U.S. patent application number 09/932293 was filed with the patent office on 2002-05-16 for triple drug therapy for the treatment and prevention of acute or chronic pain.
Invention is credited to Ockert, David M..
Application Number | 20020058656 09/932293 |
Document ID | / |
Family ID | 26926982 |
Filed Date | 2002-05-16 |
United States Patent
Application |
20020058656 |
Kind Code |
A1 |
Ockert, David M. |
May 16, 2002 |
Triple drug therapy for the treatment and prevention of acute or
chronic pain
Abstract
A triple drug therapy, pharmaceutical kit, composition, and
method of treatment regimen utilized as a combination of effective
amounts of an anxiolytic agent, centrally acting alpha
antiadrenergic agent, and central nervous system stimulant for the
reduction or prevention of dizziness, drowsiness, depression,
delirium, lethargy, mania, orthostatic hypotension, restlessness,
weakness in the extremities, and difficulty in being mobile
negative side effects caused by therapeutic agents utilized in the
treatment of acute and chronic pain syndromes.
Inventors: |
Ockert, David M.; (New York,
NY) |
Correspondence
Address: |
PRICE HENEVELD COOPER DEWITT & LITTON
695 KENMOOR, S.E.
P O BOX 2567
GRAND RAPIDS
MI
49501
US
|
Family ID: |
26926982 |
Appl. No.: |
09/932293 |
Filed: |
August 17, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60233518 |
Sep 19, 2000 |
|
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Current U.S.
Class: |
514/221 ;
514/252.12; 514/649 |
Current CPC
Class: |
A61K 45/06 20130101 |
Class at
Publication: |
514/221 ;
514/252.12; 514/649 |
International
Class: |
A61K 031/5513; A61K
031/495; A61K 031/135 |
Claims
The invention claimed is:
1. A pharmaceutical kit for the treatment of acute and chronic pain
syndrome comprising the combination of: at least one anxiolytic
agent; at least one centrally acting alpha antiadrenergic agent;
and at least one central nervous system stimulant agent.
2. The pharmaceutical kit of claim 1, wherein said kit contains an
effective amount of said anxiolytic agent to reduce or prevent
anxiety, an effective amount of said centrally acting alpha
antiadrenergic agent to reduce or prevent central and peripheral
nerve agitation, and an effective amount of said central nervous
system stimulant agent to reduce or prevent negative e side effects
associated with acute and chronic pain syndrome treatment.
3. The pharmaceutical kit of claim 2, wherein said anxiolytic agent
comprises at least one member selected from the group consisting of
a benzodiazepine, azaspirodecanedione, piperazine derivative,
gabapentin, derivatives thereof, and pharmaceutically acceptable
salts thereof.
4. The pharmaceutical kit of claim 3, wherein said anxiolytic agent
is a benzodiazepine selected from the group consisting of diazepam,
alprazolam, clonazepam, clorazepate, chlordiazepoxide, halazepam,
lorazepam, oxazepam, derivatives thereof, and pharmaceutically
acceptable salts thereof.
5. The pharmaceutical kit of claim 4, wherein said benzodiazepine
is chlordiazepoxide.
6. The pharmaceutical kit of claim 5, wherein said effective amount
of said chlordiazepoxide is about 50-60 mg per dose.
7. The pharmaceutical kit of claim 3, wherein said benzodiazepine
is lorazepam and said effective amount of said lorazepam is about
0.25-10 mg per dose.
8. The pharmaceutical kit of claim 2, wherein said anxiolytic agent
is gabapentin and said effective amount of said gabapentin is from
about 300 mg to 4000 mg per day.
9. The pharmaceutical kit of claim 2, wherein said centrally acting
alpha antiadrenergic agent comprises of at least one member
selected from the group consisting of methyldopa, clonidine,
guanfacine, lofexidine, guanabenz, derivatives thereof and
pharmaceutically acceptable salts thereof.
10. The pharmaceutical kit of claim 9, wherein said centrally
acting alpha antiadrenergic agent is clonidine and said effective
amount of said clonidine is about 0.05-0.7 mg per dose.
11. The pharmaceutical kit of claim 2, wherein said central nervous
system stimulant agent comprises of at least one member selected
from the group consisting of an amphetamine, methylphenidate,
pemoline, caffeine, centrally acting alpha-1 agonist, derivatives
thereof, and pharmaceutically acceptable salts thereof.
12. The pharmaceutical kit of claim 11, wherein said central
nervous system stimulant is dextroamphetamine sulfate and said
effective amount of said dextroamphetamine sulfate is about 1-20 mg
per dose.
13. The pharmaceutical kit of claim 12, wherein said
dextroamphetamine sulfate is in a sustained release form.
14. The pharmaceutical kit of claim 11, wherein said central
nervous system stimulant agent is modafinil and said effective
amount of said modafinil is about 50-400 mg or greater per
dose.
15. The pharmaceutical kit of claim 14, wherein said effective
amount of said modafinil is about 200 mg per dose.
16. The pharmaceutical kit of claim 2, wherein said anxiolytic
agent comprises at least one member selected from the group
consisting of a benzodiazepine, azaspirodecanedione, piperazine
derivative, gabapentin, derivatives thereof, and pharmaceutically
acceptable salts thereof; wherein said centrally acting alpha
antiadrenergic agent comprises at least one member selected from
the group consisting of methyl dopa, clonidine, guanfacine,
lofexidine, guanabenz, derivatives thereof and pharmaceutically
acceptable salts thereof; wherein said central nervous system
stimulant agent comprises of at least one member selected from the
group consisting of an amphetamine, methylphenidate, pemoline,
caffeine, centrally acting alpha-1 agonist, derivatives thereof and
pharmaceutically acceptable salts thereof; and further wherein said
benzodiazepine comprises of at least one member selected from the
group consisting of diazepam, alprazolam, clonazepam, chlorazepate,
chlordiazepoxide, halazopam, lorazepam, oxazepam, derivatives
thereof, and pharmaceutically acceptable salts thereof.
17. The pharmaceutical kit of claim 16, wherein said combination
comprises about 0.25-10 mg of lorazepam, about 0.05-0.7 mg of
clonidine, and about 1-20 mg of dextroamphetamine sulfate per dose
of said combination.
18. The pharmaceutical kit of claim 16, wherein said combination
comprises about 50-60 mg of chlordiazepoxide, about 0.05-0.7 mg of
clonidine, and about 1-20 mg of dextroamphetamine sulfate per dose
of said combination.
19. The pharmaceutical kit of claim 16, wherein said combination
comprises about 0.25-10 mg of said lorazepam, about 0.05-0.7 mg of
said clonidine, and about 50-400 mg or greater of modafinil per
dose of said combination.
20. The pharmaceutical kit of claim 16 wherein said combination
comprises about 50-60 mg of said chlordiazepoxide, about 0.05-0.7
mg of clonidine, and about 50-400 mg or greater of modafinil per
dose of said combination.
21. The pharmaceutical kit of claim 16, wherein said combination
comprises about 0.25-10 mg of lorazepam, about 0.05-0.7 mg of
clonidine, about 50-400 mg or greater of said modafinil, and about
1-20 mg of dextroamphetamine sulfate per dose of said
combination.
22. The pharmaceutical kit of claim 16, wherein said combination
comprises about 50-60 mg or less of chlordiazepoxide, about
0.05-0.7 mg of clonidine, about 1-20 mg dextroamphetamine sulfate,
and about 50-400 mg or greater of modafinil per dose of said
combination.
23. A pharmaceutical composition for the treatment of acute and
chronic pain syndrome comprising a combination of at least one
anxiolytic agent; at least one centrally acting alpha
antiadrenergic agent; and at least one central nervous system
stimulant agent.
