U.S. patent application number 11/910966 was filed with the patent office on 2008-10-16 for methods for the treatment of substance abuse and dependence.
This patent application is currently assigned to Hythiam, Inc.. Invention is credited to Joseph Dunn, Sanjay Sabnani, Donald Wesson.
Application Number | 20080255097 11/910966 |
Document ID | / |
Family ID | 37087555 |
Filed Date | 2008-10-16 |
United States Patent
Application |
20080255097 |
Kind Code |
A1 |
Sabnani; Sanjay ; et
al. |
October 16, 2008 |
Methods for the Treatment of Substance Abuse and Dependence
Abstract
The present invention relates to methods of and compositions for
treating and relieving symptoms and disease associated with
indications caused by a physiological drive to alleviate a
sensation of anxiety. More specifically, the present invention
relates to methods of and compositions for treating and relieving
symptoms associated with substance abuse and withdrawal. The
present invention relates to methods of and compositions for
treating and relieving symptoms associated with addiction to
antidepressants, opiates, nicotine or marijuana. In one method, a
patient is treated with a composition that directly or indirectly
modulates GABA.sub.A by modulating the expression of the GABA.sub.A
receptor a.sub.4 subunit.
Inventors: |
Sabnani; Sanjay;
(Northridge, CA) ; Wesson; Donald; (Oakland,
CA) ; Dunn; Joseph; (Los Gatos, CA) |
Correspondence
Address: |
JOHN S. PRATT, ESQ;KILPATRICK STOCKTON, LLP
1100 PEACHTREE STREET
ATLANTA
GA
30309
US
|
Assignee: |
Hythiam, Inc.
Los Angeles
CA
|
Family ID: |
37087555 |
Appl. No.: |
11/910966 |
Filed: |
April 7, 2006 |
PCT Filed: |
April 7, 2006 |
PCT NO: |
PCT/US06/13099 |
371 Date: |
April 22, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60669033 |
Apr 7, 2005 |
|
|
|
60729013 |
Oct 21, 2005 |
|
|
|
60728979 |
Oct 21, 2005 |
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Current U.S.
Class: |
514/220 ;
514/284; 514/678 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 1/14 20180101; A61K 31/58 20130101; A61K 31/137 20130101; A61P
25/22 20180101; A61P 25/36 20180101; A61K 31/122 20130101; A61P
43/00 20180101; A61P 25/30 20180101; A61P 25/18 20180101; A61P
25/34 20180101; A61K 31/5517 20130101 |
Class at
Publication: |
514/220 ;
514/678; 514/284 |
International
Class: |
A61K 31/5517 20060101
A61K031/5517; A61K 31/12 20060101 A61K031/12; A61K 31/4353 20060101
A61K031/4353 |
Claims
1-26. (canceled)
27. A method of treating addiction to anti-depressants, opiates,
nicotine or marijuana in a patient comprising administering to the
patient a composition comprising a compound that selectively
modulates GABA.sub.A receptor expression and a pharmaceutically
acceptable carrier.
28. The method of claim 27, wherein the compound is flumazenil or
miltirone.
29. The method of claim 28, wherein the flumazenil is administered
in a therapeutically effective quantity.
30. The method of claim 29, wherein the therapeutically effective
quantity of flumazenil is between 0.5 mg/day and 10 mg/day.
31. The method of claim 28, wherein the flumazenil is administered
at a rate of between 0.1 and 0.3 mg over predetermined time
intervals for a total administration of between 0.5 mg/day and 10
mg/day.
32. The method of claim 31, wherein the predetermined time interval
is in the range of 1 and 15 minutes.
33. The method of claim 28, wherein the flumazenil is administered
at a rate of between 0.1 and 0.3 mg over predetermined time
intervals for a total administration of between 1.0 mg/day and 3.0
mg/day.
34. The method of claim 27, further comprising administering an
inhibitor of neurosteroid production in a pharmaceutically
acceptable carrier prior to administering the composition
comprising the compound that selectively modulates GABA.sub.A
receptor expression.
35. The method of claim 34, wherein the inhibitor of neurosteroid
production is a 5-alpha-reductase inhibitor.
36. The method of claim 35, wherein the 5-alpha-reductase inhibitor
is finasteride.
37. The method of claim 36, wherein the finasteride is administered
in an amount of less than 10 mg/day.
38. A method of treating addiction to anti-depressants, opiates,
nicotine or marijuana in a patient comprising: assessing the
patient for treatment compatibility; preparing the patient for
treatment; and, administering to the patient a composition
comprising a compound that selectively modulates GABA.sub.A
receptor expression in a pharmaceutically acceptable carrier.
39. The method of claim 38, wherein preparing the patient for
treatment includes withdrawing the patient from current
treatment.
40. The method of claim 38, wherein preparing the patient for
treatment includes placing the patient in a state of
withdrawal.
41. The method of claim 40, wherein the patient is a female patient
and the female patient is placed in a state of withdrawal by
administering to the female patient a contraceptive and then
ceasing administration of the contraceptive.
42. The method of claim 40, wherein the patient is placed in a
state of withdrawal by administering to the patient a composition
comprising an inhibitor of neurosteroid production in a
pharmaceutically acceptable carrier.
43. The method of claim 38, wherein the compound is flumazenil.
44. The method of claim 43, wherein the flumazenil is administered
in a therapeutically effective quantity.
45. The method of claim 44, wherein the therapeutically effective
quantity of flumazenil is between 0.5 mg/day and 10 mg/day.
46. The method of claim 43, wherein the flumazenil is administered
at a rate of between 0.1 and 0.3 mg over predetermined time
intervals for a total administration of between 0.5 mg/day and 10
mg/day.
47. The method of claim 46, wherein the predetermined time interval
is in the range of 1 and 15 minutes.
48. The method of claim 43, wherein the flumazenil is administered
at a rate of between 0.1 and 0.3 mg over predetermined time
intervals for a total administration of between 1.0 mg/day and 3.0
mg/day.
49. The method of claim 42, wherein the inhibitor of neurosteroid
production is a 5-alpha-reductase inhibitor.
50. The method of claim 49, wherein the 5-alpha-reductase inhibitor
is finasteride.
51. The method of claim 50, wherein the finasteride is administered
in an amount of less than 10 mg/day.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present invention relies on, for priority, U.S.
Provisional Patent Application No. 60/669,033, entitled "Improved
Method for the Treatment of Substance Abuse", filed on Apr. 7,
2005, U.S. Provisional Patent Application No. 60/728,979 entitled
"Methods for the Treatment of Substance Abuse and Dependence",
filed on Oct. 21, 2005, and U.S. Provisional Patent Application No.
60/729,013 entitled "Methods for Treating Anxiety-Related
Diseases", filed on Oct. 21, 2005.
FIELD OF THE INVENTION
[0002] The present invention relates to methods of and compositions
for treating and relieving symptoms and disease associated with
indications caused by a physiological drive to alleviate a
sensation of anxiety. More specifically, the present invention
relates to methods of and compositions for treating and relieving
symptoms associated with substance abuse and withdrawal. The
present invention relates to methods of and compositions for
treating addiction to antidepressants, opiates, nicotine or
marijuana.
[0003] The present invention is also relates to a methodology for
diagnosing a person in an altered GABA.sub.A receptor state. In
particular, the methodology is directed toward determining the
relative receptivity of a patient to the treatment methodologies of
the present invention by qualitatively or quantitatively measuring
progesterone levels in a patient, or, more preferably, the
allopregnanolone levels within a patient's brain.
[0004] The present invention also relates to a treatment
methodology that, in a first stage, improves a patient's
physiological receptivity to treatment. In particular, the
methodology is directed toward preventing the up-regulation of
endogenous neuroactive steroids or actively down-regulating the
production of endogenous neuroactive steroids to avoid
cross-tolerance effects between exogenous and endogenous
substances.
[0005] The present invention also relates to a treatment
methodology that, in a second stage, employs methods of and
compositions for modulating the expression of certain GABA.sub.A
receptor subunits, thus treating the withdrawal symptoms associated
with psychological and physiological addiction and dependence in a
comprehensive treatment plan. The present invention also relates to
optionally employing conventional treatment programs in combination
with the methods of and compositions of the present invention in a
comprehensive treatment plan.
[0006] More specifically, the present invention relates to methods
of, devices for, and treatment protocols for using pharmaceutical
compositions from a class of compounds that directly or indirectly
modulates GABA.sub.A by modulating the expression of the GABA.sub.A
receptor .alpha..sub.4 subunit.
[0007] The present invention also relates to a class of compounds,
and methods of identifying such compounds, that modulates the
expression of certain GABA.sub.A receptor subunits. More
specifically, the compound of choice is one that a) acts as a
partial agonist of GABA.sub.A; b) inhibits the upregulation of the
GABA.sub.A receptor 4 subunit and/or increases the relative ratio
of the GABA.sub.A receptor .alpha..sub.1 subunit to the GABA.sub.A
receptor .alpha..sub.4 subunit; and c) does not cause the
upregulation of the GABA.sub.A receptor .alpha..sub.4 subunit
and/or does not cause the decrease of the relative ratio of the
GABA.sub.A receptor .alpha..sub.1 subunit to the GABA.sub.A
receptor .alpha..sub.4 subunit once the composition is no longer
present in the patient's system.
BACKGROUND OF THE INVENTION
[0008] Substance addiction and abuse is a multi-factorial
neurological disease. Over time, repeated exposure to various
substances, both endogenous and exogenous, causes modification of
the neurotransmission circuits and adaptations in post-receptor
signaling cascades. There are several effects of this neuronal
modification. Among them, there is a reduction in the ability of
natural rewards to activate the reward pathways leading to
depressed motivation and mood and an increased compulsion to
compensate for the physiological change.
[0009] While the common perception underlying addiction is that of
a "reward circuit", pleasure may not necessarily be a strong enough
impetus to drive people towards their addictions. Rather, addictive
behavior arises from an intense desire to manage and/or avoid the
anxiety that arises when someone is experiencing withdrawal.
[0010] Traditional treatments for substance dependency, such as
benzodiazepine abuse, have been based upon cognitive-behavioral
therapy or drug therapy, or a combination thereof. Conventional
methods of treatment fail, however, in that they do not address the
physiochemical changes that occur with addiction and dependence.
Thus, conventional treatments for controlling withdrawal symptoms
and cravings for addictive substances have had limited success and
often have undesirable side effects.
[0011] What is therefore needed are improved methods of,
compositions for, and treatment protocols for preventing
psychological addiction to, and physiological dependence upon
addictive substances.
[0012] What is also needed is an improved treatment methodology for
controlling cravings and withdrawal symptoms caused by substance
abuse.
[0013] What is also needed is an improved methodology and protocol
for treating substance abuse, which results in reduced patient
dropout rates.
SUMMARY OF THE INVENTION
[0014] According to its major aspects and broadly stated, the
present invention is directed towards methods of, and compositions
for, preparing a patient for treatment and modulating the
expression of certain GABA.sub.A receptor subunits. The present
invention therefore treats withdrawal symptoms associated with
psychological addiction and physiological dependence upon various
exogenous and endogenous substances in the context of a
comprehensive treatment plan of behavioral and/or pharmacological
treatment.
[0015] The multiple phase treatment methodology of the present
invention employs one or more compounds to reset physiochemical
changes in a patient that is experiencing withdrawal from addictive
and/or dependency-inducing substances, including but not limited to
opioids and derivatives, nicotine, benzodiazepines, caffeine,
cannabis, or anti-depressant drugs.
[0016] The present invention relates to methods of and compositions
for treating and relieving symptoms and disease associated with
indications caused by a physiological drive to alleviate a
sensation of anxiety. More specifically, the present invention
relates to methods of and compositions for treating and relieving
symptoms associated with substance abuse and withdrawal. In one
embodiment, a patient is treated with a composition from a class of
compounds that directly or indirectly modulates GABA.sub.A by
modulating the expression of the GABA.sub.A receptor .alpha..sub.4
subunit.
[0017] The present invention also provides methods that, in a first
stage, improve an individual's physiological receptivity to
treatment. In particular, the methodology is directed toward
preventing the up-regulation of endogenous neuroactive steroids or
actively down-regulating the production of endogenous neuroactive
steroids to avoid cross-tolerance.
[0018] The present invention also provides methods that, in a
second stage, employs methods of, and compositions for, modulating
the expression of certain GABA.sub.A receptor subunits, thus
treating the withdrawal symptoms associated with psychological and
physiological addiction and dependence in a comprehensive treatment
plan. The present invention also relates to optionally employing
conventional treatment programs in combination with the methods of
and compositions of the present invention in a comprehensive
treatment plan.
[0019] Methods are also provided for treating anti-depressant
addiction by administering a compound from a class of compounds
that selectively modulates GABA.sub.A receptor expression. In one
embodiment, the method includes the steps of assessing a patient
for treatment compatibility; preparing a patient for treatment; and
administering a compound from the class of compounds that
selectively modulates GABA.sub.A receptor expression to a
patient.
[0020] Methods are also provided for treating opiate addiction
comprising the step of administering a compound from a class of
compounds that selectively modulates GABA.sub.A receptor
expression. In one embodiment, the method includes the steps of
assessing a patient for treatment compatibility; preparing a
patient for treatment; and administering a compound from the class
of compounds that selectively modulates GABA.sub.A receptor
expression to a patient.
[0021] Methods are also provided for treating nicotine addiction
where the method includes the steps of assessing a patient for
treatment compatibility; preparing a patient for treatment; and
administering a compound from the class of compounds that
selectively modulates GABA.sub.A receptor expression to a
patient.
[0022] Methods are also provided for treating marijuana addiction
where the method includes the steps of assessing a patient for
treatment compatibility; preparing a patient for treatment; and
administering a compound from the class of compounds that
selectively modulates GABA.sub.A receptor expression to the
patient.
[0023] The present invention also provides a class of compounds,
and methods of identifying such compounds, that modulates the
expression of certain GABA.sub.A receptor subunits. More
specifically, the compound of choice is one that a) acts as a
partial agonist of GABA.sub.A; b) inhibits the upregulation of the
GABA.sub.A receptor .alpha..sub.4 subunit and/or increases the
relative ratio of the GABA.sub.A receptor .alpha..sub.1 subunit to
the GABA.sub.A receptor .alpha..sub.4 subunit; and c) does not
cause the upregulation of the GABA.sub.A receptor .alpha..sub.4
subunit and/or does not cause the decrease of the relative ratio of
the GABA.sub.A receptor .alpha..sub.1 subunit to the GABA.sub.A
receptor .alpha..sub.4 subunit once the composition is no longer
present in the patient's system.
[0024] It is therefore an object of the invention to provide
methods and compositions for inhibiting the formation of
neurosteriods.
[0025] It is another object of the invention to provide methods and
compositions for modulating chloride channels such as GABA.sub.A
receptors.
[0026] It is another object of the invention to provide methods and
compositions for treating symptoms of stimulant substance
abuse.
[0027] It is another object of the invention to provide methods and
compositions for treating addiction to antidepressants, opiates,
nicotine or marijuana.
[0028] Another object of the invention is to provide for the use of
a GABA.sub.A receptor modulator in the preparation of a medicament
to treat addiction to antidepressants, opiates, nicotine or
marijuana.
[0029] Another object of the invention is to provide for the use of
a neurosteroid production inhibitor in the preparation of a
medicament to treat addiction to antidepressants, opiates, nicotine
or marijuana.
[0030] These and other objects, features and advantages of the
present invention will become apparent after a review of the
following detailed description of the disclosed embodiments and
claims and the drawings provided.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] The Detailed Description should be considered in light of
the drawings, as briefly described below:
[0032] FIG. 1 illustrates the spectrum between inhibition and
substantially or completely reduced inhibition via the direct
and/or indirect allosteric modulation of GABA.sub.A;
[0033] FIG. 2 illustrates the internal thought filtering mechanism
in a person's brain;
[0034] FIG. 3a is a first schematic presentation of a plurality of
GABA.sub.A receptor subunits;
[0035] FIG. 3b is a second schematic presentation of a plurality of
GABA.sub.A receptor subunits;
[0036] FIG. 3c is an illustration of the insensitivity of the
modulated GABA.sub.A receptor to benzodiazepines. Note the .alpha.1
subunit: .alpha.1.beta.2.gamma.2-containing GABA.sub.A receptors
are the most common GABA receptors in the brain.
[0037] FIG. 4 is a chemical diagram of the blockade of the
conversion of progesterone to allopregnanolone via inhibitors of
neurosteroid production.
DETAILED DESCRIPTION OF THE INVENTION
I. Introduction
[0038] Drug addiction is a disorder characterized by compulsive
drug intake, loss of control over intake, and impairment in social
and occupational function. Allostatic changes in reward function
lead to excessive drug intake, providing a framework with which to
identify the neurobiologic mechanisms involved in the development
of drug addiction. Neuropharmacologic studies have provided
evidence for the dysregulation of specific neurochemical mechanisms
in brain reward and stress circuits that result in negative
reinforcement or essentially, decreased efficacy of brain reward
pathways, further resulting in addiction. The allostatic model
integrates molecular, cellular and circuitry neuroadaptations in
brain motivational systems produced by chronic drug ingestion with
genetic vulnerability. Both positive and negative changes in mood
are strongly correlated with allostasis in substance dependence. In
addition, it has been shown that substance abuse leads to prolonged
alterations in neurophysiological responses to
corticotrophin-releasing factor (CRF) and neuropeptide Y (NPY),
peptides known to influence stress responses.
[0039] Substance abuse, however, may be more accurately
characterized as disease further characterized by an individual's
need to avoid adverse effects. In a typical dependence and
subsequent withdrawal situation, repeated exposure to drugs causes
neurological dysfunction which sets in motion a cascade of changes
by which motivation and drive (via the anterior cingulate), reward
(via the nucleus accumbens and ventral tegmental area), and memory
and learning functions (via the amygdala and hippocampus) are
modified, resulting in the loss of cortical inhibitory influence
(orbitofrontal cortex, where control is located). This loss of
inhibitory control contributes to craving and irrational behavior
to obtain and consume drug regardless of consequences, despite the
fact that, in many cases, the reward center is decreasingly
responsive.
[0040] The GABAergic system, responsible for most inhibitory
control, typically begins with the GABA.sub.A receptor and
glutamate receptors in allostatic equilibrium. Allostatic
equilibrium refers to the normal complement of receptors on the
cell membrane in a normal individual not experiencing dependency,
tolerance, or withdrawal. Intake of a particular substance leads to
feeling of reward and reduced anxiety in a subject. The "substance"
is defined as any substance that will relieve anxiety. Long-term
use and subsequent withdrawal from a substance, however, causes
GABA dysregulation mediated through GABA.sub.A receptors, causing
the glutamate and GABA.sub.A receptors to lose their relative
allostatic equilibrium, further resulting in modified levels of
inhibition.
[0041] Thus, when the GABA.sub.A receptor is dysregulated, the
clinical manifestation of this dysregulation is initially anxiety.
In addition, the anxiety is often accompanied by compulsive
behavior. Certain compulsive behaviors, such as but not limited to
drug abuse, gambling, compulsive sexual activity, and compulsive
video game playing, can lead to increased euphoria, neurosteroid
production and brain simulation. Subsequent discontinuation of
these activities can result in withdrawal syndrome that manifests
itself through heightened anxiety and GABA.sub.A regulator
dysregulation.
[0042] In a non-dependent subject, the most common GABA.sub.A
receptor in the brain is the .alpha..sub.1.beta..sub.2.gamma..sub.2
receptor, which is a benzodiazepine sensitive receptor. The
.alpha..sub.1 subunit is an important binding site for
benzodiazepines. During a person's withdrawal from an addictive
substance, the amount of .alpha..sub.1 subunits decreases relative
to the amount of .alpha..sub.4 subunits. Withdrawal from the
substance often causes symptoms of depression, anxiety,
impulsivity, and dysphoria, as GABA uptake is decreased due to the
reduced number of GABA.sub.A receptor .alpha..sub.1 subunits
relative to GABA.sub.A receptor .alpha..sub.4 subunits.
