at the cessation of surgery. Patients
receive a dose of a test agent (e.g. 0.01 .mu.g/kg of oxytocin) in
0.1 ml of normal saline or they receive a placebo of saline alone.
A patient's facial pain ratings are then determined on the visual
analogue scale (VAS) at 10 minute intervals for 2 hours. A second
set of patients undergoing a similar surgical procedure to the hand
also receive an intranasal application of either the test agent or
saline placebo. Patient's hand pain ratings are then determined on
the visual analogue scale (VAS) at 10 minute intervals for 2
hours.
Example 5
[0142] Sprague-Dawley rats (Charles River Laboratories) were
anesthetized with isofluorane and a platinum electrode was inserted
transcranially into the trigeminal ganglion. Nerve impulses (action
potential) were recorded from single pain sensing nerve cells in
the trigeminal ganglion in response to application of noxious laser
pulses to the face of the rats. After recording responses to
several identical laser pulses, 10 nmoles of oxytocin was applied
to the nose of the rats. Thereafter, identical laser pulses were
once again applied and recorded.
[0143] FIG. 2 shows the average nerve impulses per a laser pulse
for pre-oxytocin and post-oxytocin treatment. Oxytocin
significantly (p<0.05) reduced the neuronal response to noxious
laser pulses applied to the animal's face. These data showed that
at least part of the analgesic effect of nasal application of
oxytocin was by way of direct inhibition of neurons in the
trigeminal nerve.
Example 6
[0144] Male Sprague-Dawley rats (Charles River Laboratories) were
anesthetized with isoflurane and used in the following experiments.
In the anesthetized rats, single unit, extracellular recordings
were performed in trigeminal nucleus caudalis while stimulating the
ipsilateral facial skin with constant-current bipolar electrical
stimulation. Epoxylate-insulated, tungsten microelectrodes (10
MOhm) were used under stereotaxic coordinate control.
[0145] FIG. 3 demonstrates the effect of intranasal oxytocin
electrical stimulation-induced responses of trigeminal nucleus
caudalis wide dynamic range (WDR) neurons. Shown are responses
(action potentials per 30 stimuli) to repeated stimulation of a
rat's face before oxytocin administration (pre-oxytocin). After
administration with oxytocin at approximately 0.1 IU, responses
were recorded every five minutes for 65 minutes. A second
administration of oxytocin at the same dosage was administered at
approximately 70 minutes after the first dose. The approximate site
of the administration of the electrical stimulation is indicated by
the black spot on a map of the rat's face (FIG. 3B). FIG. 3C shows
raw data recorded during electrical stimulation before oxytocin
administration. FIG. 3D shows raw data recorded during electrical
stimulation 30 minutes after intranasal oxytocin
administration.
[0146] Oxytocin treatment caused a significant reduction in
responses beginning 10 minutes after a first administration and
continued until 50 minutes post treatment when responses began to
increase (FIG. 3A). At approximately 70 minutes after the first
treatment, a second dose of oxytocin was administered. Within 10
minutes, the second oxytocin treatment caused a significant
reduction in responses. These data demonstrated that intranasal
administration of oxytocin could cause a large effect (i.e.
reduction in action potentials) but also that the effect was
reproducible within a short period of time.
Example 7
[0147] Male Sprague-Dawley rats (Charles River Laboratories) were
anesthetized with isoflurane and used in the following experiments.
In the anesthetized rats, single unit, extracellular recordings
were performed in trigeminal nucleus caudalis while stimulating the
ipsilateral facial skin with diode laser or constant-current
bipolar electrical stimulation. Epoxylate-insulated, tungsten
microelectrodes (10 MOhm) were used under stereotaxic coordinate
control.
[0148] FIG. 4 demonstrates the effect of intranasal octreotide on
long-pulse laser-induced responses of trigeminal nucleus caudalis
wide dynamic range (WDR) neurons. Shown are responses (action
potentials per second) to an 8 second-duration, 425 mA intensity
laser stimulus to the site indicated by the black spot on a map of
the rat's face (FIG. 4E). FIG. 4A shows a baseline response before
treatment (pre-octreotide). FIG. 4B shows response 5 minutes after
octreotide treatment (0.025 ml of 0.05 mg/ml). FIG. 4C shows the
response ten minutes after octreotide treatment. FIG. 4D shows the
respond 25 minutes after octreotide treatment.
[0149] There was no detectable reduction in response five minutes
post-octreotide treatment, but the response at 10 minutes
post-treatment was reduced from 42 to 5 spikes, a reduction of 88%.
The response had recovered by 25 minutes post-treatment. These data
show that intranasally administered octreotide can reduce the
responses of pain-transmitting neurons in the trigeminal sensory
system.
Example 8
[0150] Male Sprague-Dawley rats (Charles River Laboratories) were
anesthetized with isoflurane and used in the following experiments.
FIG. 5 demonstrates the effect of intranasal octreotide on
electrical stimulus-induced windup. Windup is the phenomenon by
which multiple, consecutive, supramaximal stimuli of
constant-intensity electrical stimuli evoke progressively greater
responses by the neuron, and has been shown to be a good model for
testing central neuronal excitability. Needle electrodes were
inserted subcutaneously at the site indicated in FIG. 5A by the
black spot on the rat's head, and the skin was stimulated at 0.66
Hz, 2 msec duration, 3.times. C-fiber threshold for >25 times.
FIG. 5B shows the responses (spikes/stimulus) to 25 stimulations
before (solid squares) and 10 minutes after (open triangles) an
intranasal administration of octreotide (0.025 ml of 0.05
mg/ml).