24. The pharmaceutical composition of claim 23, wherein said
composition comprises of an effective amount of said anxiolytic
agent to reduce or prevent anxiety, an effective amount of said
centrally acting alpha antiadrenergic agent to reduce or prevent
central and peripheral nerve agitation, and an effective amount of
said central nervous system stimulant agent to reduce or prevent
negative side effects associated with acute and chronic pain
syndrome treatment.
25. The pharmaceutical composition of claim 24, wherein said
anxiolytic agent comprises at least one member selected from the
group consisting of a benzodiazepine, azaspirodecanedione,
piperazine derivative, gabapentin, derivatives thereof, or
pharmaceutically acceptable salts thereof.
26. The pharmaceutical composition of claim 25, wherein said
anxiolytic agent is a benzodiazepine selected from the group
consisting of diazepam, alprazolam, clonazepam, clorazepate,
chlordiazepoxide, halazepam, lorazepam, oxazepam, derivatives
thereof, or pharmaceutically acceptable salts thereof.
27. The pharmaceutical composition of claim 26, wherein said
benzodiazepine is chlordiazepoxide.
28. The pharmaceutical composition of claim 27, wherein said
effective amount of said chlordiazepoxide is about 50-60 mg per
dose.
29. The pharmaceutical composition of claim 26, wherein said
benzodiazepine is lorazepam and said effective amount of said
lorazepam is about 0.25-10 mg per dose.
30. The pharmaceutical composition of claim 24, wherein said
centrally acting alpha antiadrenergic agent comprises of at least
one member selected from the group consisting of methyldopa,
clonidine, guanfacine, lofexidine, guanabenz, derivatives thereof
and pharmaceutically acceptable salts thereof.
31. The pharmaceutical composition of claim 24, wherein said
centrally acting alpha antiadrenergic agent comprises of at least
one member selected from the group consisting of methyldopa,
clonidine, guanfacine, guanabenz, lofexidine, derivatives thereof
and pharmaceutically acceptable salts thereof.
32. The pharmaceutical composition of claim 31, wherein said
centrally acting alpha antiadrenergic agent is clonidine and said
effective amount of said clonidine is about 0.05-0.7 mg per
dose.
33. The pharmaceutical composition of claim 24, wherein said
central nervous system stimulant agent comprises of at least one
member selected from the group consisting of an amphetamine,
methylphenidate, pemoline, caffeine, centrally acting alpha-1
agonist, derivatives thereof, and pharmaceutically acceptable salts
thereof.
34. The pharmaceutical composition of claim 33, wherein said
central nervous system stimulant is dextroamphetamine sulfate and
said effective amount of said dextroamphetamine sulfate is about
1-20 mg per dose.
35. The pharmaceutical composition of claim 34, wherein said
effective amount of said dextroamphetamine sulfate is in a
sustained release form.
36. The pharmaceutical composition of claim 33, wherein said
central nervous system stimulant agent is modafinil and said
effective amount of said modafinil is about 50-400 mg or greater
per dose.
37. The pharmaceutical composition of claim 36, wherein said
effective amount of said modafinil is about 200 mg per dose.
38. The pharmaceutical composition of claim 37, wherein said
composition comprises about 0.25-10 mg lorazepam, about 0.05-0.7 mg
clonidine, and about 1-20 mg dextroamphetamine sulfate per dose of
said combination.
39. The pharmaceutical composition of claim 38, wherein said
combination comprises about 100 mg or less chlordiazepoxide, about
0.05-0.7 mg clonidine, and about 1-20 mg dextroamphetamine sulfate
per dose of said combination.
40. The pharmaceutical composition of claim 38, wherein said
combination comprises about 0.25-10 mg lorazepam, about 0.05-0.7 mg
clonidine, and about 50-400 mg or greater of modafinil per dose of
said combination.
41. The pharmaceutical composition of claim 38, wherein said
combination comprises about 100 mg or less chlordiazepoxide,
0.05-0.7 mg clonidine, and about 50-400 mg or greater of modafinil
per dose of said combination.
42. The pharmaceutical composition of claim 38, wherein said
combination comprises about 0.25-10 mg of lorazepam, about 0.05-0.7
mg of clonidine, about 50-400 mg or greater of modafinil, and about
1-20 mg dextroamphetamine sulfate per dose of said combination.
43. The pharmaceutical composition of claim 38, wherein said
combination comprises about 100 mg or less chlordiazepoxide, about
0.05-0.7 mg clonidine, about 1-20 mg of dextroamphetamine sulfate,
and about 50-400 mg or greater modafinil per dose of said
combination.
44. A method for treating and preventing acute and chronic pain
syndrome, administering separately, but contemporaneously, a
combination of at least one anxiolytic agent, at least one
centrally acting alpha antiadrenergic agent, and at least one
central nervous system stimulant agent.
45. The method of claim 44, wherein the method contains an
effective amount of said anxiolytic agent to reduce or prevent
anxiety, an effective amount of said centrally acting alpha
antiadrenergic agent to reduce or prevent central and peripheral
nerve agitation, and an effective amount of said central nervous
system stimulant agent to reduce or prevent negative side effects
associated with acute and chronic pain syndrome treatment.
46. The method of claim 45, wherein said anxiolytic agent comprises
at least one member selected from the group consisting of a
benzodiazepine, azaspirodecanedione, piperazine derivative,
gabapentin, derivatives thereof, and pharmaceutically acceptable
salts thereof, and further wherein said benzodiazepine comprises at
least one member selected from the group consisting of diazepam,
alprazolam, clonazepam, clorazepate, chlordiazepoxide, halazepam,
lorazepam, oxazepam, derivatives thereof, and pharmaceutically
acceptable salts thereof.
47. The method of claim 46, wherein said anxiolytic agent is
chlordiazepoxide.
48. The method of claim 47, wherein said effective amount of said
chlordiazepoxide is about 50-60 mg administered about every 6-8
hours around the clock initially and gradually tapering said
effective amount of said chlordiazepoxide thereafter for a period
of about 5-14 days.
49. The method of claim 46, wherein said anxiolytic agent is
lorazepam and said effective amount of said lorazepam is about
0.25-10 mg administered about every 6-8 hours during the day and
about every 3-4 hours during the night initially, and gradually
tapering said effective amount of said lorazepam thereafter for a
period of about 5-14 days.
50. The method of claim 45, wherein said centrally acting alpha
antiadrenergic agent comprises of at least one member selected from
the group consisting of methyldopa, clonidine, guanfacine,
lofexidine, guanabenz, derivatives thereof and pharmaceutically
acceptable salts thereof.
51. The method of claim 46, wherein said centrally acting alpha
antiadrenergic agent comprises at least one member selected from
the group consisting of methyldopa, clonidine, guanfacine,
guanabenz, lofexidine, derivatives thereof and pharmaceutically
acceptable salts thereof.
52. The method of claim 46, wherein said centrally acting alpha
antiadrenergic agent is clonidine and said effective amount of
clonidine is about 0.05-0.7 mg administered about every 6-8 hours
for a period of about 5-14 days.
53. The method of claim 46, wherein said central nervous system
stimulant comprises at least one member selected from the group
consisting of an amphetamine, methylphenidate, pemoline, caffeine,
centrally acting alpha-1 agonist, derivatives thereof, and
pharmaceutically acceptable salts thereof.
54. The method of claim 53, wherein said central nervous system
stimulant is dextroamphetamine sulfate and said effective amount of
said dextroamphetamine sulfate is about 1-20 mg administered about
every 4-6 hours during the day and up to about 5 mg during the
night if needed for a period of about 5-14 days.
55. The method of claim 54 wherein said central nervous system
stimulant is dextroamphetamine sulfate and said effective amount of
dextroamphetamine sulfate is about 1-20 mg in a sustained release
form administered about every 12 hours to about once daily for a
period of about 5-14 days.
