U.S. patent application number 09/754840 was filed with the patent office on 2001-08-30 for method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists.
Invention is credited to Crain, Stanley M., Fleischner, Gerald M., Shen, Ke-fei.
Application Number | 20010018413 09/754840 |
Document ID | / |
Family ID | 22992965 |
Filed Date | 2001-08-30 |
United States Patent
Application |
20010018413 |
Kind Code |
A1 |
Crain, Stanley M. ; et
al. |
August 30, 2001 |
Method and composition for treating irritable bowel syndrome using
low doses of opioid receptor antagonists
Abstract
This invention relates to a method for treating a subject with
irritable bowel syndrome ("IBS") which comprises long-term
administration of an opioid receptor antagonist at an appropriately
low dose which will selectively antagonize excitatory opioid
receptor functions, but not inhibitory opioid receptor functions,
in myenteric neurons in the intestinal tract as well as in neurons
of the central nervous system ("CNS"). The administration of the
opioid receptor antagonist at a low dose enhances the potency of
the inhibitory effects of endogenous opioid peptides present in the
intestinal tract and the CNS, thereby reducing abdominal pain and
stool frequency resulting from abnormally supersensitized
excitatory opioid receptor functions. The invention also relates to
a composition for treating a subject with IBS, which comprises an
effective dose of an opioid receptor antagonist, and a
pharmaceutically acceptable carrier.
Inventors: |
Crain, Stanley M.; (Leonia,
NJ) ; Shen, Ke-fei; (Flushing, NY) ;
Fleischner, Gerald M.; (Chappaqua, NY) |
Correspondence
Address: |
Craig J. Arnold
AMSTER, ROTHSTEIN & EBENSTEIN
90 Park Avenue
New York
NY
10016
US
|
Family ID: |
22992965 |
Appl. No.: |
09/754840 |
Filed: |
January 4, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09754840 |
Jan 4, 2001 |
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09261361 |
Mar 3, 1999 |
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6194382 |
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Current U.S.
Class: |
514/17.7 ;
514/282 |
Current CPC
Class: |
A61P 1/12 20180101; A61K
31/00 20130101; A61K 31/485 20130101; A61P 1/00 20180101 |
Class at
Publication: |
514/2 ;
514/282 |
International
Class: |
A61K 038/33; A61K
031/485 |
Claims
What is claimed is:
1. A method for treating irritable bowel syndrome in a subject in
need of such treatment, comprising administering to said subject an
amount of an excitatory opioid receptor antagonist effective to
treat irritable bowel syndrome in said subject.
2. The method according to claim 1, wherein said amount of the
excitatory opioid receptor antagonist is effective to block at
least one of hypersensitivity and hyperexcitability of visceral
sensory and visceral motor neurons associated with irritable bowel
syndrome.
3. The method according to claim 1, wherein said amount of the
excitatory opioid receptor antagonist is effective to treat
abdominal pain and at least one of abnormal consistency and
abnormal frequency of stools in said subject.
4. The method according to claim 1, wherein said excitatory opioid
receptor antagonist is a member selected from the group consisting
of naltrexone, nalmefene, diprenorphine, naloxone, etorphine,
dihydroetorphine, biphalin, and similarly acting opioid alkaloids
or peptides.
5. The method according to claim 1, wherein said excitatory opioid
receptor antagonist is naltrexone.
6. The method according to claim 5, wherein said naltrexone i s
administered at a dose effective to relieve abdominal pain
associated with IBS and wherein said dose is further ineffective to
induce dysphoria.
7. The method according to claim 5, wherein said naltrexone is
administered at a dose between about 0.1 mg/day and about 5
mg/day.
8. The method according to claim 5, wherein said naltrexone is
administered at a dose between about 0.3 mg/day and about 3
mg/day.
9. The method according to claim 5, wherein said naltrexone is
administered at a dose between about 2 .mu.g/kg body weight/day and
about 70 .mu.g/kg body weight/day.
10. The method according to claim 5, wherein said naltrexone is
administered at a dose between about 4 .mu.g/kg body weight/day and
about 45 .mu.g/kg body weight/day.
11. The method according to claim 1, wherein said excitatory opioid
receptor antagonist is nalmefene.
12. The method according to claim 11, wherein said nalmefene is
administered at a dose effective to relieve abdominal pain
associated with IBS and wherein said dose is further ineffective to
induce dysphoria.
13. The method according to claim 11, wherein said nalmefene is
administered at a dose between about 0.01 mg/day and about 1
mg/day.
14. The method according to claim 1, wherein said excitatory opioid
receptor antagonist is administered in one or more forms selected
from the group consisting of orally, parenterally, transdermally,
or by suppository.
15. The method according to claim 1, wherein said excitatory opioid
receptor antagonist is administered orally.