[0151] The total number of action potentials during the stimulation
period was reduced from 506 before octreotide treatment to 408 10
minutes after octreotide administration, a reduction of 19.4%.
FIGS. 5C-5F depict raw data sweeps during the same recording period
and electrical stimulation. FIGS. 5C and 5D depict the responses to
the 1st and 15th stimuli before octreotide administration, and
FIGS. 5E and 5F depict the responses to the 1.sup.st and 15.sup.th
stimuli 10 minutes post-octreotide administration. This data
demonstrates that octreotide can modulate neuronal excitability of
second-order neurons in the trigeminal nucleus caudalis.
[0152] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it will be apparent to those skilled in the art
that certain changes and modifications may be practiced without
departing from the invention. Therefore, the descriptions and
examples should not be construed as limiting the scope of the
invention.
[0153] All publications, patents, and patent applications cited
herein are hereby incorporated by reference in their entirety.
Sequence CWU 1
1
28 1 5 PRT Artificial Sequence Synthetic peptide 1 Tyr Gly Gly Phe
Leu 1 5 2 5 PRT Artificial Sequence Synthetic peptide 2 Tyr Gly Gly
Phe Met 1 5 3 36 PRT Artificial Sequence Synthetic peptide 3 Tyr
Gly Gly Phe Met Lys Lys Met Asp Glu Leu Tyr Pro Leu Glu Val 1 5 10
15 Glu Glu Glu Ala Asn Gly Gly Phe Val Leu Gly Lys Arg Thr Arg Tyr
20 25 30 Gly Gly Phe Met 35 4 31 PRT Homo sapiens 4 Tyr Gly Gly Phe
Met Thr Ser Glu Lys Ser Gln Thr Pro Leu Val Thr 1 5 10 15 Leu Phe
Lys Asn Ala Ile Ile Lys Asn Ala Tyr Lys Lys Gly Glu 20 25 30 5 15
PRT Artificial Sequence Synthetic peptide AMIDATION 15 5 Tyr Gly
Gly Phe Met Thr Ser Glu Ser Gln Thr Pro Leu Val Thr 1 5 10 15 6 17
PRT Artificial Sequence Synthetic peptide 6 Tyr Gly Gly Phe Leu Arg
Arg Ile Arg Pro Lys Leu Lys Trp Asp Asn 1 5 10 15 Gln 7 13 PRT
Artificial Sequence Synthetic peptide 7 Tyr Gly Gly Phe Leu Arg Arg
Gln Phe Lys Val Val Thr 1 5 10 8 10 PRT Artificial Sequence
Synthetic peptide 8 Tyr Gly Gly Phe Leu Arg Lys Tyr Pro Lys 1 5 10
9 9 PRT Artificial Sequence Synthetic peptide 9 Tyr Gly Gly Phe Leu
Arg Lys Tyr Pro 1 5 10 8 PRT Artificial Sequence Synthetic peptide
10 Tyr Gly Gly Phe Leu Arg Arg Ile 1 5 11 13 PRT Artificial
Sequence Synthetic peptide 11 Tyr Gly Gly Phe Leu Arg Arg Ile Arg
Pro Lys Leu Lys 1 5 10 12 4 PRT Artificial Sequence Synthetic
peptide AMIDATION 4 12 Tyr Pro Trp Phe 1 13 4 PRT Artificial
Sequence Synthetic peptide AMIDATION 4 13 Tyr Pro Phe Phe 1 14 7
PRT Artificial Sequence Synthetic peptide VARIANT 2 Xaa = (D)Ala
AMIDATION 7 14 Tyr Xaa Phe Gly Tyr Pro Ser 1 5 15 7 PRT Bovine 15
Tyr Pro Phe Pro Gly Pro Ile 1 5 16 7 PRT Homo sapiens 16 Tyr Pro
Phe Val Glu Pro Ile 1 5 17 3 PRT Artificial Sequence Synthetic
peptide 17 Tyr Pro Phe 1 18 4 PRT Artificial Sequence Synthetic
peptide 18 Tyr Pro Phe Pro 1 19 4 PRT Artificial Sequence Synthetic
peptide AMIDATION 4 19 Tyr Pro Phe Pro 1 20 5 PRT Artificial
Sequence Synthetic peptide 20 Tyr Pro Phe Pro Gly 1 5 21 8 PRT
Artificial Sequence Synthetic peptide 21 Tyr Pro Phe Pro Gly Pro
Ile Pro 1 5 22 7 PRT Artificial Sequence Synthetic peptide VARIANT
2 Xaa = (D)Ala AMIDATION 7 22 Tyr Xaa Phe Asp Val Val Gly 1 5 23 7
PRT Artificial Sequence Synthetic peptide VARIANT 2 Xaa = (D)Ala
AMIDATION 7 23 Tyr Xaa Phe Glu Val Val Gly 1 5 24 7 PRT Artificial
Sequence Synthetic peptide VARIANT 2 Xaa = (D)Met AMIDATION 7 24
Tyr Xaa Phe His Leu Met Asp 1 5 25 7 PRT Artificial Sequence
Synthetic peptide VARIANT 2 Xaa = (D)Ala 25 Tyr Xaa Phe Gly Tyr Pro
Ser 1 5 26 4 PRT Artificial Sequence Synthetic peptide AMIDATION 4
26 Tyr Pro Phe Pro 1 27 9 PRT Artificial Sequence Synthetic peptide
27 Cys Tyr Ile Gln Asn Cys Pro Leu Gly 1 5 28 4 PRT Artificial
Sequence Synthetic peptide 28 Tyr Gly Gly Phe 1
* * * * *