56. The method of claim 45, wherein said anxiolytic agent comprises
at least one member selected from the group consisting of a
benzodiazepine, azaspirodecanedione, piperazine derivative,
gabapentin, derivatives thereof, and pharmaceutically acceptable
salts thereof; wherein said centrally acting alpha antiadrenergic
agent comprises at least one member selected from the group
consisting of methyldopa, guanabenz, guanfacine, clonidine,
lofexidine, derivatives thereof, and pharmaceutically acceptable
salts thereof, wherein said central nervous system stimulant agent
comprises at least one member selected from the group consisting of
an amphetamine, methylphenidate, pemoline, caffeine, centrally
acting alpha-1 agonist, derivatives thereof, and pharmaceutically
acceptable salts thereof; and further wherein to said
benzodiazepine comprises at least one member selected from the
group consisting of diazepam, alprazolam, clonazapam, clorazepate,
chlordiazepoxide, halazepam, lorazepam, oxazepam, derivatives
thereof, and pharmaceutically acceptable salts thereof.
57. The method of claim 56, wherein said combination is about 50-60
mg of chlordiazepoxide administered about every 6-8 hours around
the clock initially and gradually tapering said chlordiazepoxide
thereafter; about 0.05-0.7 mg of clonidine administered about every
6-8 hours; and about 1-20 mg of said dextroamphetamine sulfate
administered about every 4-6 hours during the day and up to about 5
mg during the night if needed for a period of about 5-14 days.
58. The method of claim 56, wherein said combination is about 50-60
mg of said chlordiazepoxide administered about every 6-8 hours
around the clock initially and gradually tapering said
chlordiazepoxide thereafter; about 0.05-0.7 mg of clonidine
administered about every 6-8 hours; and about 1-20 mg of said
dextroamphetamine sulfate in a sustained release form administered
about every twelve hours to about once daily for a period of about
5-14 days.
59. The method of claim 56, wherein said combination is about
0.25-10 mg of said lorazepam administered about every 6-8 hours
during the day and about every 3-4 hours during the night
initially, and gradually tapering said lorazepam thereafter; about
0.05-0.7 mg of said clonidine administered about every 6-8 hours;
and about 1-20 mg of said dextroamphetamine sulfate administered
about every 4-6 hours during the day and up to about 5 mg during
the night if needed for a period of about 5-14 days.
60. The method of claim 56, wherein said effective amount of said
combination is about 0.25-10 mg of lorazepam administered about
every 6-8 hours during the day and about every 3-4 hours during the
night initially, and gradually tapering said lorazepam thereafter;
about 0.05-1.4 mg of clonidine about every 6-8 hours; and about
1-20 mg of dextroamphetamine sulfate in a sustained release form
administered about every 12 hours to about once daily for a period
of about 5-14 days.
61. The method of claim 56, wherein said effective amount of said
combination is about 0.25-10 mg of lorazepam administered about
every 6-8 hours during the day and about every 3-4 hours during the
night initially, and gradually tapering said lorazepam thereafter;
about 0.05-0.7 mg of clonidine about every 6-8 hours; and about
50-400 mg of modafinil administered about every 12 hours to about
once daily for a period of about 5-14 days.
62. The method of claim 56, wherein said effective amount of said
combination is about 50-60 mg of chloridazepoxide administered
about every 6-8 hours around the clock initially, and gradually
tapering said chlordiazepoxide thereafter; about 0.05-0.7 mg of
clonidine about every 6-8 hours; and about 50-400 mg of said
modafinil administered about every 12 hours to about once daily for
a period of about 5-14 days.
63. The method of claim 56, wherein said combination is about
0.25-10 mg of said lorazepam administered about every 6-8 hours
during the day and about every 3-4 hours during the night
initially, and gradually tapering said lorazepam thereafter; about
0.05-0.7 mg of clonidine about every 6-8 hours; and about 1-20 mg
of dextroamphetamine sulfate administered about every 4-6 hours
during the day and up to about 5 mg during the night if needed; and
about 50-400 mg of modafinil administered about every 12 hours to
about once daily for a period of about 5-14 days.
64. The method of claim 56, wherein said effective amount of said
combination is about 50-60 mg of chlordiazepoxide, administered
about every 6-8 hours around the clock initially, and gradually
tapering said chlordiazepoxide thereafter; about 0.05-0.7 mg of
clonidine administered about every 6-8 hours; about 1-20 mg of said
dextroamphetamine sulfate administered about every 4-6 hours during
the day and up to about 5 mg during the night if needed; and about
50-400 mg of said modafinil administered about every 12 hours to
about once daily for a period of 5-14 days.
65. The method of claim 56, wherein said effective amount of said
combination is about 50-60 mg or less of said chlordiazepoxide,
administered about every 6-8 hours around the clock initially, and
gradually tapering said chlordiazepoxide thereafter; about 0.05-0.7
mg of said clonidine administered about every 6-8 hours; about 1-20
mg of said dextroamphetamine sulfate in a sustained release form
administered once daily or about every 12 hours, and about 50-400
mg of said modafinil administered about every 12 hours to about
once daily for a period of 5-14 days.
66. The method of claim 56, wherein said effective amount of said
combination is about 0.25-10 mg of lorazepam administered about
every 6-8 hours during the day and about every 3-4 hours during the
night initially, and gradually tapering said lorazepam thereafter;
about 0.05-0.7 mg clonidine administered about every 6-8 hours;
about 1-20 mg of said dextroamphetamine sulfate in a sustained
release form administered once daily or about every 12 hours; and
about 50-100 mg modafinil administered about every 12 hours to
about once daily for period of about 5-14 days.
67. The method of claim 56, wherein said anxiolytic agent comprises
gabapentin administered in an amount of from about 300-4000 mg per
day.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority under 35 U.S.C.
.sctn.119(e) on U.S. Provisional Application No. 60/233,518, filed
Sep. 19, 2000, the entire disclosure of which is incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention:
[0003] The present invention relates to the treatment and
prevention of acute or chronic pain syndromes.
[0004] 2. Description of the Related Art/Background
Information:
[0005] Pain sensation is complex and variable. Experiences
considered painful by one subject may not be equally painful to
another and may vary in the same subject depending on the
circumstances presented. In addition, subjective experiences, i.e.
"phantom limb pain" make it clear that there is a strong
psychological component to pain. Wingard et al., Human
Pharmacology: Molecular to Clinical, Mosby-Year Book, Inc., 1991,
p. 383.
[0006] Several groups of compounds are used to relieve pain,
depending on the severity and duration of the pain sensation, and
on the nature of the painful stimulus. Drugs used to relieve mild,
moderate or severe pain without causing unconsciousness are
generally called analgesics. Mild analgesics that are termed
non-narcotic agents include aspirin, acetaminophen and
non-steroidal anti-inflammatory drugs. Should non-narcotic based
agents prove ineffective, narcotic/opioid analgesic agents such as
morphine, codeine, meperidine, and the like are used to treat more
severe acute or chronic forms of pain. Ibid., pp. 383, 391-92.
[0007] Generally, there are two different types of nociceptive
(noxious) stimuli, which are intense enough to be perceived as pain
within the human body and can be alleviated by narcotic and
non-narcotic analgesic agents. One type, somatic pain, consists of
an intense, localized, sharp or stinging sensation. Somatic pain is
believed to be mediated by fast-conducting lightly myelinated
A-delta fibers that have a high threshold (i.e. require a strong
mechanical stimulus to sense pain) and enter into the spinal cord
through the dorsal horn of the central nervous system where they
terminate mostly in lamina I of the spinal cord. Ibid., p. 383.