Benzodiazepines do not bind favorably to the .alpha..sub.4 subunit,
and, therefore, the .alpha..sub.4.beta..sub.2.gamma..sub.2 receptor
is considered a benzodiazepine insensitive receptor. People who
have a high amount of .alpha..sub.4 receptor subunits relative to
.alpha..sub.1 receptor subunits can be considered to be in a
"withdrawal state". The present invention is thus directed towards
restoring an individual to a non-withdrawal state, or a "normal"
receptor balance, from a "withdrawal state".
[0043] The present invention is also directed towards methods of
and compositions for treating and relieving symptoms and disease
associated with indications caused by a physiological drive to
alleviate a sensation of anxiety. The present invention is also
directed towards methods of and compositions for treating and
relieving symptoms associated with substance abuse and
withdrawal.
[0044] The present invention is further directed towards a class of
compounds, and methods of identifying such compounds, that
modulates the expression of certain GABA.sub.A receptor subunits.
More specifically, the compound of choice is one that a) acts a
partial agonist of GABA.sub.A; b) inhibits the up-regulation of the
GABA.sub.A receptor .alpha..sub.4 subunit and/or increases the
relative ratio of the GABA.sub.A receptor .alpha..sub.1 subunit to
the GABA.sub.A receptor .alpha..sub.4 subunit; and c) does not
cause the up-regulation of the GABA.sub.A receptor .alpha..sub.4
subunit and/or does not cause the decrease of the relative ratio of
the GABA.sub.A receptor .alpha..sub.1 subunit to the GABA.sub.A
receptor .alpha..sub.4 subunit once the composition is no longer
present in the patient's system.
[0045] The present invention is also directed towards a methodology
for diagnosing a person in an altered GABA.sub.A receptor state. In
particular, the methodology is directed toward determining the
relative receptivity of a patient to the treatment methodologies of
the present invention by measuring progesterone levels in a
patient, or, more preferably, the allopregnanolone levels within a
patient's brain.
[0046] The present invention is also directed towards a treatment
methodology that, in a first stage, improves a patient's
physiological receptivity to treatment. In particular, the
methodology is directed toward preventing the up-regulation of
endogenous neuroactive steroids or actively down-regulating the
production of endogenous neuroactive steroids to avoid
cross-tolerance.
[0047] The present invention is also directed towards a treatment
methodology that, in a second stage, employs methods of and
compositions for modulating the expression of certain GABA.sub.A
receptor subunits in combination with conventional treatment
programs, thus treating the withdrawal symptoms associated with
psychological and physiological addiction and dependence in a
comprehensive treatment plan.
[0048] More specifically, the present invention is directed towards
methods of, devices for, and treatment protocols for using
pharmaceutical compositions from a class of compounds that directly
or indirectly modulates GABA.sub.A by modulating the expression of
the GABA.sub.A receptor .alpha..sub.4 subunit.
[0049] The present invention is further directed towards methods
of, devices for, and treatment protocols for treating substance
abuse, dependence, and tolerance.
II. The GABAergic System
[0050] a. Gamma-Aminobutyric Acid (GABA)
[0051] GABA is a neurotransmitter that acts at inhibitory synapses
in the brain and spinal cord. The GABA system is found, among other
places, in the hippocampus, an area of the brain associated with
memory formation. Glutamic acid, or glutamate, is important in
brain function, as an excitatory neurotransmitter and as a
precursor for the synthesis of GABA in GABAergic neurons. Glutamate
activates both ionotropic and metabotropic glutamate receptors,
described in further detail below. GABA signals interfere with
registration and consolidation stages of memory formation.
[0052] b. GABA Receptor Types
[0053] The GABA receptors are a group of receptors with GABA as
their endogenous ligand. Several classes of GABA receptors are
known, including ionotropic receptors, which are ion channels
themselves, and metabotropic receptors, which are G-protein coupled
receptors that open ion channels via intermediaries. Glutamate and
GABA mediate their actions by the activation of their
receptors.
[0054] The ionotropic GABA receptors (GABA.sub.A receptors) are
based on the presence of eight subunit families consisting of 21
subunits (.alpha..sub.1-6, .beta..sub.1-4, .gamma..sub.1-4,
.delta., .epsilon., .pi., .theta., .rho..sub.1-3) and display an
extraordinarily structural heterogeneity. GABA.sub.A receptors are
composed of five circularly arranged, homologous subunits and are
important sites of drug action. Most often, the GABA.sub.A receptor
isomers comprise two .alpha. subunits, two .beta. subunits and one
.gamma. subunit. The metabotropic GABA receptors (GABA.sub.B
receptors) consist of two subunits: GABA.sub.B1 and GABA.sub.B2.
Physiological responses following activation of GABA.sub.B
receptors require the co-assembly of GABA.sub.B1 and GABA.sub.B2.
GABA.sub.C receptors also exist natively.
[0055] c. GABA.sub.A Receptor Subunits
[0056] The GABA.sub.A receptor system is implicated in a number of
central nervous system disorders, making GABA.sub.A receptor
ligands potential therapeutic agents. GABA.sub.A receptors are
ligand-gated ion channels that belong to the same super family of
receptors as glycine, nicotinic cholinergic, and serotonin
5HT.sub.3 receptors. Enhanced function of several GABA.sub.A
receptors accounts for the major actions of benzodiazepines,
described in greater detail below. In addition, a number of
compounds have exhibited functional selectivity for GABA.sub.A
receptors.
[0057] The GABA.sub.A receptor complex is a pentameric receptor
protein structure formed by co-assembly of subunits from seven
different classes. Five subunits are situated in a circular array
surrounding a central chloride-permeable pore. It has been
suggested that the mechanism for ligand-induced channel opening in
nicotinic acetylcholine receptors involves rotations of the
subunits in the ligand binding domain. Assuming that GABA.sub.A
receptors utilize a similar mechanism for channel opening, since
GABA.sub.A receptors belong to the same super family as the
nicotinic acetylcholine receptors, large substituents may interfere
with the channel opening (steric hindrance) resulting in
antagonistic effects of certain compounds. In addition, the
activation of GABA receptors will influence several other systems,
ultimately resulting in a general acute modification of the overall
function of the central nervous system.
[0058] The particular combination of subunits yields receptors with
different pharmacological and physiological properties, however,
the GABA.sub.A receptor composition is not immutable. Withdrawal
from anxiolytic benzodiazepines, which produce their effects by
facilitating GABA.sub.A receptor mediated inhibition, yields an
increase in the steady state mRNA levels of .alpha..sub.4 and
.beta..sub.1 subunit mRNA in both the cortex and hippocampus. It
should be noted that the .delta. subunit is often associated with
GABA.sub.A receptor subtypes containing the .alpha..sub.4
subunit.
[0059] GABA and GABA.sub.A receptors are involved in disease states
such as seizures, depression, anxiety and sleep disorders. GABA and
some of the other indirectly or directly acting GABA.sub.A receptor
agonists (GABA-mimetics), including allopregnanolone and
tetrahydrodeoxycorticosterone respectively, bind specifically to a
recognition site located at the interface between an .alpha. and a
.beta. subunit. The classical benzodiazepines, however, such as
diazepam and flunitrazepam, bind to an allosteric site located at
the interface between an .alpha. and a .gamma. subunit.
[0060] More specifically, GABA binds to the cleft between .alpha.
and .beta. subunits, an action which gates open the chloride
channel to allow for the influx of chloride ions into the cell.
This typically hyperpolarizes the cell, having an inhibitory action
on neuronal activity, by making the membrane potential of the cell
more negative, and consequentially, increases the depolarization
threshold to generate an action potential.
[0061] Most depressant and sedative drugs such as the
benzodiazepine tranquilizers, barbiturates, anesthetics and alcohol
are believed have a modulatory effect on the GABA.sub.A receptor at
unique sites where they can enhance the actions of GABA in
accumulating negatively charged chloride ions into the cell,
inducing sedative or anesthetic effects.
[0062] The conformational restriction of various parts of the
molecule of GABA and biosteric replacements of the functional
groups of the amino acid leads to a broad spectrum of specific
GABA.sub.A agonists. Some of these molecules have played a key role
in the understanding of the pharmacology of the GABA.sub.A receptor
family.
[0063] The absence or presence of a particular .alpha. subunit
isoform in the GABA.sub.A receptors confers selectivity for certain
drugs. Different .alpha. subunits also mediate distinct
pharmacological actions of benzodiazepines, including
sedative-hypnotic and anxiolytic effects. Long-term administration
of benzodiazepines results in the development of tolerance to some
of the effects of these drugs, thus reducing their clinical
efficacy. While the molecular basis for these dependencies remains
unclear, tolerance and dependence appear to be related to the
pharmacodynamics of benzodiazepines.
[0064] Long-term administration of benzodiazepines modifies the
expression of genes that encode various GABA.sub.A subunits. These
changes in gene expression alter the sensitivity of GABA.sub.A
receptors to their pharmacological modulators and thereby underlie
the development of tolerance to or dependence on these drugs. The
subunit composition of GABA.sub.A receptor determines their
affinity for benzodiazepine receptor ligands as well as the
efficacy of these ligands. For example, classical benzodiazepine
agonists (e.g. diazepam), imidazopyridines, imidazoquinolones and
pyrazolopyrimidines show no affinity for or efficacy at GABA.sub.A
receptors that contain .alpha..sub.4 or .alpha..sub.6 subunits.
[0065] The subunit composition of native GABA.sub.A receptors plays
an important role in defining their physiological and
pharmacological function. It is possible to characterize the
physiological, pharmacological, and pathological roles of
GABA.sub.A receptors by understanding the mechanisms by which the
subunit composition of GABA.sub.A receptors is regulated. Thus, the
expression of specific GABA.sub.A receptor subunit genes may be
affected by various physiological and pharmacological modulators,
including but not limited to, pharmacological agents, endogenous
neurosteroids, and food.
[0066] For example, long-term exposure to and subsequent withdrawal
of benzodiazepines, zalpelon, zolpidem, or neurosteroids result in
selective changes in the expression of specific GABA.sub.A receptor
mRNA, including an increase of the .alpha..sub.4 subunit mRNA, and
polypeptide subunits and in GABA.sub.A receptor function in
cultured cells. Withdrawal from diazepam or imidazenil was
associated with both a reduced ability of diazepam to potentiate
GABA action and the ability of flumazenil to potentiate GABA
action. Chronic benzodiazepine treatment and subsequent withdrawal
lead to a change in the receptor subunit composition, and these new
synthesized receptors are less responsive to benzodiazepines. The
up-regulation of the .alpha..sub.4 subunit, however, may be
necessarily coupled with the down-regulation of other subunits for
the development of benzodiazepine dependence.
[0067] Withdrawal of zalpelon or zolpidem, like that of diazepam,
induced a marked increase in the amount of .alpha..sub.4 subunit
mRNA. These effects of zalpelon and zolpidem on GABA.sub.A receptor
gene expression are consistent with the reduced tolerance liability
of these drugs, compared with that of diazepam, as well as with
their ability to induce both physical dependence and withdrawal
syndrome.
[0068] Ethanol withdrawal-induced increases in the amounts of
.alpha..sub.4 subunit mRNA and protein are associated with reduced
sensitivity of GABA.sub.A receptors to GABA and benzodiazepines.
The effects of alcohol are similar to those of drugs that enhance
the function of GABA.sub.A receptors, which gate the Cl-currents
that mediate most inhibitory neurotransmission in the brain, as
described above. Acutely high doses of alcohol potentiate
GABA-gated currents at both native and recombinant GABA.sub.A
receptors, and chronically alter GABA.sub.A receptor expression.
Ethanol elicits its central effects through modulation of
neurotransmission mediated by various receptors, especially that
mediated by GABA.sub.A receptors. It has been shown that long-term
ethanol administration also affects the subunit composition and,
consequently, the functional properties of native GABA.sub.A
receptors. The pharmacological profile of ethanol is similar to
that of benzodiazepine and also results in the development of
cross-tolerance and dependence.
[0069] Exposure to diazepam at the time of ethanol withdrawal
antagonizes the withdrawal-induced increase in the abundance of the
.alpha..sub.4 subunit mRNA. The replacement of ethanol with
diazepam also blocked the ethanol withdrawal-induced impairment in
cellular metabolism. Cells exposed to GHB at the time of ethanol
withdrawal results in an inhibition in the increase in the
abundance of the .alpha..sub.4 subunit mRNA.
[0070] The modulatory action of flumazenil in cells that are
exposed to ethanol is similar to that measured in cells not exposed
to ethanol. In contrast, however, in ethanol withdrawn cells, 3
.mu.M flumazenil potentiates the GABA evoked Cl-current consistent
with the ethanol withdrawal-induced up-regulation of the
.alpha..sub.4 subunit in these cells. The substitution of 10 .mu.M
diazepam or 100 mM GHB for ethanol negated the positive modulation
of 3 .mu.M flumazenil induced by ethanol withdrawal.
[0071] The presence of the .alpha..sub.4 subunit in recombinant
GABA.sub.A receptors is associated with a reduced sensitivity to
classical benzodiazepine agonists and to zolpidem as well as with a
distinct pattern of regulation (positive rather than no allosteric
modulation) by flumazenil.
[0072] In general, chronic treatment with agonists that act at
different sites of the GABA.sub.A receptor results in changes in
the biochemical and functional properties of the receptor that are
accompanied by changes in the abundance of specific receptor
subunit mRNAs. In addition, chronic treatment with substances that
modulate GABA.sub.A function via a neurosteroid pathway results in
changes in the biochemical and functional properties of the
receptor that are accompanied by changes in the abundance of
specific receptor subunit mRNAs. The observation that the ethanol
withdrawal-induced increase in the expression of the .alpha..sub.4
subunit gene in cultured cerebellar granule cells is prevented by
diazepam is consistent with the fact that benzodiazepine treatments
are effective in treating alcohol withdrawal symptoms in humans.
Thus, a rapid and marked increase in the abundance of the
.alpha..sub.4 subunit induced by ethanol withdrawal might therefore
contribute to the development of diazepam-sensitive withdrawal
symptoms in humans.
III. GABA and Neurosteroids
[0073] Characterizations of the role of GABA.sub.A receptors
require an understanding of the mechanisms by which subunit
composition is regulated. The long-term administration of
sedative-hypnotic, anxiolytic, or anticonvulsant drugs can affect
expression of GABA.sub.A receptor subunit genes as well as the drug
sensitivity and function of these receptors, suggesting that the
mechanisms responsible for such changes might also underlie the
physiological modulation of GABA.sub.A receptors by endogenous
compounds such as neurosteroids.
[0074] The neuroactive steroids
3.alpha.-hydroxy-5.alpha.-pregnan-20-one (allopregnanolone) and
3.alpha.,21-dihydroxy-5.alpha.-pregnan-20-one
(allotetradihydrodeoxycorticosterone, or THDOC) induce anxiolytic,
sedative, hypnotic, and anticonvulsant effects similar to
benzodiazepines and other anxiolytic drugs. The concentrations of
these neurosteroids are increased in the brain of humans both in
response to treatment with anxiogenic, antidepressant or
antipsychotic drugs as well as physiological or pathological
conditions (such as depression, stress, the luteal phase of the
menstrual cycle, and pregnancy) that affect mood and emotional
state. Additional studies implicate endogenous allopregnanolone as
a physiological regulator of both basal and stress-induced dopamine
release in the rat brain.
[0075] Steroid metabolites react with the GABA receptor complex to
alter brain excitability. Several of these steroids accumulate in
the brain after local synthesis or after metabolism of adrenal
steroids. Neurosteroids are synthesized in the peripheral and
central nervous system, from cholesterol or steroidal precursors
imported from peripheral sources. Both progesterone and estrogen
alter excitability of neurons of the central nervous system. For
example, estrogen reduces inhibition at the GABA.sub.A receptor,
enhances excitation at the glutamate receptor, and increases the
number of excitatory neuronal synapses. In contrast, progesterone
enhances GABA-mediated inhibition, increases GABA synthesis, and
increases the number of GABA.sub.A receptors. In particular,
progesterone and its metabolites have been demonstrated to have
profound effects on brain excitability. The levels of progesterone
and its metabolites vary with the phases of the menstrual cycle,
decreasing prior to the onset of menses. Progesterone is readily
converted to allopregnanolone (3.alpha.-OH-5.alpha.-pregnan-20-one
or 3.alpha.,5.alpha.-THP) in human brains. Allopregnanolone-induced
GABA.sub.A receptor dysregulation has been closely linked to major
anxiety-related diseases, thus linking anxiety to allopregnanolone
"withdrawal".
[0076] Neurosteroids rapidly alter neuronal excitability thorough
interaction with neurotransmitter-gated ion channels.
Allopregnanolone is a positive potent modulator of the GABA.sub.A
receptor and enhances the action which gates open the chloride
channel to allow influx of chloride ions into the cell. This
typically hyperpolarizes the cell, having an inhibitory action on
neuronal activity, and thus allopregnanolone acts as a sedative or
anxiolytic agent and decreases anxiety.
[0077] GABA.sub.A-modulatory allopregnanolone, as described above,
is also responsible for producing anxiogenic withdrawal symptoms.
The withdrawal profile shown therein is similar to that reported
for other GABA.sub.A-modulatory drugs such as the benzodiazepines,
barbiturates, and ethanol. Thus, the actions of neuroactive
steroids on traditional transmitter receptor in the brain lead to
alterations in the GABA.sub.A receptor subunit composition that
result in changes in the intrinsic channel properties of the
receptor and behavioral excitability. Changes are also associated
with significant increases in both the mRNA and protein for the
.alpha..sub.4 subunit of the GABA.sub.A receptor in the
hippocampus. It has also been demonstrated that chronic
administration of progesterone inhibits the upregulation of the
.alpha..sub.4 subunit of the GABA.sub.A receptor and/or suppresses
receptor activity.
[0078] Thus, the endogenous neurosteroid allopregnanolone exhibits
withdrawal properties, similar to GABA-modulators such as
tranquilizers and alcohol, as described above, increasing anxiety
susceptibility following abrupt discontinuation after chronic
administration. The increase in neuronal excitability has been
attributed to upregulation of the GABA.sub.A .alpha..sub.4 subunit.
Thus, the .alpha..sub.4.beta..sub.2.gamma. is preferentially
expressed following hormone withdrawal. Blockade of the
.alpha..sub.4 gene transcript prevents withdrawal properties.
[0079] The increase in expression of the GABA.sub.A receptor
.alpha..sub.4 subunit relative to the GABA.sub.A receptor
.alpha..sub.4 subunit can thus be attributed to many factors. These
include, but are not limited to 1) compositions, both endogenous
and exogenous, which, upon withdrawal, increase the GABA.sub.A
receptor .alpha..sub.4 subunit relative to the GABA.sub.A receptor
.alpha..sub.1 subunit; and 2) compositions, both exogenous or
endogenous that result in the increase of expression of the
GABA.sub.A receptor .alpha..sub.4 subunit or the decrease of
expression of the GABA.sub.A receptor .alpha..sub.1 subunit.
[0080] Certain substances, both endogenous and exogenous, can cause
modifications in the allostatic control of GABA.sub.A, directly or
indirectly, via an endogenous neurosteroid pathway. Most substances
that cross the blood-brain barrier in sufficient quantity can
stimulate a neuroprotective, neurosteroid response. In general, the
more neuroexcitatory the substance, the more neurosteroid response
is achieved. With the up-regulation of neurosteroids, GABA.sub.A
receptor activity is enhanced, causing a constant state of
activation which, over time, may cause neurosteroid tolerance.