16. A pharmaceutical composition for treating irritable bowel
syndrome in a subject in need of such treatment, comprising an
amount of an excitatory opioid receptor antagonist effective to
treat irritable bowel syndrome in said patient.
17. The pharmaceutical composition according to claim 16, wherein
said amount of the excitatory opioid receptor antagonist is
effective to block at least one of hypersensitivity and
hyperexcitability of visceral sensory and visceral motor neurons
associated with irritable bowel syndrome.
18. The pharmaceutical composition according to claim 16, wherein
said amount of the excitatory opioid receptor antagonist is
effective to treat abdominal pain and at least one of abnormal
consistency and abnormal frequency of stools in said subject, and a
pharmaceutically acceptable carrier.
19. The pharmaceutical composition according to claim 16, wherein
said excitatory opioid receptor antagonist is a member selected
from the group consisting of naltrexone, nalmefene, diprenorphine,
naloxone, etorphine, dihydroetorphine, biphalin, and similarly
acting opioid alkaloids or peptides.
20. The pharmaceutical composition according to claim 16, wherein
said excitatory opioid receptor antagonist is naltrexone.
21. The pharmaceutical composition according to claim 20, wherein
said naltrexone is present at a dose effective to relieve abdominal
pain associated with IBS and wherein said dose is further
ineffective to induce dysphoria.
22. The pharmaceutical composition according to claim 20, wherein
said naltrexone is present at a dose between about 0.1 mg and about
5 mg.
23. The pharmaceutical composition according to claim 20, wherein
said naltrexone is present at a dose between about 0.3 mg and about
3 mg.
24. The pharmaceutical composition according to claim 16, wherein
said excitatory opioid receptor antagonist is nalmefene.
25. The pharmaceutical composition according to claim 24, wherein
said nalmefene is present at a dose effective to relieve abdominal
pain associated with IBS and wherein said dose is further
ineffective to induce dysphoria.
26. The pharmaceutical composition according to claim 24, wherein
said nalmefene is present at a dose between about 0.01 mg and about
1 mg.
27. The pharmaceutical composition according to claim 16, wherein
said pharmaceutical composition is in a form effective for
administration to said patient by any member from the group
consisting of orally, parenterally, transdermally, or by
suppository.
28. The pharmaceutical composition according to claim 16, wherein
said excitatory opioid receptor is in a form effective to be
administered orally.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a method for treating a subject
with irritable bowel syndrome ("IBS") which comprises administering
a low dose of an opioid receptor antagonist to the subject.
Specifically, this invention relates to a method for treating a
subject with IBS by the long-term administration of an opioid
receptor antagonist at an appropriately low dose which will
selectively antagonize excitatory opioid receptor functions, but
not inhibitory opioid receptor functions, in myenteric neurons in
the intestinal tract as well as in neurons of the central nervous
system ("CNS"). The administration of the opioid receptor
antagonist at a low dose enhances the potency of the inhibitory
effects of endogenous opioid peptides present in the intestinal
tract and the CNS, thereby reducing abdominal pain and stool
frequency resulting from abnormally supersensitized excitatory
opioid receptor functions. The invention also relates to a
composition for treating a subject with IBS, which comprises an
effective dose of an opioid receptor antagonist, and a
pharmaceutically acceptable carrier.
BACKGROUND OF THE INVENTION
[0002] Irritable bowel syndrome is a functional bowel disorder in
which abdominal pain is associated with defecation or a change in
bowel habit. IBS has elements of an intestinal motility disorder, a
visceral sensation disorder, and a central nervous disorder. While
the symptoms of IBS have a physiological basis, no physiological
mechanism unique to IBS has been identified. Rather, the same
mechanisms that cause occasional abdominal discomfort in healthy
individuals operate to produce the symptoms of IBS. The symptoms of
IBS are therefore a product of quantitative differences in the
motor reactivity of the intestinal tract, and increased sensitivity
to stimuli or spontaneous contractions.
[0003] Due to a lack of readily identifiable structural or
biochemical abnormalities in this syndrome, the medical community
has developed a consensus definition and criteria, known as the
Rome criteria, to aid in diagnosis of IBS. According to the Rome
criteria, IBS is indicated by abdominal pain or discomfort which is
(1) relieved by defection and/or (2) associated with a change in
frequency or consistency of stools, plus two or more of the
following: altered stool frequency, altered stool form, altered
stool passage, passage of mucus, and bloating or feeling of
abdominal distention (Dalton, C. and Drossman, D. A., Am Fam
Physician 1997 55(3):875-880). Thus, a hallmark of IBS is abdominal
pain that is relieved by defecation, and which is associated with a
change in the consistency or frequency of stools. IBS may be
diarrhea-predominant, constipation-predominant, or an alternating
combination of both.