[0008] The second type of pain, sometimes referred to as visceral
pain, is characterized as a diffuse, dull, aching or burning
sensation. Visceral pain is believed to be mediated largely by
unmyelinated, slower-conducting C-fibers that are polymodal (i.e.,
mediate mechanical, thermal, or chemical stimuli). C-fibers also
enter the spinal cord through the dorsal horn of the central
nervous system where they terminate mostly in the outer layer of
lamina II of the spinal cord. Ibid., p. 383. Both somatic and
visceral pain can be sensed centrally and peripherally within the
human body.
[0009] Central sensitization, i.e. central pain, takes place within
the dorsal horn of the spinal cord, the brain stem, and brain.
Amplification of nociceptive input in the spinal cord produces
secondary hyperalgesia around the site of injury once central
sensitization has begun. Central sensitization is believed to be
evoked by A-beta low-threshold mechanoreceptors. Often, central
sensitization is initiated by slow synaptic potentials through
A-delta and C fibers within the dorsal horn of the central nervous
system. The long duration of these slow potentials permit summation
of potentials during repetitive nociceptor input and generates
progressively greater and longer-lasting depolarization in dorsal
horn neurons. Several seconds of C fiber input results in several
minutes of postsynaptic depolarization.
[0010] This depolarization is believed to result from the
activation of N-methyl-D-aspartic acid (NMDA) receptors like
glutamate, and activation of the NK-1 tachykinin receptor by
substance P and neurokinin A. Activation of these receptors allows
an inrush of calcium through ligand and voltage-gated ion channels
and activation of guanosine triphosphate (GTP) binding proteins.
"Pain and Memory", Pain Clinical Updates, Vol. VII, Iss. 1, Spring
1999, p. 2. These second messengers in turn simulate protein kinase
C activity, which enhances the function of ion channels and
intracellular enzymes by phosphorylating proteins. Ibid., p. 3.
[0011] Another mechanism of central sensitization involves the
production of intracellular nitric oxide. It has been proposed that
activation of the NMDA receptor leads to an influx of calcium ion,
which activates a central enzyme nitric oxide synthetase.
Intracellular nitric oxide release stimulates transduction of
protein kinase C, increases the effects of glutamate, and may
interfere with the release of inhibitory neurotransmitters from
inhibitory neurons within the central nervous system, causing
increases in pain in both the acute and chronic syndromes. Nitric
oxide antagonism is therefore another strategy to prevent central
sensitization. Ibid., p. 3.
[0012] Peripheral sensitization, i.e. peripheral pain, is generally
caused by activating A-delta and C nociceptors. Peripheral
sensitization is induced by neurohumoral alterations at the site of
injury to the human body and surrounding tissue area. Biochemicals
released by tissue injury, such as potassium, prostaglandins,
bradykinin, and the like excite nociceptors or increase their
sensitivity at the injured site (primary hyperalgesia). Substance
P, released by an axon reflex, induces vasodilation and mast cell
degranulation, resulting in the release of histamine and serotonin
which aid in pro-inflammatory reactions, which in turn sensitize
adjacent A-delta and C nociceptors further causing pain
stimulation. Increased transduction produces continuous nociceptive
input that can induce allodynia, primary hyperalgesia, and
secondary hyperalgesia. Ibid., p. 2.
[0013] Also within the central nervous system are endogenous pain
control systems, which descend the spinal cord through the
dorsolateral funiculus to the spinal dorsal horn where they inhibit
neurons that are activated by binociceptive stimuli. The higher
brain centers connected to these descending systems include the
pariaqueductal gray region and various subregions of the medulla
within the brain. The neurotransmitters for these systems include
substance P, somatostatin, vasoactive intestinal polypeptide,
cholecystokinin, calcitonin gene-related peptide, norepinephrine,
serotonin and opioid peptides. Ibid., pp. 383-84.
[0014] The spinal cord itself also contains opioid receptors, which
are mainly localized within laminae-I to III of the dorsal horn
within the tract of Lissauer. Of these, the highest density of
opioid receptors is generally localized in the inner segment of
lamina II. Ibid., p. 384. There are multiple types of opioid
receptors within the central nervous system designated as mu,
kappa, sigma, and delta receptors, with additional subclasses for
each of these receptor types. Activation of these receptors in the
brain is believed to be responsible with production of analgesic
effects. For example, it is believed that kappa receptors, which
exist in the brain's spinal cord, produce analgesia at the spinal
level. The majority of the psychotomimetic effects of opioid drugs,
i.e. dysphoria and hallucinations are believed to be mediated by
sigma receptors. Delta receptors have a different distribution in
the brain, and are thought to be the primary receptor for
endogenous opioid pentapeptides, such as enkephalins. Ibid., p.
385.
[0015] These types of receptors are located on the membranes of
neurons and interaction of agonists, such as narcotic analgesics,
with these receptors generally leads to a reduction in excitability
and firing rate within the neuron causing a decrease in pain
sensation. Agonists of mu receptors, for example, increase the
outward flux of potassium ions, which may make the neuron less
excitable, causing a decrease in pain. Agonists of kappa receptors
more directly inhibit the entry of calcium into a neuron through
voltage-dependent calcium channels, again causing a decrease in
pain in this manner. Agonists of mu and delta receptors are
believed to decrease neuronal cAMP synthesis to decrease pain
sensation. Ibid., p. 387.
[0016] Thus, the use of opioids, NSAIDS, and many other analgesics
within the prior art reduce both central and peripheral
sensitization through interaction with the various pain-based
receptors within the human body. For example, morphine and most
other opioid analgesics elicit an inhibitory neuronal effect within
central nervous and gastrointestinal (GI) systems within the human
body by interacting with areas of the brain receiving input from
the spinal pain-transmitting pathways containing opioid receptors.
By suppressing neuronal activity at these receptor points, opioid
narcotics produce analgesia and control the pain threshold within a
human patient. Yet, opioid narcotics are not without certain
negative side effects.
[0017] Because opioids cause neuronal depression, frequent side
effects which limit the use of such agents in pain treatment
settings include drowsiness, lethargy, difficulty in being mobile,
respiratory depression, excessive central nervous system
depression, weakness in the extremities, and dizziness. Frequently,
a patient's respiratory or central nervous system depression by an
opioid analgesic will limit the opioid's use or cause its
discontinuance from that patient's pain treatment program. This
causes prolonged treatment, or use of other agents which may not be
as clinically and therapeutically effective.
[0018] In addition, patients being treated with opioids also
develop tolerance to the agent, requiring higher doses, addition of
other opioids to the pain treatment regimen, and the ability to
develop physical and psychological addiction to such agents.
Further, the prior art has shown that opioids also can exhibit
excitatory effects upon opioid receptors. Yet, these excitatory
effects manifest themselves as side effects which include
restlessness, delirium, mania, and strychnine-like seizure
reactions. Such excitatory effects do not occur in all subjects
treated with an opioid analgesic, but do appear more prevalently
when a patient is treated with morphine or a morphine-like agent.
Wingard et al., Human Pharmacology: Molecular to Clinical,
Mosby-Year Book, Inc., 1991, p. 390.
[0019] Finally, other typical side effects of opioid analgesics
include miosis, or constriction of the pupils, nausea, vomiting,
prolongation of stomach emptying time, decreased propulsive
contractions of the small intestine, and increased tone large
intestine to slow transit materials through the GI tract. Ibid.,
pp. 390-91. As a result, most opioid analgesics are only utilized
to treat moderate to severe pain, and are used on a short-term
basis, only because of these side effects. Ibid., pp. 391-92.