Therefore, once the neuroexcitatory substance is no longer present,
the brain's neurosteroid levels will decrease to natural levels,
causing the individual to go through a state of "withdrawal" from
the neurosteroid.
[0081] In the course of this "withdrawal", certain GABA.sub.A
receptor subunits may be expressed, or suppressed, in a manner that
causes the person's brain to be susceptible to greater feelings of
anxiety. In particular, his brain's GABA.sub.A receptor
.alpha..sub.1 subunits decrease in relative amounts to GABA.sub.A
receptor .alpha..sub.4 subunits. As a result of neurosteroid
"withdrawal" and the subsequent up-regulation of .alpha..sub.4
subunits relative to .alpha..sub.1 subunits, the GABA receptor is
no longer effectively modulated by GABA, and, therefore, results in
the person experiencing a greater sense of anxiety.
[0082] In one embodiment, an individual's lowered degree of
inhibitory control over his thoughts is caused by the modification
of the receptivity of the synaptic GABA.sub.A receptors to the
neurotransmitter GABA in the individual's brain. For example,
substance abuse diminishes GABA receptivity; thus, the exogenous
substance or "drug" modulates the GABA.sub.A receptor. When the
user ceases consumption of the exogenous substance, due to changes
in the GABA.sub.A receptor composition upon withdrawal (i.e.
increased relative amount of GABA.sub.A receptor .alpha..sub.4
subunits compared to GABA.sub.A receptor .alpha..sub.1 subunits),
the receptor is not effectively modulated by GABA, thus causing
anxiety.
[0083] FIG. 1 illustrates the spectrum between inhibition and
disinhibition via the direct and/or indirect allosteric modulation
of GABA.sub.A. Spectrum 100 further depicts the range between
inhibition 105 and disinhibition 110. An increase in an exogenous
or endogenous substance that directly or indirectly enhances the
function of GABA or the GABA.sub.A receptor 115 can result in an
increase in GABA agonism and thus an increase in inhibition,
anxiolysis, amnesia, and sedation, and even a comatose state.
[0084] However, as mentioned in greater detail above, stress, drug
use, and even behavior activates these adaptive responses and
disrupts homeostasis--the brain's internal balance. Upon withdrawal
of both endogenous and exogenous substances, there is a marked
increase in the .alpha..sub.4 subunit 120 of relative to the
.alpha..sub.1 subunit 125 of the GABA.sub.A receptor 115, as shown
in spe0ctrum 150. The increase of the .alpha..sub.4 subunit 120 of
the GABA.sub.A receptor 115 causes the receptor to become
insensitive to benzodiazepines and other compositions that act upon
and/or enhance the function of GABA and the GABA.sub.A receptor.
Therefore, when the systems involved in allostasis do not
self-regulate (i.e. do not shut off when not needed or do not
activate when needed), the brain experiences a compensatory drive
to address this inactive or constantly active state, often
exhibited in the form of anxiety or cravings.
IV. Anxiety and Inhibition
[0085] Anxiety may be defined in a plurality of ways, including a
vague unpleasant emotion that is experienced in anticipation of
some, often ill-defined misfortune, a complex combination of the
feeling of fear, apprehension and worry often accompanied by
physical sensations such as palpitations, chest pain and/or
shortness of breath, a feeling of apprehension, fear, nervousness,
or dread accompanied by restlessness or tension, and/or a
debilitating condition of fear, which interferes with normal life
functions. Anxiety is evaluated clinically using diagnostic
inventories such as the Hamilton Anxiety Rating Scale (Guy,
William, "048 HAMA Hamilton Anxiety Scale," ECDEU Assessment
Manual, U.S. Department of Health and Human Services, Public Health
Service--Alcohol, Drug Abuse, and Mental Health Administration,
Rev. 1976, pp. 194-198) or the Beck Anxiety Inventory (Encephale.
1994 January-February; 20(1): 47-55), which are herein incorporated
by reference.
[0086] In one embodiment, anxiety comprises a physiological state
in which an individual has a lowered degree of inhibitory control
over his thoughts, as described above with respect to FIG. 1. Such
lowered degree of inhibitory control may be caused by the turning
off, inhibition, or otherwise down-modulation of an internal
thought filtering mechanism in the person's brain. Referring to
FIG. 2, the internal thought filtering mechanism 200 comprises
certain centers within a person's prefrontal cortex 205, including
the orbitofrontal cortex 210, which is considered responsible for
exerting control, and the anterior cingulate 215, which is
considered responsible for motivation and drive impulses. These
brain centers are substantially affected by certain physiological
inputs, such as a reward circuit that comprises the nucleus
accumbens 220 and ventral tegmental 225 areas of the brain.
[0087] When normally regulated, the orbitofrontal cortex 210 can
exert control over a person's thoughts and avoid having an
individual feel "overwhelmed" by vague, unpleasant emotions and
feelings of fear, apprehension and worry. If GABA.sub.A receptor
functionality is somehow impaired, however, GABA dysregulation
occurs and can result in an impaired ability of the orbitofrontal
cortex 210 to exert control over a person's thoughts and,
therefore, a lowered degree of inhibitory control.
[0088] Consequently, the individual becomes compulsively driven to
"address" this anxiety by making sure he obtains whatever
substance, or engage in whatever activity, his brain believes it
needs in order to eliminate the feelings of anxiety, e.g. regain
inhibitory control over his thoughts. Therefore, it is the
physiological drive to address feelings of anxiety that causes an
individual to consciously engage in behavior which could be
classified as self-destructive, such as substance abuse.
[0089] In the absence of a solution to address anxiety, a person is
in a constant stress response state which, both psychologically and
physiologically, directs the person to search for and obtain a
solution to the anxiety. Many indications are implicated as being
caused by the physiological drive to address feelings of anxiety.
As discussed below, certain indications are caused by the
psychological addiction and physiological dependence upon various
substances, both exogenous and endogenous.
[0090] Exogenous substances, such as opioids, benzodiazepines,
cannabis, caffeine, nicotine, and other drugs, directly or
indirectly affect GABA.sub.A receptor functionality and, when those
exogenous substances are withheld from an individual, cause the
expression of the GABA.sub.A receptor .alpha..sub.4 subunit
(hereinafter generally referred to as the .alpha..sub.4 subunit) to
increase relative to the expression of the .alpha..sub.1
subunit.
[0091] In particular, during use, such substances may directly or
indirectly stimulate GABA.sub.A via a neurosteroid mediated
pathway. When those substances are later withheld, the amount of
.alpha..sub.4 subunits relative to .alpha..sub.1 subunits
increases. This ratio change is often temporary and is subject to
reversal. However, a distinct pathophysiology emerges when it
becomes non-reversing, namely when .alpha..sub.4 subunits no longer
down-regulate relative to .alpha..sub.1 subunits. As described
above, when such pathophysiology gets established, the GABA.sub.A
receptor therefore becomes less sensitive to benzodiazepines and
effectively, modulation by the neurotransmitter GABA, and is less
capable of exerting inhibitory control over an individual's
thoughts and behavior.
[0092] In one embodiment, it is possible to calculate a GABA-active
steroid score ("GS Score") for nearly all substances. For every
substance that crosses the blood brain barrier, or is active on the
central nervous system, there is a minimum threshold level needed
of that particular substance to effectively raise levels of
GABA-active steroids. Thus, the GS Score correlates direct agonism
of GABA.sub.A and the indirect modulation of GABA.sub.A via a
neurosteroid mediated pathway, such as, but not limited to
allopregnanolone. For example, but not limited to such example,
cocaine has a lower GS Score than aspartame, since cocaine is more
potent and it takes a lower threshold dose of cocaine to raise
levels of GABA-active steroids. The GS Score is a methodology for
measuring and assigning a numeric value to the relative addictive
properties of substances.
[0093] Referring to FIG. 3a, a benzodiazepine sensitive GABA.sub.A
receptor 300a is shown. The GABA.sub.A receptor comprises a
plurality of subunits, including two .beta..sub.2 subunits 305a, a
.gamma..sub.2 subunit 310a, and two .alpha..sub.1 subunits 315a. By
affecting the functionality and expression of receptor subunit
mRNAs, certain endogenous and exogenous substances cause the
expression of the GABA.sub.A receptor .alpha..sub.4 subunit to
increase relative to the expression of the .alpha..sub.1 subunit.
Referring to FIG. 3b, the modified GABA.sub.A receptor 300b
comprises a plurality of subunits, including two .beta..sub.2
subunits 305b, a .gamma..sub.2 subunit 310b, and two .alpha..sub.4
subunits 315b. As shown in FIG. 3c, the GABA.sub.A receptor
therefore becomes less sensitive to benzodiazepines and
effectively, modulation by the neurotransmitter GABA, and is less
capable of exerting inhibitory control over an individual's
thoughts and behavior.
[0094] Endogenous substances may also have similar effects.
Specifically, GABA-modulatory steroids, such as progesterone and
deoxycorticosterone (DOC) and their metabolites allopregnanolone
and tetrahydrodeoxycorticosterone respectively, affect GABA.sub.A
receptor functionality and thus, when progesterone or DOC is
decreased or "withdrawn" in an individual, cause the expression of
the GABA.sub.A receptor .alpha..sub.4 subunit to increase relative
to the expression of the .alpha..sub.1 subunit.
[0095] In addition, an increase in the level of endogenous
neurosteroid is associated with tolerance. Thus, engaging in
activities that increase neurosteroid production is an often
temporary solution, because as described above, a distinct
pathophysiology emerges and when it becomes non-reversing, namely
when .alpha..sub.4 subunits no longer down-regulate relative to
.alpha..sub.1 subunits. This loss of inhibitory control impairs an
individual's ability to act on cravings and thus contributes to
irrational behavior to engage in activities regardless of
consequences.
[0096] Many systems within the body are subject to inhibitory
control via GABAergic neurons located in the brain. In the event
that an endogenous system is subject to inhibitory feedback by
GABA, then the dysregulation of GABA.sub.A receptors can result in
reduced inhibition or disinhibition of that particular system.
Thus, it can be determined whether a primary system is
dysregulated, and thus disinhibited, often noted because a patient
exhibits a particular indication or disease state, and more
specifically, a disease state where higher levels of an endogenous
marker are present. For example, but not limited to such example,
abnormal cholesterol levels are indicative of dysregulation of a
primary system. If, however, a primary system is not dysregulated,
then it can be determined whether an inhibitory system is
disinhibited or dysregulated, and whether that inhibitory system is
restored in the presence of endogenous neurosteroids, such as
allopregnanolone and progesterone.
[0097] For example, but not limited to such example, prolactin
inhibits dopamine, and thus when a patient presents with lower
levels of dopamine, it is suggested that prolactin is not being
subjected to inhibitory feedback, resulting in increased levels of
prolactin. Increased levels of prolactin may be, at least in part,
due to GABA.sub.A receptor dysregulation, and thus
disinhibition.
V. Compositions Used in the Novel Treatment Methodologies of the
Present Invention
[0098] The compositions described herein, and the compounds
identified through the screening methodologies described herein,
are intended to be used as drugs in the treatment methodologies
described below. As used in this description, the term drug is used
to refer to prescription or non-prescription pharmaceutical
compositions and/or medications that include an active ingredient
and, optionally, non-active, buffering, or stabilizing ingredients,
including pharmaceutically acceptable carriers or excipients
suitable for the form of administration of said pharmaceutical
compositions. It should be appreciated that the administration of
the drug may be achieved through any appropriate route of
administration, for example, orally, inhaled, anally, sublingual,
bucally, transdermally, nasally, implant, or parenterally, for
which it will be formulated using the appropriate excipients for
the form of administration.
[0099] Table 1 is attached hereto and offers an exemplary listing
of pharmacological compounds in the classes of compounds described
herein. It should be noted however, that Table 1 is not an
exhaustive list of all of the compositions that can be used with
the present invention and that the present invention is not limited
to the use of such compounds.
[0100] a. Compounds that Inhibit Neurosteroid Production
[0101] In one embodiment, the present invention is directed towards
a method of using a compound from a class of compounds that inhibit
neurosteroid production ("Inhibitors of Neurosteroid Production").
In one embodiment, the compound is one that inhibits the conversion
of progesterone to its metabolite allopregnanolone. In another
embodiment, the compound is one that inhibits the conversion of
progesterone metabolite 5.alpha.-dihydroprogesterone into
allopregnanolone.
[0102] As shown in FIG. 4, progesterone is first converted to
5.alpha.-dihydroprogesterone via an enzyme called
5.alpha.-reductase. 5.alpha.-dihydroprogesterone is then converted
to 5.alpha.,3.alpha.-pregnanolone (allopregnanolone) via the
3.alpha.-hydroxysteroid oxidoreductase enzyme.
[0103] Reference will now be made to specific classes of inhibitors
of neurosteroid production for use in the present invention. While
the classes and inhibitors of neurosteroid production are described
generally herein, it should be understood to those of ordinary
skill in the art that any number of inhibitors of neurosteroid
production that prevent the conversion of progesterone into its
metabolite allopregnanolone can be used in the present invention
and that the list is not exhaustive.
[0104] In one embodiment, an individual is administered a
therapeutically effective amount of a 5-alpha-reductase inhibitor
which blocks the conversion of progesterone into allopregnanolone.
One exemplary 5-alpha-reductase inhibitor is finasteride or analogs
or derivatives thereof. Preferably, the 5.alpha.-reductase
inhibitor is capable of acting as a Type I inhibitor, a Type II
inhibitor, or a combination thereof, and inhibits the
5.alpha.-reductase enzyme from converting progesterone to
5.alpha.-dihydroprogesterone and thus from creating progesterone
metabolite allopregnanolone.
[0105] There are currently accepted dosing regimens for
5-alpha-reductase inhibitors. The present invention contemplates
operating within the maximum limits of currently accepted dosing
regimens in order to maximally decrease the production of
allopregnanolone and make the individual most receptive to
treatment.
[0106] In one embodiment, an individual is administered a
therapeutically effective amount of a 3-alpha-hyrodxysteroid
oxidoreductase inhibitor which blocks the conversion of
progesterone metabolite 5.alpha.-dihydroprogesterone into
allopregnanolone. One exemplary 3-alpha-hyrodxysteroid
oxidoreductase is indomethacin or analogs or derivatives thereof.
There are currently accepted dosing regimens for
3-alpha-hyrodxysteroid oxidoreductase inhibitors. The present
invention contemplates operating within the maximum limits of
currently accepted dosing regimens in order to effectively decrease
the production of allopregnanolone and make the individual most
receptive to treatment.
[0107] Bitran et al (1995) have demonstrated that treatment with a
5-alpha-reductase inhibitor prevents the conversion of progesterone
to allopregnanolone and eliminates the anxiolytic activity of
progesterone. In addition, it has been suggested that the
anxiogenic withdrawal properties of allopregnanolone can be
prevented by previous administration of a 3.alpha.-hydroxysteroid
oxidoreductase blocker such as indomethacin.
[0108] i. 5.alpha.-Reductase Inhibitors
[0109] The 5.alpha.-reductase inhibitors are a group of drugs with
anti-androgenic activity that effectively decrease the amount of
the 5.alpha.-reductase enzyme and thus inhibit neurosteroid
production.
[0110] 1. Finasteride
[0111] Finasteride is a synthetic 4-azasteroid compound, and is a
5alpha-reductase inhibitor. Finasteride is
4-azaandrost-1-ene-17-carboxamide,N-(1,1-dimethylethyl)-3-oxo-,(5.alpha.,-
17.beta.)-. The empirical formula of finasteride is
C.sub.23H.sub.36N.sub.2O.sub.2 and its molecular weight is
372.55.
[0112] Finasteride is a competitive and specific 5.alpha.-reductase
inhibitor. Finasteride has no affinity for the androgen receptor
and has no androgenic, antiandrogenic, estrogenic, antiestrogenic,
or progestational effects.
[0113] Progesterone is metabolically converted to the GABA.sub.A
receptor-potentiating neuroactive steroid allopregnanolone by
5.alpha.-reductase isoenzymes followed by 3.alpha.-hydroxysteroid
oxidoreduction. Finasteride acts as a competitive
5.alpha.-reductase inhibitor and thus blocks the production of
allopregnanolone from progesterone.
[0114] In one embodiment, finasteride is delivered using at least
one oral tablet with a total daily dose of less than 10 mg,
preferably less than 5 mg. It should be appreciated that, to the
extent approved by regulatory authorities, finasteride can also be
delivered in gel capsules or via injection or infusion. Finasteride
should not be used by women of childbearing age. Finasteride's side
effects include breast enlargement and tenderness, skin rash,
swelling of lips, abdominal pain, back pain, decreased libido,
decreased volume of ejaculate, diarrhea, dizziness, headache,
impotence, and testicular pain.
[0115] 2. Dutasteride
[0116] Dutasteride is a synthetic 4-azasteroid compound that is a
selective inhibitor of both the Type I and Type II isoforms of the
steroid 5.alpha.-reductase, an intracellular enzyme. Dutasteride is
chemically designated as (5.alpha.,17.beta.)-N-{2,5
bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide.
The empirical formula of dutasteride is
C.sub.27H.sub.30F.sub.6N.sub.2O.sub.2, representing a molecular
weight of 528.5.
[0117] As a competitive Type I and Type II 5.alpha.-reductase
inhibitor, dutasteride inhibits the conversion of progesterone to
allopregnanolone. Dutasteride does not bind to the human androgen
receptor.
[0118] In one embodiment, dutasteride is delivered using at least
one capsule with a total daily dose of less than 10 mg, preferably
less than 0.5 mg. It should be appreciated that, to the extent
approved by regulatory authorities, dutasteride can also be
delivered in tablets or via injection or infusion. Dutasteride
should not be used by women of childbearing age. Dutasteride's side
effects include cough, difficulty swallowing, dizziness, fast
heartbeat, hives or welts, itching skin, puffiness or swelling of
the eyelids or around the eyes, face, lips, or tongue, redness of
skin, shortness of breath, skin rash, swelling of face, fingers,
feet, and/or lower legs, tightness in chest, unusual tiredness or
weakness, wheezing, abnormal ejaculation, decreased interest in
sexual intercourse, decreased sexual performance or desire,
impotence, inability to have or keep an erection, loss in sexual
ability, desire, drive, or performance, or swelling of the breasts
or breast soreness.
[0119] 3. Other 5.alpha.-Reductase Inhibitors
[0120] The present invention also encompasses the use of other
5-alpha reductase inhibitors, including a) 4-aza-4-methyl-5
alpha-pregnane-3,20-dione (AMPD), which inhibits pituitary
progesterone 5-alpha reduction, b) cyproterone acetate, and c)
spironolactone, which is a diuretic that blocks two pathways to the
production of androgens, or male hormones, one of which is the
inhibition of 5.alpha.-reductase.
[0121] The present invention also encompasses the use of organic
sources of 5-alpha reductase inhibition, including organic sources
such as saw palmetto. Saw palmetto (Serenoa repens) is a natural
source of a 5.alpha.-reductase inhibitor. Some studies suggest that
it may be comparable to finasteride if taken for six months. Saw
Palmetto is advantageous because it is 1) substantially free of
side effects and 2) cost effective.
[0122] ii. Other Inhibitors of Neurosteroid Production
[0123] The present invention further includes the use of
3.alpha.-hydroxysteroid oxidoreductase blockers. Gallo and Smith
(1993) suggest that the anxiogenic withdrawal property of
progesterone could be prevented by previous administration of a
3.alpha.-hydroxysteroid oxidoreductase blocker. In one embodiment,
indomethacin is used. Indomethacin is a non-steroidal
anti-inflammatory drug (NSAID) that reduces fever, pain and
inflammation. It is similar to ibuprofen and naproxen. Indomethacin
is effective in reducing the production of prostaglandins.