[0004] Persons with IBS exhibit hypersensitivity, particularly
hyperalgesia, in response to painful distensions in the small bowel
and colon and to normal intestinal function. Furthermore, there are
also increased or unusual areas of visceral pain. The abdominal
pain is often poorly localized, and may be migratory and/or
variable in nature. The pain may be worsened by meals and reduced
upon defecation. Furthermore, IBS symptoms, including hyperalgesia,
are commonly initiated or exacerbated by stress (Dalton, C. and
Drossman, D. A., Am Fam Physician 1997 55(3):875-880).
[0005] IBS is estimated to affect up to 20% of the adult population
worldwide. Women apparently are more often affected than men, and
the prevalence of irritable bowel syndrome is lower among the
elderly (Camilleri, M. and Choi, M. -G., Aliment Pharmacol Ther
1997 11(1):3-15). It also seems clear that psychological factors,
either stress or overt psychological disease, modulate and
exacerbate the physiological mechanisms that operate in IBS
(Drossman, D. A. et al., Gastroenterology 1988 95:701-708).
[0006] Some studies suggest that only about 10% to 50% of those
afflicted with IBS actually seek medical attention. Nonetheless,
IBS still accounts for up to about 3.5 million physician visits per
year, and is the most common diagnosis in gastroenterologists'
practice, accounting for about 25% of all patients (Camilleri and
Choi, 1997). In a study published in 1993, persons afflicted with
IBS were found to have more frequent doctor visits, a lower quality
of life, and to miss three times as many days from work as those
with no bowel symptoms (Drossman, D. A., Dig Dis Sci 1993
38:1569-1580). As a consequence, persons with IBS incur higher
health care costs than those without IBS (Talley, N. J. et al.,
Gastroenterology 1995 109:1736-1741).
[0007] Attempts to treat IBS generally focus on either (1)
treatments directed to the intestinal tract (so-called "end organ
therapy") or (2) treatments directed to affective disorders
mediated by the CNS which are associated with IBS (Farthing, M. J.
G., Drugs 1998 56(1):11-21). Among the former are gut transit
accelerants, such as wheat bran, soluble fiber, and polycarbophil
calcium, for constipation-predominant IBS; antidiarrheals, such as
loperamide, diphenoxylate, and codeine phosphate, for
diarrhea-predominant IBS; and anticholinergics and smooth muscle
relaxants, such as cimetropium bromide, pinaverium bromide,
octilium bromide, trimebutine, and mebeverine, for
diarrhea-predominant IBS and abdominal pain. In addition,
alterations in diet have been targeted for those patients with food
sensitivities or food allergies.
[0008] The end organ therapy treatments for IBS have proved
ineffective or contain inherent drawbacks that limit their
usefulness. For example, while the gut accelerants are useful to
accelerate gut transit, they also exacerbate abdominal pain and
bloating. Likewise, while antidiarrheals, such as loperamide, are
often effective in treating diarrhea-predominant IBS, they are
ineffective in treating the additional symptoms associated with
IBS, such as abdominal pain. As a consequence, end organ therapy
often is limited to patients with mild or moderate symptoms.
[0009] The anticholinergics and smooth muscle relaxants are
effective in relieving pain associated with IBS, although their
effects on other symptoms associated with IBS is unclear
(Committee, Gastroenterology 1997 112:2120-2137; Pace, F. et al.,
Digestion 1995 56:433-442). In addition, some of the most effective
compounds in these classes are not available for use in the United
States, since they have not been approved by the Federal Food and
Drug Administration (Committee, 1997). Finally, dietary alterations
are of limited utility for a small segment of IBS patients.
[0010] Central nervous system treatments have received attention as
potential IBS therapies because of the well recognized link between
affective disorders and IBS, and also because of the disturbances
in bowel health that occurs in individuals with these disorders.
The tricyclic antidepressants, such as amitriptyline, imipramine,
and doxepin, are frequently used to treat IBS, due to the
neuromodulatory and analgesic properties of these compounds, which
are independent of their psychotropic effects. However, because of
their psychotropic properties, administration of these drugs
requires long-term care, and are usually only given to patients
with severe or refractory symptoms, impaired daily function, and
associated depression or anxiety attacks. Furthermore, the newer
antidepressants, in particular the specific serotonin reuptake
inhibitors, such as fluoxetine, serraline, and paroxetine, have not
been shown to be more effective than the tricyclic antidepressants,
although some anecdotal evidence suggests these compounds may have
fewer side effects (Committee, 1997).
[0011] Nalmefene glucuronide, an opioid receptor antagonist, has
been investigated as a treatment for constipation-predominant IBS
(Chami, T. N., et al., Am J Gastroenterol 1993 88:1568 [abstract]).