[0020] As an alternative to opioid analgesics, non-narcotic based
drugs may be utilized to treat mild to moderate pain, and generally
because of their lower central nervous system and respiratory
depressive effects, can be given over longer periods of time than
opioid analgesics. Such non-narcotic agents include acetylsalicylic
acid (aspirin), centrally acting alpha antiadrenergic agents,
diflusinal, salsalate, acetaminophen, and nonsteroidal
anti-inflammatory agents such as ibuprofen, naproxen, and
fenoprofen. Ibid., p. 400.
[0021] The mechanism by which acetylsalicylic acid, acetaminophen,
diflusinal, salsalate, and nonsteroidal anti-inflammatory agents
act to reduce mild to moderate pain is through prostaglandin
synthesis inhibition resulting in a decrease in pain receptor
stimulation. Prior art studies in humans have shown that certain
prostaglandins elicit headaches, pain, and can produce hyperalgesia
within the central and peripheral neuronal zones of the human body.
Aspirin and related compounds inhibit the enzyme cyclooxygenase and
prevent the formation of prostaglandin endoperoxides, PGG and PGH,
normally formed from arachidonic acid, to reduce or prevent central
and peripheral nerve sensitization and nerve stimulation from
internal pain agonists. Ibid., p. 400-401.
[0022] However, even prostaglandin synthesis inhibitor agents have
shown difficulties within the prior art. Aspirin, for example, has
been shown through epidemiological data to be a factor in the
occurrence of Reye's syndrome. In addition, salicylates in general
have been shown within the prior art to cause gastrointestinal
upset, gastrointestinal hemorrhage, and anti-platelet effects.
Ibid., p. 409. Acetominophen, like aspirin, inhibits
cyclooxygenase, but has not been associated with Reye's syndrome or
the gastrointestinal effects like that of aspirin. Yet,
acetaminophen has been shown within the prior art to cause liver
damage, kidney damage, and hematological effects such as hemolytic
anemia, neutropenia, and leukopenia. Drug Facts and Comparisons,
1999 ed., 1997, p. 1450.
[0023] Lastly, non-steroidal anti-inflammatory drugs, such as
ibuprofen, many of which are derived from phenylpropionic acids,
can also be used to treat mild to moderate pain, and work mainly by
inhibiting cyclooxygenase. These agents exhibit analgesic,
anti-inflammatory, and antipyretic effects. These agents, too,
however, exhibit numerous negative side effects as well, ranging
from gastrointestinal distress, gastrointestinal hemorrhage, and
kidney damage. Ibid., p. 409410.
[0024] Centrally acting alpha antiadrenergic agents, such as
clonidine, have been shown within the prior art to reduce or
prevent central and peripheral nerve agitation. Ibid., p. 967-68,
1444-45. Prior art studies have shown that clonidine, for example,
can decrease central and peripheral nerve agitation as well as
increased blood pressure through adrenergic impulse inhibition.
Yet, centrally acting alpha antiadrenergic agents have been shown
to exhibit negative side effects such as central nervous and
cardiac system depression, dizziness, drowsiness, lethargy,
orthostatic hypotension, and weakness in the extremities. Ibid. In
addition, when a centrally acting alpha antiadrenergic agent is
added to an already existing pain treatment regimen containing an
anxiolytic agent, like lorazepam, an additive effect for dizziness,
drowsiness, central and cardiac depression, lethargy, weakness in
the extremities, orthostatic hypotension, and difficulty in being
mobile occurs. Ibid.
[0025] Anxiolytic agents such as benzodiazepines and
azaspirodecanediones, although not indicated for the treatment of
pain per se, are often employed in pain treatment regimens to
decrease the anxiety associated with pain treatment and anxiety
associated with further pain stimulus. Yet, the use of anxyiolytic
agents in such a pain treatment setting also has the problem of
frequent negative side effects.
[0026] Clinical neurology literature includes many descriptions of
patients having increased drowsiness, dizziness, depression,
weakness in the extremities, lethargy, orthostatic hypotension, and
difficulty in being mobile associated with treatments utilizing
anxiolytic agents and centrally acting alpha antiadrenergic agents
for the reduction or prevention of alcohol or narcotic withdrawal
symptoms such as anxiety, central and peripheral nerve agitation,
and hypertension associated with acute and chronic pain treatment.
Dunagan, W. and Ridner, M., Manual of Medical Therapeutics, 26th
ed., Boston, Little, Brown, 1989, p. 6-7, 474-75.
[0027] Clinical cardiology literature in the prior art includes
many descriptions of patients experiencing orthostatic hypotension
and other side effects associated with centrally acting alpha
antiadrenergic agents utilized to treat hypertension and central
and peripheral nerve agitation experienced during alcohol or
narcotic withdrawal management. Woodley, M. and Whalen A., Manual
of Medical Therapeutics, 27th ed., Boston, Little, Brown, 1992, p.
64-75.
[0028] U.S. Pat. No. 5,668,117 to Shapiro, discloses a method of
treating neurological diseases and etiology by utilizing
carbonyl-trapping agents in combination with previously known
medicaments. Shapiro discloses the ability of combining a
carbonyl-trapping agent with either a benzodiazepine or a centrally
acting alpha antiadrenergic agent.
[0029] U.S. Pat. No. 4,829,070 to Boder, discloses the use of a
redox carrier system for the site-specific delivery of a centrally
acting therapeutic agent to the brain. Boder discloses the ability
of attaching a centrally acting alpha antiadrenergic agent or
benzodiazepine to the redox carrier system and delivering those
agents to the brain.
[0030] U.S. Pat. No. 5,855,908 to Stanley, discloses a
non-dissolvable dosage form for use in the transdermal delivery of
a drug to a patient, which includes clonidine or a benzodiazepine
agent, such as lorazepam, as suitable drugs to be carried by the
transdermal system.
[0031] Despite the sophistication of new analgesic agents and
improved understanding of the neurobiological basis of pain,
current pain management treatment modalities involving narcotic,
non-narcotic, and anxiolytic therapeutic agents have not been able
to manage the side effect issues associated with the use of these
agents.
[0032] In addition, as the dizziness, drowsiness, depression,
lethargy, difficulty in being mobile, weakness in the extremities,
orthostatic hypotension, respiratory depression, gastrointestinal
distress, and renal distress side effects of these agents occur,
therapeutic regimens frequently discontinue one agent for a less
successful pain control agent. Patients experiencing side effects
become mal- or non-compliant in taking the prescribed pain
treatment regimen to manage their particular type of pain. Finally,
because of the depressive effects of these agents, healthcare
personnel treat patient populations of this type more on an
in-patient only setting to minimize liability issues and to monitor
abuse potentials by such patients taking these particular
medications.
[0033] Thus, there is a need within the prior art for a
pharmaceutical kit, composition, and a method of treatment regimen
which reduces or prevents negative side effect outcomes associated
with acute or chronic pain treatment modalities without
minimization of mild to severe pain control in a variety of patient
populations, ranging from the infant to the elderly adult.
SUMMARY OF THE INVENTION
[0034] A pharmaceutical kit, composition and method of treatment
regimen for the management of side effects associated with
therapeutic agents used to treat acute and chronic pain syndromes
has been discovered, utilizing a centrally acting alpha
antiadrenergic agent, central nervous system stimulant agent, and
an anxiolytic agent combination. The present invention reduces or
prevents the negative side effects of depression, dizziness,
drowsiness, lethargy, weakness in the extremities, difficulty in
being mobile, orthostatic hypotension, restlessness, delirium and
mania associated with therapeutic agents utilized to treat acute
and chronic pain syndromes without compromising positive clinical
effects of those same therapeutic agents.
[0035] By reducing or preventing these side effects, the present
invention also decreases the risk of injury to patients and
liability to healthcare personnel treating such patient
populations. Further, by reducing the risk, such pain treatment
patients have an increased opportunity to be treated in an
outpatient setting, which in turn decreases the healthcare cost in
treating these individuals. Further, by minimizing side effects to
patients undergoing pain syndrome treatment with the present
invention, incidences of therapeutic agent addiction
psychologically or physically are reduced or prevented.