[0124] It should be appreciated that any composition that can be
used to inhibit neurosteroid production can be used in the present
invention. In one embodiment, compounds are preferably screened to
determine whether they can be used in the treatment methodologies
of the present invention.
[0125] Specifically, an appropriate cellular model is used to model
the inhibition of neurosteroid production. The efficacy of the
composition is measured by measuring the relative levels of
progesterone and allopregnanolone in a model prior to the
administration of the composition and after the administration of
the composition. In cases where the relative levels of progesterone
and allopregnanolone decrease after administration, the composition
may be suitable as an inhibitor to neurosteroid production.
[0126] b. Compounds that Modulate the Expression of Certain
GABA.sub.A Receptor Subunits
[0127] Molecular biology studies have revealed a high degree of
structural heterogeneity of the GABA.sub.A receptors. Development
of subtype selective or specific compounds is of key importance for
the understanding of the physiological and pathological roles of
different GABA receptor subtypes and may lead to valuable
therapeutic agents. It has been shown that functional selectivity
is obtainable for a number of GABA.sub.A agonists.
[0128] Characterizations of the role of GABA.sub.A receptors
require an understanding of the mechanisms by which subunit
composition is regulated. The long-term administration of
sedative-hypnotic, anxiolytic, or anticonvulsant drugs can affect
expression of GABA.sub.A receptor subunit genes as well as the drug
sensitivity and function of these receptors, suggesting that the
mechanisms responsible for such changes might also underlie the
physiological modulation of GABA.sub.A receptors by endogenous
compounds such as neurosteroids.
[0129] The level of efficacy of a partial agonist/antagonist
depends upon the disease or dependence in question. Thus, by
measuring the level of efficacy or activity of a partial
agonist/antagonist at a receptor site, it is possible to determine
what the disease state is and determine what conformational changes
have occurred in the GABA.sub.A receptor subunits. Based upon this
information, certain compositions can be classified according to
the changes they cause in GABA.sub.A subunits. In addition, since
the GABA binding site in the GABA.sub.A receptor is located at the
interface between .alpha. and .beta. subunits, the GABA.sub.A
antagonists can bind to and stabilize a distinct inactive receptor
conformation.
[0130] The present invention is thus directed towards a class of
compounds that modulates the expression of certain GABA.sub.A
receptor subunits. More specifically, the compound is one that
serves as an agonist at the GABA.sub.A receptor, and more
specifically, at either the .alpha..sub.4 subunit or .alpha..sub.6
subunit, and is capable of positively potentiating GABA
current.
[0131] Still more specifically, the compound of choice is one that
a) acts a partial agonist of GABA.sub.A; b) inhibits the
up-regulation of the .alpha..sub.4 subunit and/or increases the
amount of the al subunit relative to the amount of the
.alpha..sub.4 subunit; and c) does not cause the up-regulation of
the .alpha..sub.4 subunit and/or does not cause the amount of the
.alpha..sub.4 subunit to increase relative to the amount of the
.alpha..sub.1 subunit once the compound is no longer present in the
patient's system.
[0132] The changes in expression of the GABA.sub.A receptor
.alpha..sub.4 subunit relative to the GABA.sub.A receptor
.alpha..sub.1 subunit can be attributed to many factors. These
include, but are not limited to 1) compositions, both endogenous
and exogenous, that transform the GABA.sub.A receptor .alpha..sub.4
subunit relative to the GABA.sub.A receptor .alpha..sub.1 subunit
and vice versa; 2) compositions that result in the decrease of
expression of the GABA.sub.A receptor .alpha..sub.4 subunit or the
increase of expression of the GABA.sub.A receptor .alpha..sub.1
subunit; and 3) compositions that do not modify existing subunit
levels, but rather prevent the upregulation of GABA.sub.A receptor
.alpha..sub.4 subunit.
[0133] Thus, the compound of choice is one that effectuates an
increase in the expression of the GABA.sub.A receptor .alpha..sub.1
subunit relative to the expression of the .alpha..sub.4 subunit.
This increase in expression of the al subunit may be effectuated by
one or more of the following: a) upregulating the expression of
.alpha..sub.1 subunits; b) downregulating the expression of
.alpha..sub.4 subunits; c) masking .alpha..sub.4 subunits; or d)
preventing the upregulation of the .alpha..sub.4 subunit.
[0134] The focus is thus on using a compound from the class of
compounds that modulates the expression of certain GABA.sub.A
receptor subunits, and more specifically, moves the relative
balance of the .alpha..sub.4 subunit to the .alpha..sub.1 subunit
closer to a normal state from an abnormal, allostatic state.
[0135] i. Flumazenil
[0136] In one embodiment, the present invention relates to the use
of a therapeutically effective quantity of a drug, and more
specifically, one that modulates the expression of GABA.sub.A
subunits, such as, but not limited to, flumazenil, in a methodology
for treatment of substance abuse. In one embodiment, the compound
may comprise certain imidazobenzodiazepines and derivatives of
ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-a][1,4]
benzodiazepine-3-carboxylate, including various substitutions of
the carboxylate functional group, such as carboxylic acids, esters,
acyl chlorides, acid anhydrides, amides, nitrites, alkyls, alkanes,
cycloalkanes, alkenes, alcohols, aldehydes, ketones, benzenes,
phenyls, and salts thereof. In another embodiment, the compound
comprises flumazenil or carboxylic acids, esters, acyl chlorides,
acid anhydrides, amides, nitrites, alkyls, alkanes, cycloalkanes,
alkenes, alcohols, aldehydes, ketones, benzenes, phenyls, and salts
thereof.
[0137] Flumazenil acts a partial agonist of GABA.sub.A, inhibits
the upregulation of the .alpha..sub.4 subunit and/or increases the
amount of the al subunit relative to the amount of the
.alpha..sub.4 subunit, and does not cause the upregulation of the
.alpha..sub.4 subunit and/or does not cause the amount of the
.alpha..sub.4 subunit to increase relative to the amount of the
.alpha..sub.1 subunit once the compound is no longer present in the
patient's system.
[0138] ii. Miltirone
[0139] In another embodiment, the compound may comprise miltirone,
as described in Mostallino et al., "Inhibition by miltirone of
up-regulation of GABA.sub.A receptor .alpha..sub.4 subunit mRNA by
ethanol withdrawal in hippocampal neurons", European Journal of
Pharmacology, 494 (2004) 83-90.
[0140] iii. Flavonoids
[0141] In another embodiment, the compound may comprise certain
flavonoids that act as a partial agonist of GABA.sub.A, inhibit the
upregulation of the .alpha..sub.4 subunit and/or increase the
amount of the .alpha..sub.1 subunit relative to the amount of the
.alpha..sub.4 subunit, and does not cause the upregulation of the
.alpha..sub.4 subunit and/or does not cause the amount of the
.alpha..sub.4 subunit to increase relative to the amount of the
.alpha..sub.1 subunit once the compound is no longer present in the
patient's system.
[0142] It should be appreciated that any composition that can
function as described above, can be used in the present invention.
In one embodiment, compounds are preferably screened to determine
whether they can be used in the treatment methodologies of the
present invention. In one embodiment, experiments are conducted to
determine whether it functions as a partial agonist of GABA.sub.A,
inhibits the upregulation of the .alpha..sub.4 subunit, and does
not cause the upregulation of the .alpha..sub.4 subunit once the
compound is no longer present in the patient's system. While one of
ordinary skill in the art can devise such experiments, an exemplary
embodiment of such an experiment is provided in Mostallino et al.,
"Inhibition by miltirone of up-regulation of GABA.sub.A receptor
.alpha..sub.4 subunit mRNA by ethanol withdrawal in hippocampal
neurons", European Journal of Pharmacology, 494 (2004) 83-90.
VI. Novel Treatment Methodologies
[0143] The present invention is directed towards a comprehensive
treatment protocol that employs methods of, and compositions for,
preparing a patient for treatment and modulating the expression of
certain GABA.sub.A receptor subunits. The present invention
therefore treats withdrawal symptoms associated with psychological
addiction and physiological dependence upon various exogenous and
endogenous substances in the context of a comprehensive treatment
plan of behavioral and/or pharmacological treatment.
[0144] The multiple phase treatment methodology of the present
invention employs one or more compounds to reset physiochemical
changes in a patient that is experiencing withdrawal from addictive
and/or dependency-inducing substances, including but not limited to
opioids and derivatives, nicotine, benzodiazepines, caffeine,
cannabis, or anti-depressant drugs. Effective treatment of such
indications requires addressing the maladaptive behaviors
underlying addiction and physiological dependence upon various
exogenous substances, namely the increased expression of the
GABA.sub.A receptor .alpha..sub.4 subunit relative to the
.alpha..sub.1 subunit.
[0145] The treatment methodology of the present invention thus
incorporates 1) determining if a person is in a receptive state for
treatment and/or causing a person to be in a receptive state for
treatment and 2) treating a person using appropriate drugs in a
comprehensive treatment protocol that includes pre-drug assessment
including optional detoxification, treatment, and aftercare. The
term "receptive state", as used herein, refers to a physiological
state in which the patient is withdrawn from both endogenous and
exogenous substances.
[0146] As used in this description, the term "substance abuse" is
used to refer to the various physical and psychological states that
manifest an individual's impaired control over substance use,
continued substance use despite adverse consequences, compulsive
substance use, and/or drug cravings. The term is intended to
include psychological dependence, physical dependence, tolerance, a
maladaptive pattern of substance use, preoccupation with substance
use, and/or the presence of withdrawal symptoms upon cessation of
use. Notwithstanding the above, the terms "addiction" and
"dependency" are used interchangeably throughout this text. While
it is traditionally understood that addiction and dependency relate
to illegal or narcotic substances, it should be understood here
that the treatment protocol of the present invention may also be
used to treat other drug addictions, withdrawal reaction from
prescribed medication, and other types of compulsive behaviors
relating to food, sex, or gambling.
[0147] As used in this description, the term "substance" refers to
a composition to which a person may exhibit withdrawal symptoms
from abrupt cessation of intake or production of the composition,
and includes, but is not limited to, opiates, nicotine,
benzodiazepines, caffeine, cannabis, and anti-depressants.
[0148] As used in this description, the term patient refers to a
male or female human being of any race, national origin, age,
physiological make-up, genetic make-up, disease predisposition,
height, or weight, and having any disease state, symptom or
illness.
[0149] It should further be appreciated that the methods and
processes of the present invention can be implemented in a computer
system having a data repository to receive and store patient data,
a memory to store the protocol steps that comprise the methods and
processes of the present invention, a processor to evaluate patient
data in relation to said protocol steps, a network interface to
communicate via a network with other computing devices and a
display to deliver information to users. In one embodiment,
specific protocol steps are stored in said memory and compared
against patient data, including behavioral, psychological or
physiological profiles, to determine which protocol steps should be
applied. Results of the comparison are communicated to a user via a
network and other computing devices or display. The methodologies
of the present invention are therefore accessed, tailored, and
communicated as a software program operating on any hardware
platform.
[0150] The exemplary treatment methodology of the present invention
comprises pre-treatment, co-treatment, and post-treatment phases
further comprising various components of an exemplary
methodology.
[0151] As described herein, reference will be made to specific
components of the individual phases of the treatment methodology.
It should be noted, however, that the individual components
comprising each phase of the methodology--pre-treatment,
co-treatment, and post-treatment--are interchangeable and may be
performed variably, and should be determined on a per-patient
basis. Thus, any reference to administering the individual
components of the phases of methodology in a particular order is
exemplary and it should be understood to one of ordinary skill in
the art that the administration of methodology may vary depending
on the assessed needs of the patient. Furthermore, while the
invention will be described in conjunction with specific
embodiments, it is not intended to limit the invention to one
embodiment. In addition, many combinations of the methodology
components described above are possible; thus, the invention is not
limited to such examples as provided.
[0152] The treatment protocols will first be generally described
and then specific examples of the treatment protocols will be
provided thereafter.
[0153] a. Pre-Treatment/Patient Assessment Phase
[0154] Prior to admittance into the treatment program of the
present invention, each patient should undergo a pre-treatment
analysis. The pre-treatment analysis may be used to determine
whether a patient is a candidate for the treatment methodology of
the present invention. In addition, the pre-treatment process may
be administered to prepare a patient for admittance into the
treatment methodology of the present invention. The pre-treatment
phase typically includes, but is not limited to a medical history
and physical examination, a psychological and behavioral
assessment, a determination of required medications, and
detoxification if needed to render the patient in a state receptive
to treatment.
[0155] The treatment methodology for substance abuse has multiple
phases and components that, in combination, provide a comprehensive
and integrated neurological, physiological, and psychosocial
approach for the substance-dependent patient. Each component has
been selected to address specific effects of chronic substance use
and the corresponding symptoms of withdrawal, with the objective of
restoring a balance in neurological circuits. The methodology does
not address the specific physical injury often associated with
substance dependence. It is, therefore, essential that each patient
be assessed and the appropriate treatments be instituted to address
physical injury, with due consideration for the potential
interaction of any medicaments used for this treatment with those
used for the dependency treatment.
[0156] While the present methodology can be applied to any patient,
it is preferred that the patient be equal to or greater than
eighteen years old.
[0157] i. Complete Physical Examination
[0158] Before starting the treatment, the patient undergoes a
medical history, physical examination and laboratory assessment,
including but not limited to a complete blood count, a biochemical
profile [for example, creatinine, glucose, urea, cholesterol (HDL
and LDL), triglycerides, alkaline phosphatase, LDH (lactic
dehydrogenase) and total proteins], hepatic function tests [GOT,
GPT, GGT, bilirubin), electrocardiogram and, if appropriate,
pregnancy test and x-ray examinations. Exclusion criteria are
applied to ensure no other acute or uncompensated illness exists
within the patient and to ensure that the patient does not require,
or is currently not taking, a drug that is contraindicated with the
GABA.sub.A receptor modulating compound being used.
[0159] i. Diagnosis of Substance Abuse, Dependence, and
Tolerance
[0160] It is preferred that the patient meet at least a portion of
recognized criteria for dependence on a particular substance, such
the DSM-IV criteria. The DSM-IV criteria is known to those of
ordinary skill in the art and can be described as a maladaptive
pattern of substance use, leading to clinically significant
impairment or distress, as manifested by any of the following,
occurring at any time in the same 12-month period: [0161]
Tolerance, as defined by either of the following: [0162] A need for
markedly increased amounts of the substance to achieve intoxication
or desired effect. [0163] Markedly diminished effect with continued
use of the same amount of the substance. [0164] FULL WITHDRAWAL, as
manifested by either of the following: [0165] The characteristic
withdrawal syndrome for the substance. [0166] The same (or a
closely related) substance is taken to relieve or avoid withdrawal
symptoms. [0167] Physiological Determination (as described in
greater detail below) [0168] The substance is often taken in larger
amounts or over a longer period than was intended (loss of
control). [0169] There is a persistent desire or unsuccessful
efforts to cut down or control substance use (loss of control).
[0170] A great deal of time is spent in activities necessary to
obtain the substance, use the substance, or recover from its
effects (preoccupation). [0171] Important social, occupational, or
recreational activities are given up or reduced because of
substance use (continuation despite adverse consequences). [0172]
The substance use is continued despite knowledge of having a
persistent or recurrent physical or psychological problem that is
likely to have been caused or exacerbated by the substance (adverse
consequences).
[0173] It should further be noted that certain exclusion criteria
should be applied to the screening of patients. The exclusion
criteria may be tailored to an outpatient or inpatient treatment
scenario. For example, it is preferred not to treat a patient on an
inpatient basis for substance abuse or dependence where the patient
has current medical or psychiatric problems that, per the screening
physician, require immediate professional evaluation and treatment,
has current medical or psychiatric problems that, per the screening
physician, render the client unable to work successfully with the
methodology or with the staff administering the treatment, has
current benzodiazepine and other sedative-hypnotic-anxiolytic use
(urine toxicology must be negative) or is taking anti-psychotic
medication(s).
[0174] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention ("Receptive State for Treatment")
[0175] It should be noted, however, that the individual components
comprising the preparation phase of the methodology are
interchangeable and may be performed variably, and should be
adapted to the patient. Thus, any reference to administering the
individual components of the preparation phase of the methodology
in a particular order is exemplary and it should be understood to
one of ordinary skill in the art that the administration of
methodology may vary depending on the assessed needs of the
patient. In addition, many combinations of the methodology
components described above are possible; thus, the invention is not
limited to such examples as provided.
[0176] i. Placing a Patient in a State of Withdrawal
[0177] As used herein, the term "withdrawal" refers to a
physiological state in which an individual has begun to have
adverse psychological and/or physiological effects from not having
a bioavailable amount of particular substance or from having a
decreasing bioavailable amount of a particular substance. More
specifically, withdrawal can be attributed to an increase in the
GABA.sub.A receptor .alpha..sub.4 subunit expression relative to
the GABA.sub.A receptor .alpha..sub.1 subunit.
[0178] The treatment methodologies of the present invention include
a first step of placing a patient in a state of withdrawal. In one
embodiment, a person is placed in a receptive state for treatment
by actively inhibiting the upregulation of endogenous neurosteroids
and/or causing the downregulation of endogenous neurosteroids. The
upregulation of neurosteroids could be caused by a number of
external factors, including the ingestion or administration of
certain substances, such as caffeine or nicotine, or psychological
stress. The present invention therefore includes the step of
avoiding all such activities that could result in the upregulation
of an individual's neurosteroid level.
[0179] In another embodiment, a person is placed in a receptive
state for treatment by actively causing the downregulation of
endogenous neurosteroids, such as allopregnanolone, through the
administration of inhibitors of neurosteroid production that block
the production of endogenous neurosteroids and/or their
metabolites. The present invention also includes the inhibition of
the modulatory effects of neurosteroids on GABA.sub.A. By doing so,
one accelerates the exposure or upregulation of .alpha..sub.4
subunits relative to .alpha..sub.1 subunits and ensures that a
substantial number of .alpha..sub.4 subunits are exposed and
available to enhance the efficacy of subsequent treatment
steps.
[0180] In one embodiment, to place the patient in a state receptive
to treatment, the patient is induced into a state of withdrawal
from the substance upon which the patient is addicted or dependent.
The withdrawal state can be initiated by withholding the substance
or by a process of sequentially decreasing daily dosing of an
agonist or partial agonist medication with similar pharmacological
properties (e.g. methadone of buprenorphine for heroin
dependence).
[0181] For example, but not limited to such example, in the case of
opiate substance abuse or dependence, the opiate user is
administered an opiate agonist that preferably has a longer
half-life and is less potent than the drug to which the patient has
an addiction. Appropriate methodologies for titrating a person down
from an addictive substance are discussed in greater detail below
with respect to exemplary treatment protocols. Administration of
certain compositions serves to flush the user's system and places
the user in a physiological state capable of effectively receiving
an administration of a drug for the purpose of alleviating cravings
and other withdrawal symptoms.
[0182] Once a patient is no longer taking the addictive substance
or has titrated his dependence down to sufficiently low levels, the
present invention further includes the step of actively causing the
downregulation of endogenous neurosteroids, such as
allopregnanolone, through the administration of agents that block
the production of endogenous neurosteroids and/or their
metabolites. The present invention also includes the inhibition of
the modulatory effects of neurosteroids on GABA.sub.A. By doing so,
one accelerates the exposure or upregulation of .alpha..sub.4
subunits relative to .alpha..sub.1 subunits and ensures that a
substantial number of undesirable subunits are exposed and
available for enhanced pharmacotherapeutic efficacy.