Over an eight-week period, eight patients received 16 mg nalmefene
glucuronide three times a week. While the patients reported
decreased transit time and increased stool frequency, nalmefene
glucuronide did not reduce abdominal pain or bloating, and stool
consistency was not improved. The present inventors believe that
the failure of nalmefene to treat pain associated with IBS can be
attributed to the fact that this study used a high dose of
nalmefene which antagonizes both excitatory and inhibitory opioid
receptor-mediated functions in the gut as well as in the CNS. This
view is supported by recent evidence that 1,000-fold lower doses of
nalmefene (ca. 15 .mu.g, IV) have been shown to markedly enhance
morphine's analgesic potency (Joshi et al., Anesthesiol. 1999, in
press), whereas doses of >0.5 mg markedly attenuate opioid
analgesia (Konieczko, K. M. et al., Br J Anaesth 1988
61(3):318-23).
[0012] Recent reports of successful treatment of IBS patients with
high doses of the kappa opioid agonist, fedotizine (30 mg, three
times daily) (Dapoigny, M. et al., Dig Dis Sci 1995 40(10):2244-9;
Gue, M. et al., Gastroenterology 1994 107(5):1327-34) may be due to
masking of supersensitized excitatory opioid receptor activity in
the gut by activation of inhibitory opioid receptor functions,
analogous to methadone maintenance of opioid addicts.
Supersensitized excitatory opioid receptor functions in the gut may
also result in tolerance to the analgesic effects of endogenous
opioids (Wang, L. and Gintzler, A. R., J Neurochem 1995
64(3):1102-6), which could account for the abnormal visceral pain
associated with IBS.
[0013] U.S. Pat. No. 5,512,578 discloses that the analgesic potency
of bimodally-acting opioid agonists can be enhanced, and the
tolerance/dependence liability reduced, upon coadministration of
ultralow doses of selective excitatory opioid receptor antagonists.
As used herein, "excitatory opioid receptor antagonists" are
compounds that bind to and inactivate excitatory opioid receptors,
but not inhibitory opioid receptors, on neurons in the nociceptive
pathways. Such selective excitatory opioid receptor antagonists
include, when administered at appropriately low doses, naloxone,
naltrexone, etorphine, and dihydroetorphine. The selective
excitatory opioid receptor antagonists attenuate excitatory, but
not inhibitory, opioid receptor functions in nociceptive (pain)
pathways of the peripheral and central nervous systems. As a
result, symptoms associated with activation of excitatory opioid
receptors, such as anti-analgesia, hyperalgesia, hyperexcitability,
physical dependence and/or tolerance effects, are blocked, whereas
the analgesic effects of bimodally acting opioid agonists, which
are mediated by the inhibitory opioid receptors, are unmasked and
thereby enhanced (see Crain, S. M. and Shen, K. -F., Proc Natl Acad
Sci U.S.A 1995 92:10540-10544; Crain, S. M. and Shen, K. -F.,
Trends Pharmacol Sci 1998 19:358-365; Ann N.Y. Acad Sci 1998
845:106-25; Shen, K. -F. and Crain, S. M., Brain Res 1997
757(2):176-90). The predictions based on these preclinical studies
have been recently confirmed by clinical studies on postsurgical
patients which demonstrated that cotreatment with morphine plus
low-dose naloxone or nalmefene markedly enhanced the analgesic
potency of morphine administered over 24-hour test periods (Joshi
et al., Anesthesiol. 1999, in press; Gan, T. J. et al.,
Anesthesiol. 1997 87:1075-1081).
[0014] U.S. Pat. No. 5,512,578 further discloses that ultralow
doses of naltrexone can, alone or in combination with low-dose
methadone, provide effective longterm maintenance treatment for
opioid addiction to prevent relapse to drug abuse. Furthermore,
ultralow doses of selective excitatory opioid receptor antagonists
can be administered alone to chronic pain patients to enhance the
analgesic potency and reduce the tolerance/dependence liability of
endogenous opioid peptides, such as enkephalins, dynorphins, and
endorphins, which are elevated in chronic pain patients (Crain and
Shen, 1995). However, there is no teaching or suggestion in U.S.
Pat. No. 5,512,578 that administration of a selective excitatory
opioid receptor antagonist would be useful in treating symptoms of
IBS. In particular, there is no teaching or suggestion that
administration of a selective excitatory opioid receptor antagonist
would be useful in treating symptoms of IBS that are unrelated to
the nociceptive pathways, such as stool frequency or
consistency.
[0015] U.S. Pat. No. 5,472,943 also discloses a method wherein
coadministration of an ultralow dose of a selective excitatory
opioid receptor antagonist with a bimodally-acting opioid agonist
selectively enhances the analgesic effect of the bimodally-acting
opioid agonist while reducing the undesirable side-effects
associated with longterm administration of the opioid agonist.
However, U.S. Pat. No. 5,472,943 does not disclose that a selective
excitatory opioid receptor antagonist can be used in the absence of
a bimodally-acting opioid agonist.