[0036] The present invention can be embodied in a variety of
pharmaceutically acceptable immediate and sustained release dosage
forms and can be delivered to the human body via a variety of
medically and pharmaceutically acceptable administration
routes.
[0037] These and other features, advantages and objects of the
present invention will be further understood and appreciated by
those skilled in the art by reference to the following
specification, claims and appended drawings. A more detailed
description of the present invention shall be discussed further
below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] FIG. 1 is a flow diagram indicating the prevention or
reduction of side effects associated with therapeutic agents used
to treat acute and chronic pain syndromes, through the use of the
triple drug combination of the preferred embodiment, without
compromising the positive clinical effects of those same
therapeutic agents.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
[0039] The preferred embodiment comprises of a pharmaceutical kit,
composition, method of treatment regimen containing a combination
of effective amounts of an anxiolytic agent, centrally acting alpha
antiadrenergic agent, and central nervous system (CNS) stimulant
agent for the reduction or prevention of the negative side effects
of drowsiness, dizziness, depression, weakness in the extremities,
lethargy, orthostatic hypotension, restlessness, delirium, mania,
and difficulty in being mobile associated with therapeutic agents
utilized to treat acute and chronic pain syndromes.
[0040] The anxiolytic agent utilized in the present invention
consists of an effective amount of a benzodiazepine,
azaspirodecanedione, piperazine derivative or gabapentin. Suitable
benzodiazepine agents include, but are not limited to, diazepam,
alprazolam, clonazepam, chlordiazepoxide, clorazepate, halazepam,
lorazepam, oxazepam, derivatives thereof, and pharmaceutically
acceptable salts thereof. Suitable azaspirodecanedione agents
include, but are not limited to, buspirone, derivatives thereof,
and pharmaceutically acceptable salts thereof. Suitable piperazine
derivatives include, but are not limited to, hydroxyzine pamoate
and hydroxyzine hydrochloride, derivatives thereof, and
pharmaceutically acceptable salts thereof.
[0041] Gabapentin is not known as an anxiolytic agent, per se. It
does, however, have anxiolytic properties, and hence for purposes
of this patent application it is included within the scope of the
term "anxiolytic agent" as used herein.
[0042] Gabapentin has been approved for "add-on" treatment of
partial epileptic seizures. This interesting drug is an analog of
the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and
was initially thought to act via GABAergic mechanisms. However,
researchers found that gabapentin does not interact with GABA
receptors, nor does it interfere with GABA metabolism. There is
some evidence that gabapentin may increase the GABA content of some
brain regions, but the significance of this finding is not known.
Unlike phenytoin or carbamazepine, gabapentin does not interact
with sodium channels, nor does it influence receptors for
benzodiazepeines, opioids, catecholamines, or acetylcholine.
Instead, gabapentin appears to act by binding a specific protein
found only on neurons in the central nervous system. This protein,
which does not appear to bind any other antiepileptic drug, is
found in highest density in areas of the neocortex that are rich in
synapses containing the excitatory neurotransmitter glutamine.
Pharmaceutical Information Associates, Ltd., Medical Sciences
Bulletin, p. 1, February 1994. It should be used in amounts of from
about 300 mg to about 4000 mg per day.
[0043] Although not wanting to be bound to any particular theory,
glutamate excitotoxicity, as discussed within clinical gabapentin
literature, plays an important role in neuronal excitability,
production of a nociceptive stimulus, and negative affective
outcome in human pain syndromes. The Natural History and the
Effects of Gabapentin in Amytrophic Lateral Sclerosis, Journal of
Neurological Science, 1998 October; 160; Supp. 1: S57-63. In vitro,
gabapentin has been shown to modulate the action of
gamma-aminobutyric acid (GABA) synthetic enzyme, glutamic acid
decarboxylase (GAD) and the glutamate synthesizing enzyme,
branched-chain amino acid transaminase. Mechanisms of Action of
Gabapentin, Review Neurology (Paris), 1997; 153 Supp. 1: S39-45.
Such actions indicate that gabapentin increases GABA synthesis and
thus enhances the resultant anxiolytic effect of GABA, which is
beneficial in pain control.
[0044] Further, gabapentin has demonstrated, in vitro, inhibitory
effects on voltage-gated ion channels (sodium, calcium).
Gabapentin, Neuropsychobiology, 1998 October; 38(3); 139-44. In
particular, it has recently been suggested that gabapentin
interacts with a high-affinity binding site in brain membranes
known as an auxiliary subunit of voltage sensitive calcium
channels. Again, although not wanting to be bound to any particular
theory, it is believed that the recently identified alpha2delta
subunit (predominantly the L-type) of a voltage-gated calcium
channel acts as a high affinity binding site for gabapentin.
Gabapentin Inhibits Calcium Currents in Isolated Rat Brain Neurons.
Neuropharmacology, 1998; 37(1): 83-91. In doing so, gabapentin
binds to such a site to inhibit intracellular calcium accumulation
within neurons to decrease their resultant level of excitability.
Id. By decreasing neuronal excitability, gabapentin has the
capability to decrease pain sensation and to exhibit an anxiolytic
type effect.
[0045] The preferred anxiolytic agent for the management of acute
or chronic pain syndromes is about 50-60 mg of chlordiazepoxide
given to a human being every 6-8 hours around the clock initially,
and gradually tapered by about 10 mg per day for a period of about
5-14 days. While not wanting to be bound by any particular theory,
it is believed that the anxiolytic agent of the preferred
embodiment reduces or prevents the anxiety, restlessness, delirium,
and mania side effects of therapeutic agents used to treat mild to
severe pain associated with acute and chronic pain syndromes. In
doing so, the anxiolytic agent decreases central and peripheral
nerve sensitization to painful stimuli by managing these negative
side effects without deleterious effect upon the positive pain
control effects of the conventional therapeutic agents used to the
mild to severe pain associated with the acute or chronic pain
syndrome.
[0046] As an alternative to the chlordizepoxide being the
anxiolytic agent within the preferred embodiment, about 0.25-10 mg
of lorazepam given to a human being about every 4-10 hours,
preferably about every 6-10 hours, and most preferably about every
6-8 hours during the day and about every 3-4 hours at night up to a
typical maximum dose of about 10 mg or greater, most preferably a
maximum of about 7 mg a day or greater can be utilized instead.
Total daily dosing will occur over about 5-14 days, with initial
doses maximizing at about 7-10 mg a day and tapering thereafter by
about 1 mg or greater each day of treatment until dosing is
completed within a period of about 5-14 days.
[0047] Those skilled in the art will appreciate and be able to
adjust the dose, dosing interval, and dosing length/treatment
period of the anxiolytic agent of the preferred embodiment in the
treatment of acute or chronic pain syndromes, based upon the
clinical response and therapeutic value required to reduce or
prevent the negative side effect outcomes associated with
therapeutic agents used to treat such syndromes. One skilled in the
art will be able to appreciate and adjust the dose, dosing
interval, and length of treatment with the anxiolytic 2W) agent of
the preferred embodiment based upon the liver and kidney function
of the patient and the amount of CNS stimulant agent used as part
of the preferred embodiment.
[0048] For example, as the dose of the CNS stimulant of the
preferred embodiment is increased or the interval dosing is
decreased, the anxiolytic agent dose can be decreased and dosing
interval increased. In addition, it should be understood by those
skilled in the art that the dose of the CNS stimulant can be used
to achieve therapeutic efficacy in managing the negative side
outcomes of the anxiolytic agent, itself, within the preferred
embodiment as the dose of the anxiolytic agent is increased to
treat anxiety, restlessness, delirium, and mania associated with
the therapeutic agents used to treat acute and chronic pain
syndromes.