[0183] Particular methods for baselining endogenous neurosteroid
production to a consistent level in the pre-treatment portion of
the protocol are discussed below, but the treatment protocol is not
limited to such methods. For the methods listed below, the present
invention contemplates operating in a dosing range of established
safety and efficacy in order to maximally decrease the production
of progesterone and make the individual most receptive to
treatment.
[0184] 1. Avoid Stress-Inducing Activities
[0185] In one embodiment, the present invention includes the step
of avoiding all such activities that could result in the
upregulation of an individual's neurosteroid level and the step of
actively causing the downregulation of endogenous neurosteroids,
such as allopregnanolone. It should be noted that stress-inducing
activities depend upon the patient and the patient's general
condition. Thus, individual recommendations may be made by the
treating physician.
[0186] 2. Avoid Neurosteroid Production Enhancing Activities
[0187] The patient is advised to not engage in activities, or
ingest any substances, that could likely increase neurosteroid
production. Such activities include sex, stressful activities,
fighting, or intense arguing. Such substances include chocolate,
illegal drugs, prescription drugs, or over the counter
medicines.
[0188] Although not preferred because these compositions may serve
to increase neurosteroid production, in certain cases, it may be
necessary to administer a composition to reduce stress.
[0189] In one embodiment, the stress-reducing composition is
gabapentin. Gabapentin is an anxiolytic and anticonvulsant
medication typically prescribed to patients suffering from epilepsy
(effectively lowers brain glutamate concentrations) and has also
been used in the treatment of anxiety disorders such as social
anxiety disorder and obsessive-compulsive disorder. Prior to
administering gabapentin to a patient, it is essential to assess
the patient for interactions and contraindications. Gabapentin is
to be used in adjunctive therapy in the treatment of epilepsy
seizures (partial) and for the management of postherpetic
neuralgia. Gabapentin is not appreciably metabolized and is
excreted unchanged with an elimination half-life of 5-7 hours.
Possible side effects from the use of gabapentin are dizziness,
somnolence, other symptoms/signs of CNS depression, nausea, ataxia,
tremor, and peripheral edema. In persons with epilepsy, abrupt
discontinuation may increase seizure frequency. No clinically
significant drug interactions have been reported in the
literature.
[0190] In another embodiment, the stress-reducing composition is a
H1 histamine receptor agonist, such as, but not limited to
hydroxyzine. Hydroxyzine is indicated for treatment of generalized
anxiety disorder symptoms and for use in the management of
withdrawal from substance dependence during both the initial phase
of inpatient treatment and post-discharge care (as necessary). It
also has anti-emetic and skeletal muscle relaxation benefits and
can be used as a sedative. This sedative effect can be useful for
treating the sleep-disordered breathing and increased periodic leg
movements that contribute to the insomnia often seen in patients
recovering from alcohol dependency. This helps address on-going
insomnia which, for some patients is significantly associated with
subsequent alcoholic relapse.
[0191] Hydroxyzine is rapidly absorbed and yields effects within
15-30 minutes after oral administration. In addition, hydroxyzine
aids the substance withdrawal process through anxiolytic,
anti-nausea, relaxant, and various other properties. It should be
noted that the effects of other sedating or tranquilizing agents
may be synergistically enhanced with the administration of
hydroxyzine. Exemplary trade names of these drugs include Atarax
and Vistaril.
[0192] 3. Avoid Heightened Progesterone Levels in Patient
[0193] In an optional embodiment, it is possible to minimize
endogenous neurosteroid production by timing the treatment in a
manner that avoids heightened progesterone cycles.
[0194] In women, progesterone levels are low during the
pre-ovulatory phase of the menstrual cycle, rise after ovulation,
and are elevated during the luteal phase. Specifically,
progesterone levels tend to be <2 ng/ml prior to ovulation, and
>5 ng/ml after ovulation. If pregnancy occurs, progesterone
levels are maintained at luteal levels initially. With the onset of
the luteal-placental shift in support of the pregnancy,
progesterone levels start to rise further and may reach 100-200
ng/ml at term. After delivery of the placenta and during lactation,
progesterone levels are low.
[0195] For example, but not limited to such example, since
progesterone levels are highest during the luteal phase of the
menstrual cycle, it is preferred not to treat a woman during this
time window. Conversely, it is preferred to treat a woman during
the pre-ovulatory phase of the menstrual cycle, when progesterone
levels are low.
[0196] Progesterone levels are low in children, men, and
postmenopausal women.
[0197] 4. Actively Modulate a Woman's Progesterone Levels
[0198] In another embodiment, a woman's progesterone is actively
modulated by the administration of prescription hormones, such as,
but not limited to, contraception with progesterone, that keeps the
woman on a constant progesterone level. Such contraception includes
progestin implants and levonorgestrel implants. Administration of
these compositions will effectively make a woman's progesterone
levels constant.
[0199] Upon withdrawal of these contraception compositions, the
woman's hormone level will decrease, thereby "unmasking" its
.alpha..sub.4 receptor subunits and placing a woman in a state most
receptive to treatment.
[0200] The present invention advantageously uses the time gap
between when administered progesterone leaves the system and when
endogenous progesterone production resumes. In one embodiment, this
minimal progesterone point window is preferably when the treatment
protocol of the present invention should begin.
[0201] In one embodiment, progesterone can be delivered orally,
sublingually, via vaginal suppositories, via injection, topically,
transdermally, or by implant. The rate of absorption of
progesterone is highly dependent upon the administration route.
Irrespective of the type used, progesterone, progestin, or other
progesterone-like compounds should be administered in sufficient
amounts to attain a heightened level of progesterone and then
terminated in sufficient time to allow for the progesterone levels
to decrease prior to treatment.
[0202] It should again be noted that Table 1 offers an exemplary
listing of pharmacological compounds in the classes of compounds
described herein. Several examples of contraception and recommended
dosing parameters are also listed in Table 1.
[0203] 5. Actively Modulate a Male's or Female's Progesterone
Levels
[0204] As mentioned above, various neurosteroid inhibitors prevent
the conversion of progesterone into allopregnanolone. In an
endogenous case, allopregnanolone is responsible for the modulation
of the GABA.sub.A receptors. By compensating for the effects of the
withdrawn substance, endogenous neurosteroids, when elevated,
"mask" GABA.sub.A receptors and prevent flumazenil from being able
to "re-set" those receptors. The administration of these drugs can
effectively drive down endogenous neurosteroid levels.
[0205] In one embodiment, the compound is a 5.alpha.-reductase
inhibitor. Preferably, the 5.alpha.-reductase inhibitor is capable
of acting as a Type I inhibitor, a Type II inhibitor or a
combination thereof and inhibits the 5.alpha.-reductase enzyme from
converting progesterone to 5.alpha.-dihydroprogesterone and thus
from creating progesterone metabolite allopregnanolone. In another
embodiment, the compound is a 3.alpha.-hydroxysteroid
oxidoreductase inhibitor, which prevents the
3.alpha.-hydroxysteroid oxidoreductase enzyme from converting
5.alpha.-dihydroprogesterone into 5.alpha.,3.alpha.-pregnanolone
(allopregnanolone).
[0206] While the class of compounds that inhibit neurosteroid
production has been described in detail above, an exemplary list of
compounds is described in detail in Table 1. It should be noted,
however, that the present invention is not limited to such
compounds and any compounds that effectively inhibit endogenous
neurosteroid production, and in particular, the conversion of
progesterone to its metabolite allopregnanolone, can be used with
the present invention.
[0207] ii. Industry-Standard Treatment Approaches
[0208] In one embodiment, the patient is subjected to standard
and/or industry-accepted treatment protocols. Several exemplary
treatment protocols are detailed in the sections below. It should
be noted, however, that the treatment protocols outlined herein are
exemplary and any number of treatment protocols may be used with
the present invention provided that they are not contraindicated
with the use of a compound from the class of compounds that
permanently increases the relative expression of the .alpha..sub.1
GABA.sub.A subunit relative to the .alpha..sub.4 GABA.sub.A
subunit.
[0209] Many of the conventional protocols described herein are
adapted by the National Guideline Clearinghouse. The National
Guideline Clearinghouse.TM. (NGC) is a comprehensive database of
evidence-based clinical practice guidelines and related documents.
NGC is an initiative of the Agency for Healthcare Research and
Quality (AHRQ), U.S. Department of Health and Human Services. NGC
was originally created by AHRQ in partnership with the Americal
Medical Association and the American Association of Health Plans
(now America's Health Insurance Plans [AHIP]). The NGC mission is
to provide physicians, nurses, and other health professionals,
health care providers, health plans, integrated delivery systems,
purchasers and others an accessible mechanism for obtaining
objective, detailed information on clinical practice guidelines and
to further their dissemination, implementation and use.
[0210] In addition, some clinical practice guidelines were adapted
from the United States Department of Health and Human Services
Substance Abuse and Mental Health Services Administration. More
specifically, protocols were adapted from the National
Clearinghouse for Alcohol and Drug Information.
[0211] Certain clinical practice guidelines were also adapted from
the Expert Consensus Guidelines are being used throughout the
country by clinicians, policy-makers, administrators, case
managers, mental health educators, patient advocates, and clinical
and health services researchers.
[0212] The use of industry-accepted treatment protocols is
optional.
[0213] c. Administration of a Compound from the Class of Compounds
that Modulates the Expression of Certain GABA.sub.A Receptor
Subunits
[0214] Whether used independently of, or part of, any other
treatment approach, the present invention requires a patient to be
administered a compound from the class of compounds that modulates
the expression of certain GABA.sub.A receptor subunits, as
described above. In one embodiment, the compound serves as an
agonist at the GABA.sub.A receptor, and more specifically, at
either the 4 subunit or .alpha..sub.6 subunit, and is capable of
positively potentiating GABA current.
[0215] It should be noted, however, that the present invention is
not limited to such subunit relative to the .alpha..sub.4
GABA.sub.A subunit, in a non-transitory manner, can be used with
the present invention.
[0216] The present invention is directed towards, in one
embodiment, the use of a compound that modulates the expression of
certain GABA.sub.A receptor subunits, such as flumazenil, in
multiple doses for a predetermined time period as part of the
treatment methodology. When administered in accordance with the
present invention, a therapeutically effective amount of the drug
is maintained in the patient, thereby significantly reducing the
upregulation of allopregnanolone. The methodology of the present
invention also provides for the administration of a compound that
modulates the expression of certain GABA.sub.A receptor subunits,
such as flumazenil, without significant side effects.
[0217] Thus, in one embodiment, a method is provided for the
treatment of substance abuse that includes the administration to a
patient in need of said treatment of a therapeutically effective
quantity of flumazenil in multiple doses during predetermined time
periods/intervals, until a therapeutically effective quantity of
flumazenil to treat substance abuse has been reached, as measured
by quantitative and/or qualitative assessments of, for example, a
patient's blood pressure, heart rate, feelings of cravings, and
feelings of anxiety. Thus, it is possible to administer flumazenil
in variable doses to obtain the desired therapeutic response,
reducing the risk of secondary effects in the patient (as a result
of reducing the quantity of drug administered per dose
applied).
[0218] In another embodiment, a method is provided for the
treatment of substance abuse that includes the administration to a
patient in need of said treatment of a therapeutically effective
quantity of flumazenil, usually between 0.5 mg/day and 20 mg/day,
between 0.5 mg/day and 15 mg/day, specifically between 1.0 and 3.0
mg/day, and more specifically between 1.5 and 2.5 mg/day, of
flumazenil, broken down into multiple doses of flumazenil between
0.1 and 0.3 mg and intended for administration during predetermined
time periods or intervals, until said therapeutically effective
quantity of flumazenil to treat substance abuse has been reached.
In one embodiment, the predetermined time period is in the range of
1 and 15 minutes and the "per dose" quantity of flumazenil is
between 0.1 and 0.3 mg.
[0219] One of ordinary skill in the art would appreciate that the
individual doses can range in amount, and the time interval between
the individual doses can range in amount, provided that the total
dose delivered is in the range of 1.0 mg/day and 3.0 mg/day and the
individual doses are delivered at relatively consistent time
intervals. Therefore, the time period intervals can range from 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, or 25 minutes or fractions thereof. Doses delivered
at each time period, separated by the time intervals, can be
between 0.1 and 0.3 mg, or fractions thereof, keeping in mind the
total drug delivered is preferably less than 3.0 mg/day. The
present invention therefore provides for the delivery of multiple,
sequential doses, delivered at substantially consistent time
intervals.
[0220] Conventional uses of flumazenil comprise either singular
doses or much larger doses over shorter periods of time and are
directed toward reversing sedative effects of anesthesia, conscious
sedation, or benzodiazepine overdose. Further, Romazicon, a brand
name for flumazenil marketed by Roche, is expressly indicated to
complicate the management of withdrawal syndromes for alcohol,
barbiturates and cross-tolerant sedatives and was shown to have an
adverse effect on the nervous system, causing increased agitation
and anxiety. For a single dose to address anesthesia and conscious
sedation, it is conventionally recommended to use a dose of 0.2 mg
to 1 mg of Romazicon with a subsequent dose in no less than 20
minutes. For repeat treatment, 1 mg doses may be delivered over
five minutes up to 3 mg doses over 15 minutes. In benzodiazepine
overdose situations, a larger dose may be administered over short
periods of time, such as 3 mg doses administered within 6 minutes.
One of ordinary skill in the art would appreciate that such
conventional uses of flumazenil are not directed toward the
treatment of substance abuse.
[0221] In addition, the administration method of the present
invention provides a better use of flumazenil to treat the symptoms
of substance abuse withdrawal and to reduce the unnecessary
consumption of said drug, thereby increasing convenience and the
quality of life of the patient and reducing cost, to treat
substance abuse in a very short period of time.
[0222] The method for the treatment of substance abuse provided by
this invention is applicable to any patient who, when the treatment
is to begin, has no medical illnesses that would make treatment
with a compound that modulates the expression of certain GABA.sub.A
receptor subunits, such as flumazenil hazardous or is taking
medication contraindicated with a compound that modulates the
expression of certain GABA.sub.A receptor subunits.
[0223] In general, the method of treatment of substance abuse
provided by this invention begins with a complete medical and
psychological examination, as described in detail above. Before,
during, and after administration of flumazenil, the symptoms of
substance abuse withdrawal, heart rate, and blood pressure are
monitored.
[0224] In one embodiment, a compound that modulates the expression
of certain GABA.sub.A receptor subunits, such as flumazenil, is
administered until qualitative and quantitative parameters
indicative of substance abuse are lowered to acceptable ranges.
[0225] In one embodiment, a compound that modulates the expression
of certain GABA.sub.A receptor subunits, such as flumazenil, is
administered at the latter of a) when the patient starts to feel
anxious (this is when receptors are "unmasked" as progesterone is
substantially no longer converted to allopregnanolone) or b) when
it is safe to administer based upon prior drugs given to the
patient.
[0226] In one embodiment, a compound that modulates the expression
of certain GABA.sub.A receptor subunits, such as flumazenil, is
administered at any rate, provided that the rate is not detrimental
to the patient, as determined by patient self-report of symptoms,
or physiological parameters such as heart rate, heart rhythm, or
blood pressure.
[0227] d. Additional Treatment Options
[0228] In some cases, in may be necessary to use, either during or
post-treatment, the following optional components of the treatment
protocol. The following optional components are exemplary and are
dependent upon a variety of factors, including but not limited to
responsiveness of the patient to treatment and if there is an
indication of a sustained increase in 5-alpha reductase
activity.
[0229] i. 5-Alpha Reductase Inhibitor
[0230] It may be necessary to continually treat a patient with a
5-alpha reductase inhibitor if there is an indication of a
sustained increase in 5-alpha reductase activity. 5-alpha-reductase
inhibitors have been described in detail above and will not be
repeated herein.
[0231] ii. Prolactin
[0232] In some cases, it may be necessary to treat a patient to
resolve increased production of prolactin, due to an increase of
estrogen levels caused by a decline in progesterone feedback. A
sustained increase in the levels of prolactin leads to impairment
of dopamine functionality, characterized by a higher stimulus
threshold for dopamine release. Exemplary drugs include dopamine
agonists, such as bromocriptine and prescription amphetamines, such
as Ritalin and Adderal.
[0233] e. Post-Treatment Phase of Protocol
[0234] After a patient successfully completes the treatment phase
of the methodology of the present invention, each patient will be
prescribed a post-treatment regimen to follow, which includes, but
is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. The components of the post-treatment phase of the
methodology of the present invention are described in greater
detail below.
[0235] Before discharge from the hospital, one or more of the
following compositions or drugs may be prescribed: gabapentin and
fluoxetine hydrochloride. Preferably, the compositions or drugs can
be administered in oral form to enable greater patient compliance
and convenience. It should be appreciated that, to the extent any
of drugs described herein are not available in the jurisdiction in
which this invention is being practiced equivalent functioning
drugs may be used.
[0236] Psychotherapy/behavioral therapy and counseling may be
critical for the success of substance-dependency treatment when
using pharmacological adjuncts. Thus, the methodology also provides
for a maintenance program that includes medications and incentives
for the patient to continue with their recovery process through
continuing care programs. Due to the complexity of substance
dependence, patients benefit most from a combination of
pharmacologic and behavioral interventions.
[0237] As part of the treatment program, patients may optionally be
instructed to attend the outpatient treatment center for several
months with decreasing frequency [i.e., once a week for the first
three months, once every two weeks during the second three months,
and once a month during the third three months].
[0238] Likewise, a semi-structured follow-up of cognitive behavior
therapy is optionally implemented. Individual and family
psychotherapy is focused on a plurality of interventions, including
cognitive restructuring, work therapy, prevention of relapse, and
stress reduction, aimed at rehabilitating the social, family, work,
personal and leisure life of the patient.
[0239] Depending upon the results of the initial examination, a
universal or patient-specific diet plan may optionally be
administered in conjunction with the methodology. Depending upon
the results of the initial examination, a universal or
patient-specific exercise programs may optionally be administered
in conjunction with the methodology.
[0240] The following examples will serve to further illustrate the
present invention without, at the same time, however, constituting
any limitation thereof. On the contrary, it is to be clearly
understood that resort may be had to various embodiments,
modifications and equivalents thereof which, after reading the
description herein, may suggest themselves to those skilled in the
art without departing from the spirit of the invention.
VII. Example 1
Protocol for the Treatment of Opioid Abuse
[0241] "Opioid" is a term used for the class of drugs with
opium-like and/or morphine-like pharmacological action. An opioid
is any agent that binds to opioid receptors, which are mainly found
in the central nervous system and gastrointestinal tract. There are
many types of opioids, including endogenous opioids produced in the
body (endorphins, dynorphins, enkephalins); opium alkaloids found
in the opium plant (morphine, codeine, thebaine); semi-synthetic
opioid derivatives (heroin, oxycodone, hydrocodone, dihydrocodeine,
hydromorphine, oxymorphone, nicomorphine); and wholly synthetic
opioid derivatives (phenylheptylamines, phenylpiperidines,
diphenylpropylamine derivatives, benzomorphan derivatives,
oripavine derivatives, morphinan derivatives, loperimide,
diphenoxylate). As used herein, the term "opiates" shall refer to
any compound that binds to opioid receptors, including natural
opium alkaloids, semi-synthetic opioids derived therefrom, and
synthetic opioids that have a similar physiochemistry to natural
opiates and generally metabolize to morphine. In a clinical
setting, opioids are used as analgesics and for relieving chronic
and/or severe pain and other disease symptoms. Some opioids,
however, are abused or used illegally for their euphoria-inducing
properties when administered intravenously or when smoked.
[0242] The present example incorporates the teachings of the
general treatment methodology described above. The components of
the pre-treatment phase of the methodology of the present invention
have been described in greater detail above and will not be
repeated herein.