[0016] Both U.S. Pat. No. 5,580,876 and U.S. Pat. No. 5,767,125
also disclose a method to selectively enhance the analgesic effect
of a bimodally-acting opioid agonist while reducing unwanted
side-effects associated with the administration of the opioid
agonist by coadministration of the opioid agonist with an amount of
an excitatory opioid receptor antagonist, such as naltrexone or
nalmefene, effective to enhance the analgesic effect of the
bimodally-acting opioid agonist while reducing the undesirable
side-effects. U.S. Pat. No. 5,580,876 and U.S. Pat. No. 5,767,125
disclose use of an excitatory opioid receptor antagonist alone for
treatment of opioid addicts, and do not teach or suggest that
administration of a selective excitatory opioid receptor antagonist
would be useful in treating symptoms of IBS. In particular, there
is no teaching or suggestion that administration of a selective
excitatory opioid receptor antagonist would be useful in treating
other symptoms of IBS, such as stool frequency or consistency.
[0017] U.S. Pat. No. 5,585,348 relates to a method for reducing
hyperalgesia associated with administration of nerve growth factor
or related growth factors. The method comprises administration of a
selective excitatory opioid receptor antagonist prior to or
simultaneously with the administration of nerve growth factor.
However, U.S. Pat. No. 5,585,348 does not disclose that the
selective opioid receptor antagonist may be administered in the
absence of nerve growth factor, and does not teach or suggest that
the administration of a selective excitatory opioid receptor
antagonist alone would be useful in treating IBS.
SUMMARY OF THE INVENTION
[0018] The present invention is directed to a method for treating a
subject with IBS. The method comprises administering to the patient
a low dose of an opioid receptor antagonist. In addition, the
present invention provides a pharmaceutical composition, comprising
an effective dose of an excitatory opioid receptor antagonist, and
a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
[0019] As used herein, "treating IBS" is considered to mean
reducing or attenuating abdominal pain and reducing or attenuating
one or more of abnormal consistency or abnormal frequency of stools
associated with IBS in a patient. The present inventors have
discovered that longterm administration of an excitatory opioid
receptor antagonist can relieve symptoms associated with IBS, in
particular the abdominal pain and the abnormal consistency and/or
frequency of stools. Accordingly, the present invention is directed
to a method for treating patients with IBS by longterm
administration of appropriately low doses of an excitatory opioid
receptor antagonist.
[0020] The primary concept of the present invention is that since
remarkably similar bimodal excitatory and inhibitory opioid
receptor functions have been demonstrated to exist in myenteric
neurons in the intestine (Xu, H. et al., Brain Res. 1989
504(1):36-42; Gintzler, A. R., Adv Exp Med Biol. 1995 373:73-83;
Wang and Gintzler, 1995) as occur in somatic sensory and CNS
neurons (Shen, K. -F. and Crain, S. M., Brain Res. 1989
491(2):227-42; Crain, S. M. and Shen, K. -F., Trends Pharmacol Sci.
1990 11(2):77-81; Crain and Shen, 1998), selective antagonism of
abnormal or supersensitized excitatory opioid receptor functions in
gut neurons by low doses of an opioid receptor antagonist may
enhance the analgesic effects of endogenous opioids on visceral
sensory neurons and attenuate hypersensitivities and
hyperexcitabilities of visceral sensory and visceral motor neurons
involved in IBS.
[0021] Abnormal levels of endogenous opioid peptides may be
generated in the gut by emotional stress, inflammatory or metabolic
disorders, or intrinsic release from gut neurons. Excitatory opioid
receptors in the gut may become supersensitized by chronic exposure
to endogenous or exogenous bimodally-acting (excitatory/inhibitory)
opioid agonists, as has been shown to occur in somatic sensory
dorsal root ganglia ("DRG") neurons (Crain, S. M. and Shen, K. -F.,
Brain Res. 1992 575:13-24; Shen, K. -F. and Crain, S. M., Brain Res
1992 597:74-83). Neurons with supersensitized excitatory opioid
receptor functions in the gut may therefore become "physically
dependent" on opioids, just as occurs in somatic sensory and CNS
neurons. Selective activation of excitatory opioid receptor
functions by application of low (i.e., nM) concentrations of
bimodally-acting opioid agonists to myenteric neurons in the guinea
pig ileum enhances the high-K.sup.+-stimulated release of the
.mu./.delta. opioid peptide, Met-enkephalin, whereas high (i.e.,
.mu.M) opioid concentrations inhibits Met-enkephalin release (Xu et
al., 1989). Intermittent increases in the release of Met-enkephalin
or other endogenous opioid peptides by activation of
supersensitized excitatory opioid receptors in the gut could,
therefore, exacerbate "dependence" and "withdrawal" symptoms
associated with IBS via a positive-feedback cycle analogous to
mechanisms proposed to mediate protracted opioid dependence in the
CNS (Crain and Shen, Brain Res 1992, Crain and Shen, 1998). In
addition, the release of the kappa opioid peptide, dynorphin, from
the peripheral (as well as central) terminals of sensory neurons
may also play a role in mediating hyperalgesic effects in IBS, in
view of evidence obtained on DRG neurons in vitro and in vivo
(Shen, K. -F. and Crain, S. M., J Neurosci 1994 14:5570-5579;
Apfel, S. C. et al., Neurosci 1995 68:1199-1206).