[0049] The centrally acting alpha antiadrenergic agent of the
preferred embodiment consists of an effective amount of methyldopa,
clonidine, guanfacine, guanabenz, lofexidine, derivatives thereof
or pharmaceutically acceptable salts thereof. It is recognized that
lofexidine is not currently approved for use in the U.S. by the FDA
but is approved for use in Europe. The preferred centrally acting
alpha antiadrenergic agent for the treatment of acute and chronic
pain syndromes is about 0.05-0.7 mg clonidine given to a human
being for a period of 6-8 hours for about 5-14 days.
[0050] Although not wanting to be bound by any particular theory,
it is believed that the use of such agents reduces or prevents
central and peripheral nerve agitation associated with acute and
chronic pain syndromes while minimizing the negative side effects
of restlessness, delirium, and mania cause by other narcotic or
non-narcotic agents, which may be added to a particular pain
treatment regimen. Typical maximal dosages of clonidine can be
about 2 mg per day or higher depending upon the patient response
required for the acute or chronic pain setting, liver and kidney
function of the patient, and the dose and dosing interval of the
central nervous system stimulant agent of the preferred embodiment
during that patient's pain treatment course.
[0051] As the dose of the CNS stimulant is increased, or the dosing
interval is decreased, the centrally acting alpha antiadrenergic
agent dose can be decreased and dosing interval increased. In
addition, it should be understood by those skilled in the art that
the dose of the CNS stimulant can be increased to achieve
therapeutic efficacy while managing the negative side effect
outcomes of the centrally acting alpha antiadrenergic and
anxiolytic agents of the preferred embodiment as the dose of those
agents are increased to treat acute and chronic pain syndromes.
[0052] The central nervous system stimulant agent of the preferred
embodiment consists of an effective amount of an amphetamine, such
as an amphetamine sulfate, dextroamphetamine sulfate,
methylamphetamine hydrochloride, combinations of such amphetamines,
derivatives thereof and pharmaceutically acceptable salts thereof;
pemoline, derivatives thereof and pharmaceutically acceptable salts
thereof; methylphenidate, derivatives and pharmaceutically
acceptable salts thereof; caffeine, derivatives and
pharmaceutically acceptable salts thereof; and centrally acting
alpha-1 agonists such as modafinil, norepinephrine, phenylephrine,
and derivatives and pharmaceutically acceptable salts thereof.
[0053] While again not wanting to be bound to any particular
theory, it is believed that the central nervous system stimulant
agent of the preferred embodiment acts to reduce or prevent
dizziness, depression, difficulty in being mobile, drowsiness,
lethargy, weakness in the extremities, and orthostatic hypotension
associated with therapeutic agents utilized to treat acute and
chronic pain syndromes such as the anxiolytic and centrally acting
alpha antiadrenergic agent components of the preferred embodiment
without detracting from the positive clinical effects provided by
those particular agents in treating acute and chronic pain
syndromes.
[0054] It is believed that the central nervous system stimulant
agent releases increased norepinephrine from central non-adrenergic
neurons, epinephrine from adrenergic neurons, and dopamine from the
human central nervous system to counteract the negative side
effects of central nervous system depressants such as narcotic,
non-narcotic, centrally acting alpha antiadrenergic, and anxiolytic
agents used to treat acute and chronic pain syndromes.
[0055] The preferred central nervous system stimulant agent of the
preferred embodiment consists of from about 1-20 mg of
dextroamphetamine sulfate in an immediate release dosage form given
to a human being about every 4-8 hours, preferably every 4-6 hours
at a regular spaced interval during the day and up to about 5 mg as
a rescue dose during the night if needed for a period of about 5-14
days. In a controlled release dosage form, the central nervous
system stimulant, dextroamphetamine sulfate, is dosed as 1-20 mg
given to a human being about every 12 hours or once daily without a
rescue dose given during the night, for a total treatment
period/dosing length of about 5-14 days.
[0056] In an alternative embodiment, for those patients requiring a
non-amphetamine based central nervous system stimulant agent or
those patients who cannot receive additional or increased
amphetamine doses due to cardiovascular risk concerns, a centrally
acting alpha-1 agonist such as modafinil, can be used as a
substitute or in addition to the amphetamine(s) component of the
central nervous system stimulant agent of the preferred
embodiment.
[0057] Centrally acting alpha-1 agonists such as modafinil
(Provigile) act postsynaptically at alpha-1 adrenergic receptors
and may also bind to dopamine carriers to increase stimulation and
mental alertness within the human body, usually without altering
the body's blood pressure or heart rate excessively, like that of
amphetamines. Further, centrally acting alpha-1 agonists do not
decrease stage 2 REM sleep like amphetamines, and thus offer a
treatment alternative for the practitioner when choosing a central
nervous system stimulant agent of the preferred embodiment.
[0058] In the alternative embodiment, the preferred central nervous
system stimulant agent is about 50-400 mg, preferably about 100-300
mg, and most preferably about 200 mg or higher per day of modafinil
given to a human being administered every 12 hours, preferably once
daily in the morning for a period of 5-14 days.
[0059] It should be understood by those skilled in the art that the
preferred embodiment of the present invention can utilize any of
the central nervous stimulant agents alone or in combination with
one another as the central nervous system stimulant agent component
of the preferred embodiment. For example, a practitioner
administering the preferred embodiment containing an amphetamine
initially as a central nervous system stimulant agent could add
modafinil as an adjunct central nervous system stimulant to a
patient's treatment therapy, where use of an additional amount of
the original amphetamine would not be desirable, due to therapeutic
and adverse effect outcome considerations. Thus, modafinil would
allow a practitioner to increase central nervous system stimulation
without increasing the negative cardiovascular side effects of the
amphetamine agent.
[0060] Those skilled in the art would be able to adjust the dose,
dosing interval and dosing length/treatment period of the central
nervous system stimulant of the present invention based upon the
clinical and therapeutic response desired for a patient undergoing
acute and chronic pain syndrome treatment, liver and kidney
function of that patient, as well as drug interaction potential
between this agent and other components of the preferred
embodiment.
[0061] All of the components of the preferred embodiment can be
used separately, but administered contemporaneously, and can be
given via a singular pharmaceutically acceptable dosage form for
each component or combination of all the components as an immediate
release or controlled release dosage form. Contemporaneously means
the three agents are administered separately over time, but have a
combined effect together after their individual administrations.
Suitable pharmaceutical dosage forms for the preferred embodiment
include, but are not limited to, tablets, capsules, caplets,
dose-paks, solutions, syrups, suppositories, transdermal
applications, creams, lotions, emulsions, powders and the like.
Preferred dosage forms for the present invention include tablets,
caplets, capsules, dose-paks, solutions, and transdermal
applications with a tablet, capsule, or caplet being the most
preferred.
[0062] The triple drug therapeutic composition, kit, and method of
treatment of the preferred embodiment can be administered to the
human body via a variety of medically and pharmaceutically
acceptable administration routes. Those routes include, but are not
limited to the oral, rectal, intravenous, intradermal,
subcutaneous, cutaneous, intramuscular, buccal, transdermal, and
other pharmaceutically and medically acceptable routes of
administration for the human body. Preferred routes of
administration for the preferred embodiment are the oral, rectal,
intravenous and intramuscular routes, with the oral route being
most preferred.