[0243] a. Pre-Treatment/Patient Assessment Phase
[0244] As described above, prior to admittance into the treatment
program of the present invention, each patient should undergo a
pre-treatment analysis. The pre-treatment analysis may be used to
determine whether a patient is an optimal candidate for the
treatment methodology of the present invention. In addition, the
pre-treatment process may be administered to prepare a patient for
admittance into the treatment methodology of the present
invention.
[0245] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention
[0246] i. Placing a Patient in a State of Withdrawal
[0247] A patient may be placed in a state of withdrawal by actively
inhibiting the upregulation of endogenous neurosteroids and/or
causing the downregulation of endogenous neurosteroids. As
previously described, this treatment step may be achieved by a)
avoiding stress-inducing activities, b) avoiding neurosteroid
production enhancing activities, c) avoiding heightened
progesterone levels in a patient, d) actively modulating a woman's
progesterone levels, or e) actively modulating a male's or female's
progesterone levels through the administration of a neurosteroid
inhibitor.
[0248] i. Additional Pre-Treatments
[0249] Even if a patient is placed in a state of withdrawal, the
patient may optionally be subjected to other pre-treatment
protocols for the substance of addiction. An exemplary protocol is
described below, and thus, it should be noted that the use of such
protocol is exemplary and the invention is not limited to such
protocol.
[0250] 1. Optional Opiate Agonist Administration
[0251] The following treatment protocol is adapted from the Center
for Substance Abuse Treatment, Medication-Assisted Treatment for
Opioid Addiction in Opioid Treatment Programs. Treatment
Improvement Protocol (TIP) Series 43. DHHS Publication No. (SMA)
05-4048. Rockville, Md.: Substance Abuse and Mental Health Services
Administration, 2005, which is herein incorporated by reference. A
few details of the protocol are described below, however, it should
be understood by one of ordinary skill in the art that the
Treatment Improvement Protocol referenced above should be consulted
for details. Treatment Improvement Protocols (TIPs) are
best-practice guidelines for the treatment of substance abuse
disorders, provided as a service of SAMHSA's Center for Substance
Abuse Treatment (CSAT).
[0252] In an optional first step, the opiate user is administered
an opiate agonist that preferably has a longer half-life and is
less potent than the drug to which the patient has an addiction.
Preferably, the medicament is an opiate agonist, such as, but not
limited to buprenorphine or methadone, and creates a dependency in
the patient on a substance that is less addictive and
self-titrating. In a preferred embodiment, the substance is
titrated down to slowly wean the patient off of its effects.
Substitution to complete withdrawal, however, is very difficult and
some patients have emergence of opiate withdrawal symptoms that may
result in relapse to illicit opiate use. Thus, in the optional
first step, the opiate agonist is decreased to the minimum dose
that the patient can tolerate without relapse.
[0253] a. Methadone
[0254] Methadone [chemical name
6-(dimethylamino)-4,4-diphenyl-3-heptanone] is a synthetic opioid
analgesic with low addiction potential. It is chemically unlike
morphine or heroin, but acts on the opioid receptors and produces
many of the same effects. It is typically administered orally or
intravenously. Methadone is longer lasting than morphine-based
drugs and has a typical half-life of 24 hours or more, permitting
administration only once a day in opioid detoxification and
maintenance treatment programs. A patient is typically slowly
weaned off of methadone.
[0255] While tolerance, dependence and withdrawal symptoms may
develop, they develop much slower and are less acutely severe than
those of morphine and heroin. Closely related to methadone, a
synthetic compound levo-alphacetylmethadol (LAMM) has a 48-72 hour
duration of action and can be administered less frequently. Both
LAAM and methadone are controlled substances and can only be used
on an inpatient basis.
[0256] b. Buprenorphine
[0257] Buprenorphine [chemical name
(2S)-2-[(-)-(5R,6R,7R,14S)-9a-cyclopropylmethyl-4,5-epoxy-3-hydroxy-6-met-
hoxy-6,14-ethanomorphinan-7-yl]-3,3-dimethylbutan-2-ol] is a
partial opioid agonist at .mu.-opioid receptors on GABA neurons and
also an opioid antagonist. Buprenorphine is a thebaine derivative,
and its analgesic effect is due to the agonism of the .mu.-opioid
receptor. It is also a .kappa. antagonist. Naloxone can partially
revert the effects of buprenorphine. It has a long effect of about
48 hours, due to its slow dissociation from the opioid receptors.
Buprenorphine is administered as hydrochloride as either
intramuscular or intravenous injection or as sublingual tablets. It
is not administered orally, due to high first-pass metabolism.
Unlike methadone, buprenorphine can be used on an outpatient basis,
as it is not a controlled substance.
[0258] 2. Optional Opiate Antagonist Administration
[0259] Once the patient has stabilized at a dose level that is as
low as possible, but not low enough to trigger cravings and
withdrawal, an opioid antagonist is optionally administered, such
as naloxone, naltrexone, or nalmefene. Opiate antagonist
administration, serves to flush opioids from the user's system and
places the user in a physiological state capable of effectively
receiving an administration of compound from the class of compounds
that modulates GABA.sub.A receptor expression for the purpose of
alleviating cravings and other withdrawal symptoms.
[0260] a. Naloxone
[0261] Naloxone [chemical name
17-allyl-4,5.alpha.-epoxy-3,14-dihydroxymorphinan-6-one] is a drug
used to counter the effects of overdosing on opioids such as heroin
and morphine. It is a thebaine derivative and has an extremely high
affinity for .mu.-opioid receptors. Naloxone is a .mu.-opioid
receptor competitive agonist, and its rapid blocking of these
receptors often leads to rapid onset of withdrawal symptoms. As a
competitive agonist, naloxone displaces a substantial portion of
receptor-bound opioid molecules, thus resulting in a reversal of
effects .delta.-opioid receptors. Naloxone is usually injected
intravenously for fast action, showing signs of reversal of
respiratory depression and reversal of coma within 30 seconds. It
is a short-duration pharmaceutical, with a half-life of
approximately 60-100 minutes. Its effects last about 45
minutes.
[0262] b. Naltrexone
[0263] Naltrexone [chemical name
17-(cyclopropylmethyl)-4,5.alpha.-epoxy-3,14-dihydroxymorphinan-6-one]
is structurally similar to naloxone but has a slightly increased
affinity for K-opioid receptors over naloxone, can be administered
orally, and has a longer duration of action. In addition,
naltrexone can be administered in a sustained-release form via an
injection. It is an opioid receptor antagonist used in the
management of alcohol dependence and opioid dependence. Naltrexone,
and its active metabolite 6-.beta.-naltrexol are competitive
antagonists at .mu.- and .kappa.-opioid receptors, and to a lesser
extent .delta.-opioid receptors. Because it reversibly blocks or
attenuates the effects of opioids, naltrexone is used in the
management of opioid dependence. Naltrexone is typically used for
rapid detoxification procedures. It has a longer duration that
naloxone, with a single oral dose being able to block injected
heroine effects for 48 hours.
[0264] c. Nalmefene
[0265] Nalmefene [chemical name
17-(cyclopropylmethyl)-4,5.alpha.-epoxy-6-methylenemorphinan-3,14-diol,
hydrochloride salt], an opioid antagonist, is the 6-methylene
analogue of naltrexone. It is used to prevent or reverse the
effects of opioids and has no opioid agonist activity.
[0266] c. Administration of a Compound from the Class of Compounds
that Modulates GABA.sub.a Receptor Expression
[0267] Once the pre-treatment protocol has been adhered to and
completed, a patient is administered a compound from the class of
compounds that modulates GABA.sub.A receptor expression, such as
flumazenil, as described above in the general treatment
methodology.
[0268] d. Additional Treatment Options
[0269] Once the treatment protocol has been administered,
additional treatment options may be administered, as described
above in the general treatment methodology.
[0270] e. Post-Treatment Phase of Protocol
[0271] Once the treatment protocol has been administered, a
post-treatment protocol is administered, as described above in the
general treatment methodology.
[0272] f. Hypothetical Treatment Example 1
[0273] Male, 45 years old, has been using heroin for 8 years and,
under DSM IV criteria, after undergoing pre-treatment assessment,
has been diagnosed as being addicted to heroin.
[0274] Patient Preparation Four weeks prior to scheduled treatment,
he is initiated on a scheduled finasteride administration of 5 mg
per day. Three days prior to scheduled treatment, the finasteride
administration is terminated and the patient is instructed to not
engage in any stress-inducing activities or ingest any substances
that would likely increase neurosteroid production.
[0275] Day 1 of Treatment: Male patient is administered flumazenil,
via infusion, at an amount less than 15 mg/day. The patient's heart
rate and blood pressure are monitored, along with the patient's own
qualitative assessment of his health, including, but not limited
to, subjective feelings of anxiety. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0276] Day 2 of Treatment: Male patient is administered flumazenil,
via infusion, at a rate of at least 2.5 mg/day.
[0277] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 2.5 mg/day.
[0278] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0279] g. Hypothetical Treatment Example 2
[0280] Male, 45 years old, has been using heroin for 8 years and,
under DSM IV criteria, after undergoing pre-treatment assessment,
has been diagnosed as being addicted to heroin.
[0281] Patient Preparation One week prior to scheduled treatment,
male patient is subjected to a conventional protocol for the
treatment of opiate addiction, such as described above. In one
embodiment, male patient is administered opiate agonist
buprenorphine in an amount therapeutically effective to begin
titrating the substance down in the patient. There is no
pre-determined time period for administering buprenorphine to the
patient. When the patient is titrated to sufficiently low levels,
the treatment protocol of the present invention is started. In one
embodiment, a sufficiently low level of buprenorphine is 3 mg.
[0282] Day 1 of Treatment: Male patient's buprenorphine dosage is
reduced by 0.25 mg, and thus male patient is administered 2.75 mg
of buprenorphine. In addition, male patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0283] Day 2 of Treatment: Male patient's buprenorphine dosage is
again reduced by 0.25 mg, and thus male patient is administered
2.50 mg of buprenorphine. Male patient is administered flumazenil,
via infusion, at a rate of at least 1.0 mg/day. The total dose and
rate are modified by the responsible physician based on an
evaluation of the patient's heart rate, blood pressure, and
subjective reports.
[0284] Day 3 of Treatment: Male patient's buprenorphine dosage is
again reduced by 0.25 mg, and thus male patient is administered
2.25 mg of buprenorphine. Male patient is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0285] Maintenance Phase Until Next Treatment: If needed, male
patient is advised that he may take buprenorphine in the amount of
no more that 2.25 mg/day until the next treatment.
[0286] Day 21 of Treatment: Male patient's buprenorphine dosage is
reduced by half, and thus male patient is administered 1.125 mg of
buprenorphine. In addition, male patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0287] Day 22 of Treatment: Male patient's buprenorphine dosage is
again reduced by half, and thus male patient is administered 0.50
mg of buprenorphine. In addition, male patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0288] Day 23 of Treatment: Male patient is instructed to stop
taking all medications, including buprenorphine.
[0289] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0290] h. Hypothetical Treatment Example 3
[0291] Male, 45 years old, has been using heroin for 8 years and,
under DSM IV criteria, after undergoing pre-treatment assessment,
has been diagnosed as being addicted to heroin.
[0292] Patient Preparation One week prior to scheduled treatment,
male patient is subjected to a conventional protocol for the
treatment of opiate addiction, such as described above. In one
embodiment, male patient is administered opiate agonist
buprenorphine in an amount therapeutically effective to begin
titrating the substance down in the patient. There is no
pre-determined time period for administering buprenorphine to the
patient. When the patient is titrated to sufficiently low levels,
the treatment protocol of the present invention is started. In one
embodiment, a sufficiently low level of buprenorphine is 4 mg.
[0293] Day 1 of Treatment: Male patient's buprenorphine dosage is
reduced by 1 mg, and thus male patient is administered 3 mg of
buprenorphine. In addition, male patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0294] Day 2 of Treatment: Male patient's buprenorphine dosage is
again reduced by 1 mg, and thus male patient is administered 2 mg
of buprenorphine. Male patient is administered flumazenil, via
infusion, at a rate of at least 1.0 mg/day. The total dose and rate
are modified by the responsible physician based on an evaluation of
the patient's heart rate, blood pressure, and subjective
reports.
[0295] Day 3 of Treatment: Male patient's buprenorphine dosage is
again reduced by 1 mg, and thus male patient is administered 1 mg
of buprenorphine. Male patient is again administered flumazenil,
via infusion, at a rate of at least 1.0 mg/day.
[0296] Day 4 of Treatment: Male patient is instructed to stop
taking all medications, including buprenorphine.
[0297] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0298] i. Hypothetical Treatment Example 4
[0299] Male, 45 years old, has been using heroin for 8 years and,
under DSM IV criteria, after undergoing pre-treatment assessment,
has been diagnosed as being addicted to heroin.
[0300] Patient Preparation: Male patient is administered
buprenorphine in the lowest possible dose that patient can tolerate
with substantially minimal or no withdrawal symptoms, thus creating
a dependency in the patient on a substance that is less addictive
and self-titrating. For example, but not limited to such example,
male patient is "addicted" to an amount of heroin equivalent of 15
mg of buprenorphine.
[0301] Day 1 of Treatment: On Day 1 of treatment, patient is
administered 14 mg of buprenorphine. In addition, male patient is
administered, via infusion, flumazenil in a therapeutically
effective quantity of flumazenil of at least 1.0 mg/day. The total
dose and rate are modified by the responsible physician based on an
evaluation of the patient's heart rate, blood pressure, and
subjective reports.
[0302] Day 2 of Treatment: Male patient's buprenorphine dosage is
reduced by 1 mg, and thus male patient is administered 13 mg of
buprenorphine. Male patient is administered flumazenil, via
infusion, at a rate of at least 1.0 mg/day. The total dose and rate
are modified by the responsible physician based on an evaluation of
the patient's heart rate, blood pressure, and subjective
reports.
[0303] Days 3-14 of Treatment: Male patient's buprenorphine dosage
is reduced by 1 mg/day. In addition, male patient is again
administered flumazenil, each day, via infusion, at a rate of at
least 1.0 mg/day.
[0304] Day 15 of Treatment: Male patient is instructed to stop
taking all medications, including buprenorphine.
[0305] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
VIII. Example 2
Protocol for the Treatment of Benzodiazepine Abuse
[0306] Benzodiazepines are often used for short-term relief of
severe, disabling anxiety or insomnia. Long-term use can be
problematic due to the development of tolerance and dependency. As
described in detail above, they act on the GABA receptor
GABA.sub.A, the activation of which dampens higher neuronal
activity. Benzodiazepine use can result in a variety of side
effects, including, but not limited to drowsiness, ataxia,
confusion, vertigo, and impaired judgment. In addition,
benzodiazepines induce physical dependence and are potentially
addictive. An abrupt discontinuation of substance use may result in
convulsions, confusion, psychosis, or effects similar to delirium
tremens. Onset of withdrawal syndrome may be delayed and is
characterized by insomnia, anxiety, tremor, perspiration, loss of
appetite, and delusions. Typical treatments for benzodiazepine
abuse have been based on cognitive-behavioral therapy, weaning a
patient off of the drug, and, in some cases, administering a
benzodiazepine antagonist to counteract the drug's effects. These
methods, however, fail in that they do not address the underlying
physiochemical changes that occur with addiction.
[0307] a. Pre-Treatment/Patient Assessment Phase
[0308] As described above, prior to admittance into the treatment
program of the present invention, each patient should undergo a
pre-treatment analysis. The pre-treatment analysis may be used to
determine whether a patient is an optimal candidate for the
treatment methodology of the present invention. In addition, the
pretreatment process may be administered to prepare a patient for
admittance into the treatment methodology of the present
invention.
[0309] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention
[0310] i. Placing a Patient in a State of Withdrawal
[0311] A patient may be placed in a state of withdrawal by actively
inhibiting the upregulation of endogenous neurosteroids and/or
causing the downregulation of endogenous neurosteroids. As
previously described, this treatment step may be achieved by a)
avoiding stress-inducing activities, b) avoiding neurosteroid
production enhancing activities, c) avoiding heightened
progesterone levels in a patient, d) actively modulating a woman's
progesterone levels, or e) actively modulating a male's or female's
progesterone levels through the administration of a neurosteroid
inhibitor.
[0312] ii. Additional Pre-Treatments
[0313] In one pre-treatment approach, a patient is gradually
withdrawn through a gradual reduction of the dose. In one
embodiment, a patient is initiated on an administration of diazepam
(Valium), 15 to 25 mg four times daily. Sufficient diazepam is
administered to suppress signs of increased withdrawal (e.g.,
increased pulse, increased blood pressure, or increased
perspiration). Once a diazepam dose is reached which suppresses
signs of withdrawal, administration may continue for 2 additional
days and then may be decreased by 10% per day. When the diazepam
dose approaches 10% of the initial dose, the remaining dose is
reduced slowly over 3 to 4 days and then discontinued. In this
approach, benzodiazepine detoxification is accomplished in
approximately 14 days prior to the administration of a compound
from the class of compounds that selectively modulates GABA.sub.A
expression. It should be appreciated, however, that longer
detoxification may be required.
[0314] c. Administration of a Compound from the Class of Compounds
that Modulates GABA.sub.a Receptor Expression
[0315] Once the pretreatment protocol has been adhered to and
completed, a patient is administered a compound from the class of
compounds that modulates GABA.sub.A receptor expression, such as
flumazenil, as described above in the general treatment
methodology.
[0316] d. Additional Treatment Options
[0317] Once the treatment protocol has been administered,
additional treatment options, as described above in the general
treatment methodology, may be administered.
[0318] e. Post-Treatment Phase of Protocol
[0319] Once the treatment protocol has been administered, a
post-treatment protocol is administered, as described above in the
general treatment methodology.
[0320] f. Hypothetical Treatment Example 1
[0321] Male, 25 years old, has been using alprazolam for 5 years
and, under DSM IV criteria, after undergoing pre-treatment
assessment, has been diagnosed as being addicted to alprazolam.
[0322] Patient Preparation Four weeks prior to scheduled treatment,
he is initiated on a scheduled finasteride administration of 5 mg
per day. Three days prior to scheduled treatment, the finasteride
administration is terminated and the patient is instructed to not
engage in any stress-inducing activities or ingest any substances
that would likely increase neurosteroid production.
[0323] Day 1 of Treatment: Male patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0324] Day 2 of Treatment: Male patient is administered flumazenil,
via infusion, at a rate of at least 1.0 mg/day. The total dose and
rate are modified by the responsible physician based on an
evaluation of the patient's heart rate, blood pressure, and
subjective reports.
[0325] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0326] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0327] g. Hypothetical Treatment Example 2
[0328] Male, 35 years old, has been using alprazolam for 5 years
and, under DSM-IV criteria, after undergoing pre-treatment
assessment, has been diagnosed as being addicted to alprazolam.
[0329] Patient Preparation Four weeks prior to scheduled treatment,
he is initiated on a scheduled finasteride administration of 5 mg
per day. Three days prior to scheduled treatment, the finasteride
administration is terminated and the patient is instructed to not
engage in any stress-inducing activities or ingest any substances
that would likely increase neurosteroid production.
[0330] At least two weeks prior to treatment, patient then
undergoes a treatment-induced benzodiazepine withdrawal process. In
a preferred approach, to prevent seizures and other problems,
benzodiazepine withdrawal is accomplished by gradual reduction of
the dose. The patient is withdrawn using diazepam, 15 to 25 mg four
times daily. The patient is administered sufficient additional
diazepam to suppress signs of increased withdrawal (e.g., increased
pulse, increased blood pressure, or increased perspiration). Once a
diazepam dose is reached which suppresses signs of withdrawal, the
diazepam administration is continued for 2 days and then is
decreased by 10% per day. When the diazepam dose approaches 10%,
the dose is reduced slowly over 3 to 4 days and then
discontinued.