[0022] Excitatory opioid receptor antagonists suitable for use in
the present invention include, but are not limited to, nalmefene,
naltrexone, naloxone, etorphine and dihydroetorphine, as well as
similarly acting opioid alkaloids and opioid peptides (e.g.,
biphalin, see Horan, P. J. et al., J Pharmacol Exp Ther. 1993
265(3):1446-54; Shen, K. -F. and Crain, S. M., Brain Res 1995
701(1-2):158-66). Preferred excitatory opioid receptor antagonists
are nalmefene and naltrexone, because of their increased duration
of action as compared to naloxone and their greater bioavailability
after oral administration.
[0023] Other excitatory opioid receptor antagonists suitable for
use in the present invention may be identified by measuring their
effect on the action potential duration ("APD") of DRG neurons in
tissue cultures, as described in U.S. Pat. No. 5,472,943. In
particular, excitatory opioid receptor antagonists of the present
invention are compounds which selectively block prolongation of the
APD of DRG neurons induced by low concentrations of morphine and
other bimodally acting opioids (an excitatory opioid receptor
effect), and unmask shortening of the APD (an inhibitory opioid
receptor effect) in DRG neurons, which generally requires much
higher concentrations of these bimodally-acting opioid receptor
agonists (see U.S. Pat. No. 5,472,943).
[0024] The dose of an excitatory receptor antagonist to be
administered would vary according to the specific pharmacologic
properties of the opioid receptor antagonist employed and the
characteristics of the IBS patient. For example, where the opioid
receptor antagonist employed is naltrexone, in most cases the daily
dose would be in a range between about 0.1 mg/day and about 5
mg/day. More preferably, the dose would be in a range between about
0.3 mg/day and about 3 mg/day. Where the opioid receptor antagonist
employed is nalmefene, in most cases the daily dose would be in a
range between about 0.01 mg/day and about 1 mg/day. The dose
administered should be sufficient to relieve the abdominal pain and
other symptoms associated with IBS, but not so high as to induce
dysphoria or other adverse side effects caused by sustained
blockage of inhibitory opioid receptor functions. At such a dose,
the opioid receptor antagonist binds selectively to the excitatory
opioid receptors on the myenteric and CNS neurons and thereby
inactivates excessive excitatory opioid receptor-mediated
functions, such as hyperexcitability, hyperalgesia, tolerance,
physical dependence, and others. The inhibitory opioid receptor
functions are not attenuated by these low doses of the opioid
receptor antagonist. As a result, the excitatory opioid receptor
antagonist treatment enhances the analgesic potency and decreases
the undesirable side effects associated with chronic activation by
endogenous bimodally-acting opioid peptides, including enkephalins,
dynorphins and endorphins, which are markedly upregulated in
chronic pain patients (Crain and Shen, 1995).
[0025] Naltrexone (50 mg tablets, DuPont Merck, tradenames Trexan
or Revia) is currently approved by the FDA for longterm daily
treatment of alcohol and opioid addiction. This treatment may also
be effective in attenuating some types of IBS symptoms. However, at
the relatively high dose employed in these treatments, naltrexone
blocks all inhibitory as well as excitatory opioid receptor
functions, thereby interfering with analgesia mediated by
endogenous as well as exogenous opioids. Therefore, high-dose
naltrexone or nalmefene (tradename Revex; Cheskin, L. J. et al.,
Drug Alcohol Depend 1995 39(2):151-4), by antagonizing inhibitory
opioid receptors, will not reliably attenuate abdominal pain nor
intestinal dysmotility underlying changes in the consistency or
frequency of stools, and may also interfere with other important
inhibitory opioid receptormediated functions in the central nervous
system that regulate normal emotional and euphoric states.
Accordingly, low dose, selective excitatory opioid receptor
antagonist therapy offers an attractive alternative that reliably
attenuates abdominal pain and intestinal dysmotility underlying
changes in the consistency or frequency of stools, while retaining
significant inhibitory opioid receptor-mediated functions in the
peripheral and central nervous system.
[0026] The excitatory opioid receptor antagonists for use in the
present invention may be in the form of free bases or
pharmaceutically acceptable acid addition salts thereof. Examples
of suitable acids for salt formation include but are not limited to
methanesulfonic, sulfuric, hydrochloric, glucuronic, phosphoric,
acetic, citric, lactic, ascorbic, maleic, and the like.