[0063] By combining the pharmaceutical medicaments of the preferred
embodiment in a new and novel kit, composition, and method of
treatment regimen, the preferred embodiment achieves far superior
negative side effect management results for therapeutic agents
utilized to treat acute and chronic pain syndromes resulting in
enhanced reduction or prevention of acute and chronic mild to
severe pain. Further, the preferred embodiment reduces the risk to
patients as well as treating healthcare personnel to allow for more
outpatient treatment settings, which reduces the overall cost of
healthcare. Lastly, the preferred embodiment also decreases side
effect considerations for the anxiolytic and centrally acting
antiadrenergic agents of the preferred embodiment increasing their
acceptability, use, and positive pain reduction capabilities in
treating acute or chronic mild to severe pain syndromes.
[0064] The following observational examples illustrate the clinical
outcomes associated with use of the triple drug combination of the
preferred embodiment in treating various forms of acute or chronic
pain.
EXAMPLE ONE
[0065] Chronic Spinal Nerve Pain Treatment
[0066] A 37-year-old patient suffered a spinal nerve injury after a
car accident. Six years after the accident, the patient still
suffered from chronic back pain emanating from the point of injury
throughout the entire back. Symptoms of the neuropathy included
radiating pain down the legs and inflammation at the injury site.
Due to the back pain and a treatment period for kidney stones, the
patient received multiple doses of the prescription drug
Vicodan.
[0067] Following kidney stone treatment and back pain management,
the patient began increased use of Vicodan to a point of ingesting
15 to 20 pills per day, finally requiring narcotic abuse treatment.
While undergoing detoxification for addiction to Vicodan, the
patient received the following medication protocol:
1 Day 1: 0.4 mg clonidine, 2 mg lorazepam, and 5 mg dexedrine Day
2: 0.6 mg clonidine, 3 mg lorazepam, and 5 mg dexedrine Day 3: 0.8
mg clonidine, 4 mg lorazepam, and 5 mg dexedrine Day 4: 0.6 mg
clonidine, 3 mg lorazepam, and 5 mg dexedrine Day 5: 0.3 mg
clonidine, 1.5 mg lorazepam, and 2.5 mg dexedrine Day 6: 0.3 mg
clonidine, 1.5 mg lorazepam, and 2.5 mg dexedrine Day 7: 0.2 mg
clonidine, 1 mg lorazepam, and 2.5 mg dexedrine
[0068] During the detoxification procedure, subjective and
objective clinical assessment was completed at which time the
patient indicated a significant reduction in chronic back pain
while receiving the treatment regimen. Following the detoxification
procedure, the patient reported less pain than prior to the
procedure, yet, experienced increased pain once the triple drug
treatment regimen was discontinued. However, as a consequence of
pain rebound following withdrawal treatment, the patient was
continued on the medication protocol at very low doses, during
which time the patient again continued to experience a reduction in
chronic back pain. The results of the case report illustrate the
ability of the triple drug regimen of the preferred embodiment's
ability to significantly alleviate chronic forms of pain.
EXAMPLE 2
[0069] Tooth Pain
[0070] A 32-year-old female patient presented at the time of
narcotic abuse treatment with a history of significant, recurring,
but not chronic tooth pain. The patient required narcotic abuse
treatment following use of the prescription drug Percodan for
approximately three months to treat the tooth pain. However, the
patient experienced severe withdrawal symptoms during each
discontinuance of the narcotic analgesic. To treat the withdrawal
symptomology, the patient was given the following low-dose
detoxification treatment regimen:
2 Day 1: 0.3 mg clonidine, 1.5 mg lorazepam, and 2.5 mg dexedrine
Day 2: 2.5 mg clonidine, 0.5 mg lorazepam, and 2.5 mg dexedrine Day
3: 0.3 mg clonidine, 1.5 mg lorazepam, and 2.5 mg dexedrine Day 4:
0.2 mg clonidine, 1 mg lorazepam, and 0 mg dexedrine Day 5: 0.2 mg
clonidine, 1 mg lorazepam, and 0 mg dexedrine
[0071] During the detoxification treatment program, the patient was
able to discontinue the use of Percodan without recurrent painful
tooth episodes. The patient reported significant reduction in tooth
pain and did not experience a rebound in tooth pain following
discontinuance of the opioid as would have been expected. Following
the triple drug treatment program, the patient reported increased
tooth pain. The results of the observational case study indicate
the ability of the triple drug regimen of the preferred embodiment
to decrease acute forms of pain such as tooth pain.
EXAMPLE 3
[0072] Surgical Pain
[0073] A 41-year-old female patient had undergone corrective knee
surgery. Following the surgical procedure, the patient received the
prescription drug, Tylenol #4, to treat pain related to the
surgical procedure. Having the pain unrelieved by Tylenol #4 over a
period of eight weeks, the patient began to use heroin to relieve
the pain and quickly became addicted to the agent. The patient was
treated for withdrawal symptomology with the following
protocol:
3 Day 1: 0.6 mg clonidine, 3 mg lorazepam, and 5 mg dexedrine Day
2: 0.8 mg clonidine, 4 mg lorazepam, and 5 mg dexedrine Day 3: 0.8
mg clonidine, 4 mg lorazepam, and 5 mg dexedrine Day 4: 0.6 mg
clonidine, 3 mg lorazepam, and 5 mg dexedrine Day 5: 0.6 mg
clonidine, 3 mg lorazepam, and 5 mg dexedrine Day 6: 0.3 mg
clonidine, 1.5 mg lorazepam, and 5 mg dexedrine Day 7: 0.2 mg
clonidine, 1 mg lorazepam, and 2.5 mg dexedrine
[0074] By the second day of detoxification treatment, the patient
reported a significant reduction in knee pain. By the end of the
week of treatment, the patient reported that the knee pain had been
substantially abated. As can be seen by this observational case
study, traumatic pain such as that induced by surgical procedure
can be substantially reduced or prevented by the triple drug
regimen of the preferred embodiment.
EXAMPLE 4
[0075] Pain Associated with Alcohol and Narcotic Withdrawal
[0076] A 29-year-old patient underwent alcohol and narcotic abuse
treatment following an episode of withdrawal symptomology in which
the patient experienced the withdrawal side effects of dysphoria,
anxiety, nausea, vomiting, abdominal cramping, tremors, fever,
pupil dilation, and sweating. The patient was treated with a
detoxification regimen to manage the withdrawal symptomology caused
by the patient's daily ingestion of five "bags" of heroin and two
quarts of vodka over a period of two years. The detoxification
regimen was as follows:
4 Day 1: 0.8 mg clonidine, 4 mg lorazepam, and 5 mg dexedrine Day
2: 0.8 mg clonidine, 4 mg lorazepam, and 5 mg dexedrine Day 3: 0.4
mg clonidine, 2 mg lorazepam, and 5 mg dexedrine Day 4: 0.3 mg
clonidine, 1.5 mg lorazepam, and 5 mg dexedrine
[0077] Following Day One's course of therapy, the patient reported
a significant withdrawal symptomology such as anxiety, dysphoria,
abdominal cramping, sweating, and tremor. As the patient's
treatment regimen continued beyond Day Four with reductions in each
of the three medications listed, the patient still noted few
withdrawal symptoms and eventually was weaned from the alcohol and
narcotic usage.
[0078] It should be noted that in each of Examples 1-4, the
patient's were treated initially in an inpatient setting, and then
were moved to an outpatient setting, which could not have been done
previously utilizing pain treatment methods within the prior art.
By allowing the patients to be treated in an outpatient setting,
the patients became more compliant in the drug therapy, achieved
greater rates of return to normal daily activities, and had a
significantly reduced cost of healthcare during their course of
treatment.
[0079] The above description is considered that of the preferred
embodiments only. Modifications of the invention will occur to
those skilled in the art and to those who make or use the
invention. Therefore, it is understood that the embodiments shown
in the drawings and described above are merely for illustrative
purposes and not intended to limit the scope of the invention,
which is defined by the following claims as interpreted according
to the principles of patent law, including the Doctrine of
Equivalents.
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