[0331] Day 1 of Treatment: Male patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0332] Day 2 of Treatment: Male patient is administered flumazenil,
via infusion, at a rate of at least 1.0 mg/day. The total dose and
rate are modified by the responsible physician based on an
evaluation of the patient's heart rate, blood pressure, and
subjective reports.
[0333] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0334] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
IX. Example 3
Protocol for the Treatment of Nicotine Abuse
[0335] Nicotine is a naturally occurring liquid alkaloid with
strong stimulating effects. Nicotine readily diffuses through the
skin, lungs, or mucous membranes and travels into blood vessels,
the brain, and the rest of a person's body. When inhaled, within 10
to 15 seconds, a person achieves the stimulatory effects of
nicotine. The half-life of nicotine is about 60 minutes. Nicotine
changes brain and body functions and initially results in a rapid
release of adrenaline, thereby causing a rapid heartbeat, increased
blood pressure, and rapid, shallow breathing.
[0336] Nicotine is a drug that induces both anxiolytic and
anxiogenic effects, similar to those triggered by stressful events,
contributing to emotion and reward. Through its interaction with
nicotinic acetylcholine receptors in the brain, which are located
predominantly on pre-synaptic terminals, nicotine modulates the
release of many neurotransmitters, including serotonin, dopamine,
noradrenaline, and GABA. Nicotine may directly or indirectly act on
the GABA receptor GABA.sub.A, the activation of which dampens
higher neuronal activity. Nicotine activates the mesolimbic
dopamine system, which is critical for the reinforcing properties
of the drug. Like heroin, cocaine, and alcohol, it is suggested
that nicotine induces both a sense of well-being and physical
dependence and reduces stress-related anxiety in humans.
[0337] In addition, nicotine was demonstrated to increase the
cerebrocortical concentrations of allopregnanolone and its
precursors. Given that allopregnanolone enhances GABA.sub.A
receptor function and plays an important role in the regulation of
anxiety and mood disorders, the transient increase in the brain
concentration of this endogenous neurosteroid triggered by nicotine
may represent a homeostatic mechanism to reduce or counteract the
neuronal excitability and anxiogenic-like action elicited by
nicotine.
[0338] Given that allopregnanolone is among the most potent
positive modulators of GABA.sub.A receptors, which contribute to
inhibitory regulation of mesocortical and mesolimbic dopaminergic
neurons, the nicotine-induced increase in the brain content of
these hormones may facilitate the inhibition of these dopaminergic
pathways induced by GABA.
[0339] Long-term use can be problematic due to the development of
tolerance and dependency. An abrupt discontinuation of substance
use may result in convulsions, confusion, psychosis, or effects
similar to delirium tremens. Onset of withdrawal syndrome may be
delayed and is characterized by insomnia, anxiety, tremor,
perspiration, and loss of appetite. Typical treatments for nicotine
abuse have been based on cognitive-behavioral therapy and weaning a
patient off of the drug. These methods, however, fail in that they
do not address the physiochemical changes that occur with
addiction.
[0340] a. Pre-Treatment/Patient Assessment Phase
[0341] As described above, prior to admittance into the treatment
program of the present invention, each patient should undergo a
pre-treatment analysis. The pre-treatment analysis may be used to
determine whether a patient is an optimal candidate for the
treatment methodology of the present invention. In addition, the
pre-treatment process may be administered to prepare a patient for
admittance into the treatment methodology of the present
invention.
[0342] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention
[0343] i. Placing a Patient in a State of Withdrawal
[0344] A patient may be placed in a state of withdrawal by actively
inhibiting the upregulation of endogenous neurosteroids and/or
causing the downregulation of endogenous neurosteroids. As
previously described, this treatment step may be achieved by a)
avoiding stress-inducing activities, b) avoiding neurosteroid
production enhancing activities, c) avoiding heightened
progesterone levels in a patient, d) actively modulating a woman's
progesterone levels, or e) actively modulating a male's or female's
progesterone levels through the administration of a neurosteroid
inhibitor.
[0345] i. Other Pre-Treatment Approaches
[0346] The following clinical guidelines are adapted from
guidelines published by the United States Department of Health and
Human Services, and more specifically, the Substance Abuse and
Mental Health Services Administration (hereinafter, SAMHSA), in
Treating Tobacco Use and Dependence, which is incorporated by
reference. See Fiore M C, Bailey W C, Cohen S J, et al. Treating
Tobacco Use and Dependence. Clinical Practice Guideline. Rockville,
Md.: U.S. Department of Health and Human Services. Public Health
Service. June 2000.
[0347] In one embodiment, a patient engages in counseling and
behavioral therapies, including, but not limited to, the provision
of practical counseling (problem solving/skills training); the
provision of social support as part of treatment (intra-treatment
social support); and assistance in securing social support outside
of treatment (extra-treatment social support). In another
embodiment, a patient is prescribed a pharmacotherapy that is known
for increasing long-term smoking abstinence rates: Bupropion SR,
Nicotine gum, Nicotine inhaler, Nicotine nasal spray, Nicotine
patch, Clonidine, and/or Nortriptyline.
[0348] It should be appreciated that, regardless of the particular
pre-treatment therapy adopted, the patient should cease such
pharmacotherapies at least one week prior to the administration of
a compound from the class of compounds that modulates GABA.sub.A
expression.
[0349] c. Administration of a Compound from the Class of Compounds
that Modulates GABA.sub.a Receptor Expression
[0350] Once the pre-treatment protocol has been adhered to and
completed, a patient is administered a compound from the class of
compounds that modulates GABA.sub.A receptor expression, such as
flumazenil, as described above in the general treatment
methodology.
[0351] d. Additional Treatment Options
[0352] Once the treatment protocol has been administered,
additional treatment options, as described above in the general
treatment methodology, may be administered.
[0353] e. Post-Treatment Phase of Protocol
[0354] Once the treatment protocol has been administered, a
post-treatment protocol is administered, as described above in the
general treatment methodology.
[0355] f. Hypothetical Treatment Example 1
[0356] Female, 30 years old, has been using nicotine for 11 years
and, is admittedly addicted to nicotine. She has been taking oral
contraceptives for at least five years.
[0357] Patient Preparation Treatment is scheduled during a time
period in which progesterone is not administered (for example, in a
21 day pill pack, treatment is scheduled beginning with the first
placebo day). If this is not possible, female patient is instructed
to withhold contraceptive use for one week prior to scheduled
treatment. Three days prior to scheduled treatment, the patient is
instructed to not engage in any stress-inducing activities or
ingest any substances that would likely increase neurosteroid
production (including oral contraceptives).
[0358] Day 1 of Treatment: Female patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0359] Day 2 of Treatment: Female patient is evaluated to determine
if a second day of treatment is necessary. If she continues to
report feelings of anxiety or cravings, she is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0360] Day 3 of Treatment: Female patient is evaluated to determine
if a third day of treatment is necessary. If she continues to
report feelings of anxiety or cravings, she is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0361] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Female patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, she is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0362] g. Hypothetical Treatment Example 2
[0363] Female, 30 years old, has been using nicotine for 11 years
and, is admittedly addicted to nicotine.
[0364] Patient Preparation Six weeks prior to scheduled treatment,
female patient is administered oral contraceptives. One week prior
to scheduled treatment, the administration of oral contraceptives
is terminated. Two weeks prior to treatment, female patient ceases
any use of nicotine and is prescribed a nicotine patch for
withdrawal symptoms. The benzodiazepine is given for up to four
days at a dose of 5 mg tds. Three days prior to scheduled
treatment, the patient is instructed to not engage in any
stress-inducing activities or ingest any substances that would
likely increase neurosteroid production (including oral
contraceptives).
[0365] Day 1 of Treatment: Female patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0366] Day 2 of Treatment: Female patient is evaluated to determine
if a second day of treatment is necessary. If she continues to
report feelings of anxiety or cravings, she is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0367] Day 3 of Treatment: Female patient is evaluated to determine
if a third day of treatment is necessary. If she continues to
report feelings of anxiety or cravings, she is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0368] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Female patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, she is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
X. Example 4
Protocol for the Treatment of Cannabis (THC) Abuse
[0369] Cannabis, or marijuana, is a plant containing THC
(delta-9-tetrahydrocannabinol), a psychoactive chemical. When
smoked, THC readily diffuses into an individual's lungs and,
consequently, into his bloodstream. THC changes brain and body
functions and initially results in a feeling of haziness and
lightheadedness and deleterious effect on short-term memory,
coordination, learning, and problem-solving.
[0370] Long-term use can be problematic due to the development of
tolerance and dependency. THC may directly or indirectly act on the
GABA receptor GABA.sub.A, the activation of which dampens higher
neuronal activity. THC use can result in a variety of side effects,
including, but not limited to learning and memory problems,
distorted perception, anxiety, paranoia, and panic attacks. In
addition, THC induces physical dependence and is addictive.
Although not medically dangerous, withdrawal symptoms include
anxiety, irritability, perspiration, sleep disturbances, moodiness,
and anorexia. Less common withdrawal symptoms include tremors,
nausea and vomiting, occasional diarrhea, and excessive
salivation.
[0371] Typical treatments for THC abuse have been based on
cognitive-behavioral therapy and weaning a patient off of the drug.
These methods, however, fail in that they do not address the
physiochemical changes that occur with addiction.
[0372] a. Pre-Treatment/Patient Assessment Phase
[0373] As described above, prior to admittance into the treatment
program of the present invention, each patient should undergo a
pre-treatment analysis. The pre-treatment analysis may be used to
determine whether a patient is an optimal candidate for the
treatment methodology of the present invention. In addition, the
pre-treatment process may be administered to prepare a patient for
admittance into the treatment methodology of the present
invention.
[0374] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention
[0375] i. Placing a Patient in a State of Withdrawal
[0376] A patient may be placed in a state of withdrawal by actively
inhibiting the upregulation of endogenous neurosteroids and/or
causing the downregulation of endogenous neurosteroids. As
previously described, this treatment step may be achieved by a)
avoiding stress-inducing activities, b) avoiding neurosteroid
production enhancing activities, c) avoiding heightened
progesterone levels in a patient, d) actively modulating a woman's
progesterone levels, or e) actively modulating a male's or female's
progesterone levels through the administration of a neurosteroid
inhibitor.
[0377] ii. Other Pre-Treatment Approaches
[0378] The following protocol is adapted from "Cannabis Dependence
and Treatment", GP Drug & Alcohol Supplement No. 10 (June
1998). In one embodiment, a patient has been diagnosed with
cannabis dependence because at least one of the following has been
true for one month or longer a) cannabis is often taken in larger
amounts or over a longer period than the person intended, b) there
is a persistent desire or one or more unsuccessful efforts to cut
down or control cannabis use, c) a great deal of time is spent in
activities necessary to get cannabis, e.g. theft, taking cannabis,
or recovering from its effects, d) frequent intoxication or
withdrawal symptoms occur when expected to fulfill major role
obligations at work, school, or home, or when cannabis is
physically hazardous, e) there are important social occupational or
recreational activities given up or reduced because of cannabis
use, f) cannabis use was continued despite knowledge of having a
persistent or recurrent social psychological or physical problem
that is caused or exacerbated by the use of cannabis, and g) there
is a marked tolerance
[0379] In one embodiment, a patient is prescribed a pre-treatment
therapy based upon a) what the patient wants; b) the severity of
the patient's cannabis-related problems; c) the safety of the
patient, i.e. the risk of suicide or harm to others from psychotic
or depressive symptoms; and d) whether the patient is ready to
quit. In one embodiment, the pre-treatment therapy comprises
prescribing medicine to address symptoms of agitation, sleep
disturbance, restlessness, and irritability. In one embodiment, the
medicine prescribed is a benzodiazepine (such as diazepam), which
may be given for up to four days at a dose of 5 mg tds.
Benzodiazepines should not be continued beyond four days in these
patients.
[0380] It should be appreciated that, regardless of the particular
medicine prescribed adopted, the patient should cease all such
pharmacotherapies at least one week prior to the administration of
a compound from the class of compounds that modulates GABA.sub.A
receptor expression.
[0381] c. Administration of a Compound from the Class of Compounds
that Modulates GABA.sub.a Receptor Expression
[0382] Once the pre-treatment protocol has been adhered to and
completed, a patient is administered a compound from the class of
compounds that modulates GABA.sub.A receptor expression, such as
flumazenil, as described above in the general treatment
methodology.
[0383] d. Additional Treatment Options
[0384] Once the treatment protocol has been administered,
additional treatment options, as described above in the general
treatment methodology, may be administered.
[0385] e. Post-Treatment Phase of Protocol
[0386] Once the treatment protocol has been administered, a
post-treatment protocol is administered, as described above in the
general treatment methodology.
[0387] f. Hypothetical Treatment Example 1
[0388] Female, 30 years old, has been using cannabis for 9 years
and, under DSM-III-R criteria, has been diagnosed as being addicted
to cannabis. She has been taking oral contraceptives for at least
five years.
[0389] Patient Preparation One week prior to scheduled treatment,
female patient withholds oral contraceptive administration. Three
days prior to scheduled treatment, the patient is instructed to not
engage in any stress-inducing activities or ingest any substances
that would likely increase neurosteroid production (including oral
contraceptives).
[0390] Day 1 of Treatment: Female patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0391] Day 2 of Treatment: Female patient is evaluated to determine
if a second day of treatment is necessary. If she continues to
report feelings of anxiety or cravings, she is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0392] Day 3 of Treatment: Female patient is evaluated to determine
if a third day of treatment is necessary. If she continues to
report feelings of anxiety or cravings, she is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0393] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Female patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, she is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0394] g. Hypothetical Treatment Example 2
[0395] Female, 30 years old, has been using cannabis for 9 years
and, under DSM-III-R criteria, has been diagnosed as being addicted
to cannabis.
[0396] Patient Preparation Six weeks prior to scheduled treatment,
female patient is administered oral contraceptives. One week prior
to scheduled treatment, the administration of oral contraceptives
is terminated. Two weeks prior to treatment, female patient ceases
any use of cannabis and is prescribed a benzodiazepine for cannabis
withdrawal symptoms. The benzodiazepine is given for up to four
days at a dose of 5 mg tds. Three days prior to scheduled
treatment, the patient is instructed to not engage in any
stress-inducing activities or ingest any substances that would
likely increase neurosteroid production (including oral
contraceptives).
[0397] Day 1 of Treatment: Female patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0398] Day 2 of Treatment: Female patient is evaluated to determine
if a second day of treatment is necessary. If she continues to
report feelings of anxiety or cravings, she is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0399] Day 3 of Treatment: Female patient is evaluated to determine
if a third day of treatment is necessary. If she continues to
report feelings of anxiety or cravings, she is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0400] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Female patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, she is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
XI. Example 5
Protocol for the Treatment of Caffeine Abuse
[0401] Caffeine, also known as trimethylxanthine, is a naturally
occurring cardiac stimulant and mild diuretic. Caffeine induces
nervousness and insomnia in normal individuals, and it increases
the level of anxiety in patients prone to anxiety and panic
attacks. As an anxiogenic, caffeine changes brain and body
functions and results in a rapid release of adrenaline, thereby
causing a rapid heartbeat, increased blood pressure, and rapid,
shallow breathing.
[0402] Caffeine may directly or indirectly act on the GABA receptor
GABA.sub.A, the activation of which dampens higher neuronal
activity. In addition, it has been suggested that neuroactive
steroids modulate the stimulant and anxiogenic effects of caffeine.
More specifically, Concas et al. demonstrated that IP
administration of caffeine resulted in dose-dependent increases in
the plasma and brain concentrations of allopregnanolone as well as
in those of its precursors pregnenolone and progesterone. Thus, the
effects of caffeine on the plasma and brain concentrations of
neuroactive steroids was shown to be similar to those of anxiogenic
drugs, including those of direct and indirect inhibitors of the
GABA.sub.A receptor complex that induce experimental anxiety in
humans. It was also demonstrated that these effects are antagonized
by systemic administration of anxiolytic drugs, further
demonstrating that both pharmacologic treatments and experimental
conditions that induce anxiety-like or conflict behavior also
induces increases in the plasma and brain concentrations of
neuroactive steroids.
[0403] In addition, it is suggested that because caffeine induces
both neurotransmitter release and anxiety-like behavior associated
with increases in the plasma and brain concentrations of
neuroactive steroids that the HPA axis might mediate such actions
of caffeine. The transient increase in the brain concentration of
allopregnanolone triggered by caffeine may reflect a physiological
mechanism for reducing the activation of the neuroendocrine and
neurochemical pathways associated with the state of arousal and for
limiting the extent of neuronal excitability; consistent with the
fact that neuroactive steroids function to counteract
overexcitation of the CNS.
[0404] Caffeine can induce physical dependence and is addictive,
thus long-term use can be problematic due to the development of
tolerance and dependency. An abrupt discontinuation of substance
use may result in anxiety and confusion. Typical treatments for
caffeine dependence and abuse have been based on
cognitive-behavioral therapy and weaning a patient off of the drug.
These methods, however, fail in that they do not address the
physiochemical changes that occur with addiction.
[0405] In further support of the effects of caffeine, Jain et al.
demonstrated that caffeine produced higher anxiety in animals
previously treated with the GABA.sub.A receptor antagonist,
bicuculline or either of the various neurosteroid biosynthesis
enzyme inhibitors viz. trilostane, finasteride, or
indomethacin.
[0406] a. Pre-Treatment/Patient Assessment Phase
[0407] As described above, prior to admittance into the treatment
program of the present invention, each patient should undergo a
pre-treatment analysis. The pre-treatment analysis may be used to
determine whether a patient is an optimal candidate for the
treatment methodology of the present invention. In addition, the
pre-treatment process may be administered to prepare a patient for
admittance into the treatment methodology of the present
invention.
[0408] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention
[0409] i. Placing a Patient in a State of Withdrawal
[0410] A patient may be placed in a state of withdrawal by actively
inhibiting the upregulation of endogenous neurosteroids and/or
causing the downregulation of endogenous neurosteroids. As
previously described, this treatment step may be achieved by a)
avoiding stress-inducing activities, b) avoiding neurosteroid
production enhancing activities, c) avoiding heightened
progesterone levels in a patient, d) actively modulating a woman's
progesterone levels, or e) actively modulating a male's or female's
progesterone levels through the administration of a neurosteroid
inhibitor.
[0411] i. Other Pre-Treatment Approaches
[0412] Caffeine abuse and addiction should follow the basic
principles of treatment of substance dependence. These factors
include: elimination of the offending substance(s); detoxification
as required; medical and psychiatric evaluation for associated
conditions and complications; education about addiction, self-care,
and recovery; relief of stress and the development of a healthy
lifestyle; and psychosocial treatment and support.
[0413] It should be appreciated that, regardless of the treatment
approach adopted, the patient should cease all pharmacotherapies at
least one week prior to the administration of a compound from the
class of compounds that modulates GABA.sub.A receptor
expression.
[0414] c. Administration of a Compound from the Class of Compounds
that Modulates GABA.sub.a Receptor Expression
[0415] Once the pre-treatment protocol has been adhered to and
completed, a patient is administered a compound from the class of
compounds that modulates GABA.sub.A receptor expression, such as
flumazenil, as described above in the general treatment
methodology.
[0416] d. Additional Treatment Options
[0417] Once the treatment protocol has been administered,
additional treatment options, as described above in the general
treatment methodology, may be administered.
[0418] e. Post-Treatment Phase of Protocol
[0419] Once the treatment protocol has been administered, a
post-treatment protocol is administered, as described above in the
general treatment methodology.