[0027] The excitatory opioid receptor antagonist may be
administered to a human or animal subject by known procedures
including but not limited to orally, sublingually, parenterally,
transdermally, and by suppository.
[0028] The excitatory opioid receptor antagonists may be formulated
in compositions with a pharmaceutically acceptable carrier. The
carrier must be "acceptable" in the sense of being compatible with
the other ingredients of the formulation and not deleterious to the
recipient thereof. Examples of suitable pharmaceutical carriers
include lactose, sucrose, starch, talc, magnesium stearate,
crystalline cellulose, methyl cellulose, carboxymethyl cellulose,
glycerin, sodium alginate, gum arabic, powders, saline, water,
among others. The formulations may conveniently be presented in
unit dosage and may be prepared by methods well-known in the
pharmaceutical art, by bringing the active compound into
association with a carrier or diluent, as a suspension or solution,
and optionally one or more accessory ingredients, e.g. buffers,
flavoring agents, surface active agents, and the like. The choice
of carrier will depend upon the route of administration.
[0029] For oral and sublingual administration, the formulation may
be presented as capsules, tablets, powders, granules or a
suspension, with conventional additives such as lactose, mannitol,
corn starch or potato starch; with binders such as crystalline
cellulose, cellulose derivatives, acacia, corn starch or gelatins;
with disintegrators such as corn starch, potato starch or sodium
carboxymethyl-cellulose; and with lubricants such as talc or
magnesium stearate.
[0030] For parenteral administration, the opioid receptor
antagonist may combined with a sterile aqueous solution which is
preferably isotonic with the blood of the recipient. Such
formulations may be prepared by dissolving solid active ingredient
in water containing physiologically compatible substances such as
sodium chloride, glycine, and the like, and having a buffered pH
compatible with physiological conditions to produce an aqueous
solution, and rendering said solution sterile. The formulations may
be present in unit or multi-dose containers such as sealed ampoules
or vials.
[0031] For transdermal administration, the opioid receptor
antagonist may be combined with skin penetration enhancers such as
propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic
acid, N-methylpyrrolidone, and the like, which increase the
permeability of the skin to the compounds, and permit the compounds
to penetrate through the skin and into the bloodstream. The
antagonist/enhancer compositions also may be combined additionally
with a polymeric substance such as ethylcellulose, hydroxypropyl
cellulose, ethylene/vinylacetate, polyvinyl pyrrolidone, and the
like, to provide the composition in gel form, which can be
dissolved in solvent such as methylene chloride, evaporated to the
desired viscosity, and then applied to backing material to provide
a patch.
[0032] For administration by suppository, the opioid receptor
antagonist may be combined with any appropriate base to form a mass
that is solid at room temperature but dissolves at body
temperature. The base may include, without limitation, cocao
butter, glycerinated gelatin, hydrogenated vegetable oils,
polyethylene glycols of various molecular weights, fatty acid
esters of polyethylene glycols, and the like.
[0033] The amount of the excitatory opioid receptor antagonist
administered is an amount effective to attenuate abdominal pain and
intestinal dysmotility which produces changes in the consistency or
frequency of stools and thereby enhance the analgesic potency of
endogenous opioid peptide agonists in the intestinal tract and in
the CNS. That is, the opioid receptor antagonist is administered at
a low dose which blocks the effects of bimodally-acting opioid
peptide agonists on higher-affinity excitatory opioid receptors
without blocking the effects on inhibitory opioid receptors. This
amount is readily determinable by one skilled in the art (Crain and
Shen, 1995, 1998; Shen and Crain, 1997).
[0034] The present invention is described in the following Clinical
Study which is set forth to aid in the understanding of the
invention, and should not be construed to limit in any way the
invention as defined in the claims which follow thereafter.
Clinical Study
[0035] An open study of low dose naltrexone administration in four
(4) patients with IBS was initiated. The patients were evaluated
for IBS, based on the Rome criteria. All patients were screened for
other disorders or medications that could cause gastrointestinal
symptoms of IBS. These included inflammatory bowel disease, cancer,
lactose intolerance, and neurological disorders, as well as the use
of narcotic medications. Each patient was considered to be
significantly incapacitated by their symptoms. Each subject was
fully informed of the benefits and possible side effects of the
study and thereafter freely gave their consent to participate in
the study.
[0036] Each patient maintained a daily diary of the symptoms prior
to and during treatment with 1-3 mg/day of naltrexone. Each
participant noted the following symptoms:
[0037] 1. Pain, relieved by defecation
[0038] 2. Stool frequency
[0039] 3. Stool consistency
[0040] 4. Abdominal distension
[0041] 5. Passage of mucus
[0042] 6. Completion of evacuation
[0043] In addition, each patient was asked to globally assess their
subjective improvement on a scale of 0-4 (zero corresponding to no
observable change, and 4 representing a marked and substantially
improved state). Patients were permitted to remain on medications
other than anticholinergics and anti-diarrheal agents (i.e., fiber
bulking agents or lactose enzyme replacement if needed).
[0044] Naltrexone (tradename Revia; 50 mg tablets; DuPont Merck)
was purchased at a pharmacy. Single tablets were crushed and
dissolved in 50 ml boiled distilled water, and stored unfrozen in a
refrigerator. Each patient received 2 ml (2 mg) orally each morning
with breakfast. Medication was prepared weekly and used for seven
doses, with the remainder being discarded. None of the four
patients reported discernible side effects.
[0045] Patient A was a 64-year-old male with lifelong symptoms of
cramping abdominal pain and unformed bowel movements associated
with mucus, usually in the morning, about 4-8 times per day. After
nine months of treatment, Patient A reported that stool frequency
was reduced to 1-2 formed bowel movements per day with no cramping
abdominal pain. Patient A assessed his global improvement on the
0-4 scale as 4.
[0046] Patient B was a 71-year-old female with constipation
episodes accompanied by cramping abdominal pain over a nine-year
period. After a sigmoid resection for bleeding from a diverticulum
two years ago, she had 10-12 diarrheal movements per day with
increased cramping that was unresponsive to anti-diarrheals
(loperamide) and a calcium carbophil bulking agent (2 tablets with
meals). After 75 days of treatment, Patient B reported stool
frequency was reduced to 2-4 bowel movements per day with total
elimination of abdominal pain associated with cramping. Patient B
assessed her global improvement on the 0-4 scale as 3.
[0047] Patient C was a 63-year-old male reporting symptoms of
abdominal cramping pain, particularly at night, abdominal
distension, and 2-3 loose bowel movements daily. After 75 days of
treatment with 2 mg/day of naltrexone, Patient C reported his
abdominal pain associated with cramping had been eliminated, and
his loose bowel movements had been halved in frequency. Patient C
assessed his global improvement on the 0-4 scale as 2.5.
[0048] Patient D was a 42-year-old male who, over a three and a
half year period of care, had reported 7-10 unformed diarrheal
movements per day, with incapacitating abdominal cramping at
various periods throughout the day. He was also known to be lactose
intolerant, and was being ameliorated by a lactose free diet and
enzyme replacement therapy at meals. Patent D required daily
loperamide and anticholinergics prior to initiation of the study.
Upon initiation of low dose naltrexone treatment, Patient D
reported immediate relief of abdominal cramping symptoms and
reduction in stool frequency by 50 percent. This improvement has
continued over a 70 day treatment period, except when Patient D
noted intake of alcoholic beverages (equivalent to ca. 25-35 gm
equivalent of ethyl alcohol), whereupon IBS symptoms recurred for
the next twenty-four hours. Patient D assessed his global
improvement on the 0-4 scale as 2.5.
[0049] Patients A and C both attempted to change dosing schedules
to every other day during the treatment period. In both cases, IBS
symptoms returned, and remained until the daily treatment schedule
was restored. Patient A also noted a return of symptoms when he
traveled and forgot to pack his medication.
[0050] A followup of each patient was performed 24 months after the
start of the study. After 24 months of treatment, Patient A was on
a schedule of 2.5-3.0 mg naltrexone/day, corresponding to a dose of
25-30 .mu.g/kg body weight/day. Patient A reported that his
abdominal cramping had completely ceased, and his frequency of
bowel actions had returned to normal levels.
[0051] Patient B reported after 12 months of treatment that she was
on a schedule of 1.5-2.3 mg naltrexone/day, corresponding to a dose
of 30-45 .mu.g/kg body weight/day. Patient B experienced a 50%
reduction in abdominal cramping, but no change in the frequency of
bowel actions.
[0052] After 24 months of the study, Patient C had been diagnosed
with fibromyalgia, and his IBS symptoms did not respond. Patient C
had been on a regimen of 1-2 mg naltrexone/day, corresponding to a
dose of 14-27 .mu.g/kg body weight/day. Patient C refused to
escalate the dose of naltrexone, and naltrexone was stopped after 6
months.
[0053] Patient D reported after nine months of treatment that he
was on a schedule of 2.5-3.0 mg naltrexone/day, corresponding to a
dose of 25-30 Ag/kg body weight/day. After 9 months of treatment,
Patient D reported a 75% decrease in cramping, and a 20% reduction
in frequency of bowel actions. At this point low-dose naltrexone
treatment was halted, and IBS symptoms returned.
[0054] All publications and patents mentioned hereinabove are
hereby incorporated by reference in their entirety.
[0055] Although the invention herein has been described with
reference to particular embodiments, it is to be understood that
these embodiments are merely illustrative of various aspects of the
invention. Thus, it is to be understood that numerous modifications
may be made in the illustrative embodiments and other arrangements
may be devised without departing from the spirit and scope of the
invention.
* * * * *