[0420] f. Hypothetical Treatment Example 1
[0421] Male, 40 years old, has been using caffeine for 15 years
and, under DSM-IV criteria, has been diagnosed as being addicted to
caffeine. He also presents with acute headaches upon caffeine
withdrawal.
[0422] Patient Preparation Four weeks prior to scheduled treatment,
he is initiated on a scheduled finasteride administration of 5 mg
per day. Three days prior to scheduled treatment, the finasteride
administration is terminated and the patient is instructed to not
engage in any stress-inducing activities or ingest any substances
that would likely increase neurosteroid production.
[0423] Day 1 of Treatment: Male patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0424] Day 2 of Treatment: Male patient is evaluated to determine
if a second day of treatment is necessary. If he continues to
report feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0425] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0426] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
XII. Example 6
Protocol for Treatment of Addiction to Non-Benzodiazepine
Anxiolytics, Sedatives, Hypnotics, and Tranquilizers/Barbiturates
(the "CNS Depressants")
[0427] Non-benzodiazepine hypnotics are used for the short term
treatment of insomnia (or difficulty in getting to sleep or staying
asleep). Some, like chlormethiazole, can be used to help with
agitation and restlessness, and to help with alcohol withdrawal
symptoms.
[0428] Barbiturates are drugs that act as central nervous system
(CNS) depressant, producing a wide range of effects--from mild
sedation to anesthesia. Today, barbiturates are infrequently used
as anticonvulsants and for the induction of anesthesia. Sometimes,
two or more barbiturates are combined in a single tablet or
capsule.
[0429] Barbiturates enhance the functioning of GABA and are general
depressants to nerve and muscle tissue. Mild to moderate
barbiturate toxicity mimics alcohol intoxication. Severe acute
barbiturate toxicity results in CNS problems, including lethargy
and coma.
[0430] In moderate amounts, barbiturates produce a state of
intoxication that is similar to the effects of alcohol. Depending
on the dose, frequency, and duration of use, one can rapidly
develop tolerance, physical dependence, and psychological
dependence on barbiturates. As a user develops tolerance toward the
barbiturate, the effective dose is close to the lethal dose. In
order to obtain the same level of intoxication, and thus
gratification, the tolerant abuser will raise his dose to a near
fatal or fatal level.
[0431] Nonbenzodiazepine sedatives such as intermediate- or
short-acting barbiturates or glutethimide are more likely than
benzodiazepines to produce lethal overdose because people who abuse
them develop tolerance for their sedative and euphoric effects but
not for their respiratory-depressant effects. Therefore, as these
people increase their dosages to get high, they suddenly can
overdose to respiratory depression. People who are opioid addicted
and abuse nonbenzodiazepine sedatives usually need inpatient
detoxification before starting MAT or may do better with referral
to a long-term, residential program such as a therapeutic
community. Nonbenzodiazepine sedatives induce cytochrome P450 3A,
an enzyme involved in methadone, levo-alpha acetyl methadol (LAAM),
and buprenorphine metabolism, and can make stabilization
difficult.
[0432] a. Pre-Treatment/Patient Assessment Phase
[0433] As described above, prior to admittance into the treatment
program of the present invention, each patient should undergo a
pre-treatment analysis. The pre-treatment analysis may be used to
determine whether a patient is an optimal candidate for the
treatment methodology of the present invention. In addition, the
pre-treatment process may be administered to prepare a patient for
admittance into the treatment methodology of the present
invention.
[0434] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention
[0435] i. Placing a Patient in a State of Withdrawal
[0436] A patient may be placed in a state of withdrawal by actively
inhibiting the upregulation of endogenous neurosteroids and/or
causing the downregulation of endogenous neurosteroids. As
previously described, this treatment step may be achieved by a)
avoiding stress-inducing activities, b) avoiding neurosteroid
production enhancing activities, c) avoiding heightened
progesterone levels in a patient, d) actively modulating a woman's
progesterone levels, or e) actively modulating a male's or female's
progesterone levels through the administration of a neurosteroid
inhibitor.
[0437] i. Other Pre-Treatment Approaches
[0438] In one embodiment, at least two weeks prior to treatment
with a compound from the class of compounds that selectively
modulates GABA.sub.A receptor expression, a patient is prevented
from taking any CNS Depressant drugs and a benzodiazepine, such as
diazepam, is prescribed at a dose of 15 to 25 mg four times daily.
Sufficient additional diazepam is administered to suppress signs of
increased withdrawal (e.g., increased pulse, increased blood
pressure, or increased perspiration). Once a diazepam dose is
reached which suppresses signs of withdrawal, it is continued for 2
more days and then decreased by 10% per day.
[0439] It should be appreciated that, regardless of the treatment
approach adopted, the patient should cease all pharmacotherapies at
least one week prior to the administration of a compound from the
class of compounds that modulates GABA.sub.A receptor
expression.
[0440] c. Administration of a Compound from the Class of Compounds
that Modulates GABA.sub.a Receptor Expression
[0441] Once the pre-treatment protocol has been adhered to and
completed, a patient is administered a compound from the class of
compounds that modulates GABA.sub.A receptor expression, such as
flumazenil, as described above in the general treatment
methodology.
[0442] d. Additional Treatment Options
[0443] Once the treatment protocol has been administered,
additional treatment options, as described above in the general
treatment methodology, may be administered.
[0444] e. Post-Treatment Phase of Protocol
[0445] Once the treatment protocol has been administered, a
post-treatment protocol is administered, as described above in the
general treatment methodology.
[0446] f. Hypothetical Treatment Example 1
[0447] Male, 32 years old, has been using zalpelon for 5 years and,
under DSM IV criteria, has been diagnosed as being addicted to
zalpelon.
[0448] Patient Preparation Four weeks prior to scheduled treatment,
he is initiated on a scheduled finasteride administration of 5 mg
per day. Three days prior to scheduled treatment, the finasteride
administration is terminated and the patient is instructed to not
engage in any stress-inducing activities or ingest any substances
that would likely increase neurosteroid production.
[0449] Day 1 of Treatment: Male patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0450] Day 2 of Treatment: Male patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0451] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0452] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0453] g. Hypothetical Treatment Example 2
[0454] Male, 32 years old, has been using zalpelon for 5 years and,
under DSM IV criteria, has been diagnosed as being addicted to
zalpelon.
[0455] Patient Preparation Four weeks prior to scheduled treatment,
he is initiated on a scheduled finasteride administration of 5 mg
per day. Two weeks prior to scheduled treatment, he is prevented
from taking any CNS Depressant drugs and is prescribed diazepam at
a dose of 15 to 25 mg four times daily. Once the diazepam dose that
suppresses signs of withdrawal is reached, it is continued for 2
more days and then decreased by 10% per day. Three days prior to
scheduled treatment, the finasteride administration is terminated
and the patient is instructed to not engage in any stress-inducing
activities or ingest any substances that would likely increase
neurosteroid production.
[0456] Day 1 of Treatment: Male patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0457] Day 2 of Treatment: Male patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0458] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0459] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
XIII. Example 7
Protocol for the Treatment of Anti-Depression Drug Withdrawal
[0460] Clinical depression is a health condition with mental and
physical components reaching criteria generally accepted by
clinicians (described in greater detail below). Physiological
symptoms of depression may be due to changes or imbalances of
chemicals which transmit information in the brain, called
neurotransmitters. Many modern anti-depressant drugs attempt to
increase levels of certain neurotransmitters, like serotonin.
Further, it has been shown that progesterone and its effects on
GABA have been implicated in depression and anti-depressant
dependence. Cessation of a CNS drug, such as selective serotonin
reuptake inhibitors, tricyclic antidepressants, and monoamine
oxides inhibitors, may cause withdrawal, an increased total
GABA.sub.A receptor .alpha..sub.4 subunits relative to GABA.sub.A
receptor .alpha..sub.1 subunits, which in turn, causes anxiety.
[0461] Khemraj et al. demonstrated that allopregnanolone plays a
role in the anticonvulsant action of fluoxetine, thus supporting
the hypothesis that modulation of GABA.sub.A receptors by
neurosteroid metabolites mediates the anticonvulsant action of
fluoxetine. In addition, Pinna et al. suggest that pharmacological
profiles of fluoxetine and fluvoxamine are correlated with the
ability of these drugs to increase the brain and cerebrospinal
fluid content of allopregnanolone, a potent positive modulator of
GABA action at GABA.sub.A receptors. This further supports that
selective serotonin reuptake inhibitors may act via dual pathways,
both regulating levels of free serotonin and increasing levels of
endogenous neurosteroid, leading to the "addictive" properties of
SSRI's.
[0462] By taking away the effect of SSRI's on allopregnanolone, it
may be possible to treat patients with higher doses of the drug to
regulate levels of serotonin, since it has been demonstrated that
the allopregnanolone upregulation occurs at lower doses that
serotonin regulation.
[0463] a. Pre-Treatment/Patient Assessment Phase
[0464] As described above, prior to admittance into the treatment
program of the present invention, each patient should undergo a
pre-treatment analysis. The pre-treatment analysis may be used to
determine whether a patient is an optimal candidate for the
treatment methodology of the present invention. In addition, the
pre-treatment process may be administered to prepare a patient for
admittance into the treatment methodology of the present
invention.
[0465] b. Preparing a Patient for Treatment with the Protocol of
the Present Invention
[0466] i. Placing a Patient in a State of Withdrawal
[0467] A patient may be placed in a state of withdrawal by actively
inhibiting the upregulation of endogenous neurosteroids and/or
causing the downregulation of endogenous neurosteroids. As
previously described, this treatment step may be achieved by a)
avoiding stress-inducing activities, b) avoiding neurosteroid
production enhancing activities, c) avoiding heightened
progesterone levels in a patient, d) actively modulating a woman's
progesterone levels, or e) actively modulating a male's or female's
progesterone levels through the administration of a neurosteroid
inhibitor.
[0468] c. Administration of a Compound from the Class of Compounds
that Modulates GABA.sub.a Receptor Expression
[0469] Once the pre-treatment protocol has been adhered to and
completed, a patient is administered a compound from the class of
compounds that modulates GABA.sub.A receptor expression, such as
flumazenil, as described above in the general treatment
methodology.
[0470] d. Additional Treatment Options
[0471] Once the treatment protocol has been administered,
additional treatment options, as described above in the general
treatment methodology, may be administered.
[0472] e. Post-Treatment Phase of Protocol
[0473] Once the treatment protocol has been administered, a
post-treatment protocol is administered, as described above in the
general treatment methodology.
[0474] f. Hypothetical Treatment Example 1
[0475] Male, 32 years old, has been using fluoxetine hydrochloride
for 5 years and, experiences anxiogenic symptoms upon withdrawal,
similar to those symptoms in the DMS-IV criteria for addiction.
[0476] Patient Preparation Four weeks prior to scheduled treatment,
male patient is initiated on a scheduled finasteride administration
of 5 mg per day. Three days prior to scheduled treatment, the
finasteride administration is terminated and the patient is
instructed to not engage in any stress-inducing activities or
ingest any substances that would likely increase neurosteroid
production, including fluoxetine hydrochloride.
[0477] Day 1 of Treatment: Male patient is administered, via
infusion, flumazenil in a therapeutically effective quantity of
flumazenil of at least 1.0 mg/day. The total dose and rate are
modified by the responsible physician based on an evaluation of the
patient's heart rate, blood pressure, and subjective reports.
[0478] Day 2 of Treatment: Male patient is evaluated to determine
if a second day of treatment is necessary. If he continues to
report feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0479] Day 3 of Treatment: Male patient is evaluated to determine
if a third day of treatment is necessary. If he continues to report
feelings of anxiety or cravings, he is again administered
flumazenil, via infusion, at a rate of at least 1.0 mg/day.
[0480] Post-Treatment: Post-completion of treatment phase, patient
is prescribed a post-treatment regimen to follow, which includes,
but is not limited to, the administration of pharmaceutical
compositions, outpatient therapy, a diet program, and an exercise
regimen. Male patient is instructed to attend the outpatient
treatment center for several months with decreasing frequency
[i.e., once a week for the first three months, once every two weeks
during the second three months, and once a month during the third
three months]. If feelings of anxiety return, he is scheduled to
repeat at least one day, and up to three days, of flumazenil
treatment.
[0481] The above examples are merely illustrative of the many
applications of the system of present invention. Although only a
few embodiments of the present invention have been described
herein, it should be understood that the present invention might be
embodied in many other specific forms without departing from the
spirit or scope of the invention. Therefore, the present examples
and embodiments are to be considered as illustrative and not
restrictive, and the invention is not to be limited to the details
given herein, but may be modified within the scope of the appended
claims. All patents, publications and abstracts cited above are
incorporated herein by reference in their entirety.
TABLE-US-00001 TABLE 1 EXEMPLARY LISTING OF PHARMACOLOGICAL
COMPOUNDS AND SUGGESTED DOSAGES FOR USE WITH THE PRESENT INVENTION
SECONDARY EXEMPLARY DRUG DRUG CLASS DRUG CLASS LISTING DOSAGE
ANALGESICS OPIATES (PAINKILLERS) ALFENTANIL FOR USE DURING GENERAL
ANESTHESIA ALFENTA (alfentanil SPONTANEOUSLY BREATHING/ASSISTED
VENTILATION: hydrochloride) Induction of Analgesia: 8-20 mcg/kg;
Maintenance of Analgesia: 3-5 mcg/kg q 5-20 min or 0.5 to 1
mcg/kg/min; Total dose: 8-40 mcg/kg ASSISTED OR CONTROLLED
VENTILATION: Incremental Injection (to attenuate response to
laryngoscopy and intubation): Induction of Analgesia: 20-50 mcg/kg;
Maintenance of Analgesia: 5-15 mcg/kg q 5-20 min; Total dose: Up to
75 mcg/kg. Continuous Infusion: (To provide attenuation of response
to intubation and incision): Infusion rates are variable and should
be treated to the desired clinical effect. Induction of Analgesia:
50-75 mcg/kg; Maintenance of Analgesia: 0.5 to 3 mcg/kg/min
(Average rate 1 to 1.5 mg/kg/min); Total dose: Dependent on
duration of procedure. Anesthetic Induction: Induction of
Analgesia: 130-245 mcg/kg; Maintenance of Analgesia: 0.5 to 1.5
mcg/kg/min or general anesthetic; Total dose: Dependent on duration
of procedure. At these doses, truncal rigidity should be expected
and a muscle relaxant should be utilized; Administer slowly (over 3
minutes); Concentration of inhalation agents reduced by 30-50% for
initial hour. MONITORED ANESTHESIA CARE (MAC) (For sedated and
responsive, spontaneously breathing patients): Induction of M.C.
3-8 mcg/kg; Maintenance of M.C. 3-5 mcg/kg q 5-20 min or 0.25 to 1
mcg/kg/min; Total dose: 3-40 mcg/kg BUPRENORPHINE Administered
sublingually as a single daily dose in the range of 12 to 16
mg/day. Buprenorphine is also delivered transdermally in 25, 50,
and 75 mcg/ hour. BUTORPHANOL This formulation of butorphanol is
administered every 3-4 hours either as a nasal spray or injected
into the buttock or hip muscle or into a vein. The FDA does not
regulate Stadol .RTM. in most states. CODEINE (also METHYL Codeine
and codeine-combo preparations are usually taken every 4-6
MORPHINE) hours. Adults: 15 to 60 mg every 4 to 6 hours (usual
adult dose, 30 mg). Children: 1 Year of Age and Older - 0.5 mg/kg
of b.d. weight or 15 mg/m2 of b.d. surface every 4 to 6 hours. 200
mg (oral) of codeine is about equal to 30 mg (oral) of morphine.
CODEINON See Hydrocodone for details. PROPOXYPHENE Acetaminophen
(Tylenol) and propoxyphene. (DARVOCET) It is formulated as a tablet
taken every 4 hours by mouth. DEXTROPROPOXYPHENE Oral analgesic
potency is one-half to one-third that of codeine, with 65 mg
approximately equivalent to about 600 mg of aspirin.
Dextropropoxyphene is prescribed for relief of mild to moderate
pain. HEROIN ILLICIT SUBSTANCE/NO APPROVED DOSING
(DIACETYLMORPHINE) DIHYDROCODEINE Dihydrocodeine is approximately
twice as potent as codeine; this is taken into consideration while
dosing dihydrocodeine. Codeine Dosage: For the treatment of mild
pain to moderate pain: Adults: 15-60 mg PO (oral) every 4-6 hours.
For the treatment of non- productive cough: Adults: 10-20 mg PO
(oral) every 4-6 hours. For the treatment of diarrhoea: Adults: 30
mg PO (oral) FENTANYL Route of administration: patch, injected,
oral transmucosal. The patch is usually changed every 72 hours or
as directed by physician. Fentanyl (DURAGESIC .RTM.) should ONLY be
used in patients who are already receiving opioid therapy, who have
demonstrated opioid tolerance, and who require a total daily dose
at least equivalent to DURAGESIC .RTM. 25 mcg/h. Patients who are
considered opioid- tolerant are those who have been taking, for a
week or longer, at least 60 mg of morphine daily, or at least 30 mg
of oral oxycodone daily, or at least 8 mg oral hydromorphone daily,
or an equianalgesic dose of another opioid. HYDROCODONE Five mg of
hydrocodone is equivalent to 30 mg of codeine when DIHYDROCODEINONE
administered orally. Also, a dose of 15 mg (1/4 gr) of hydrocodone
is equivalent to 10 mg (1/6 gr) of morphine. The typical
therapeutic dose of 5 to 10 mg is pharmacologically equivalent to
30 to 60 mg of oral codeine. HYDROMORPHONE Dilaudid .RTM. is
formulated as oral tablets and liquid, rectal suppository,
intra-muscular (buttock or hip muscle) injection, and intravenous
(I.V.) solution. Dosing is every 4-6 hours for the oral forms and
every 6-8 hours for the suppository. An I.V. drip allows for
continuous administration and around-the-clock pain relief. It can
be given intravenously, intramuscularly, rectally, or orally. LAAM
The initial dose street addicts should be 20 to 40 mg. Each
Levomethadyl Acetate subsequent dose, administered at 48- or
72-hour intervals, may be Hydrochloride, also known as adjusted in
increments of 5 to 10 mg until a pharmacokinetic and
Levo-alpha-acetylmethadol or pharmacodynamic steady-state is
reached. Patients dependent on Levacetylmethadol (LAM) methadone
may require higher initial doses. METHADONE It comes as tablets,
dispersible tablets, liquid, and liquid concentrate. Patients take
it every 3-4 hours for severe pain and every 6-8 hours for chronic
pain. MORPHINE and NO APPROVED DOSING FOR PURE MORPHINE. SEE
MORPHINONE SALTS. MORPHINE SULFATE MS Contin .RTM. comes in the
form of tablets, capsules, liquid, and rectal suppository, which
are taken every 4 hours. Long-acting tablets and capsules can be
taken every 8-12 hours or 1-2 per day, respectively. OPIUM
(NATURAL) ILLEGAL - NO FDA RECOMMENDED USAGE OXYCODONE OxyContin
.RTM. comes in liquid and tablet forms taken every 6 hours.
Long-acting tablets are available to take every 12 hours.
OXYMORPHONE Injection: Subcutaneous or intramuscular
administration: initially 1 mg to 1.5 mg, repeated every 4 to 6
hours as needed. Intravenous: 0.5 mg initially. For analgesia
during labor 0.5 mg to 1 mg intramuscularly is recommended. Rectal
Suppositories: One suppository, 5 mg, every 4 to 6 hours. PETHIDINE
(MEPERIDINE) Adults: The usual dosage is 50 mg to 150 mg
intramuscularly, subcutaneously, or orally, every 3 or 4 hours as
necessary. Children: The usual dosage is 0.5 mg/lb to 0.8 mg/lb
intramuscularly, subcutaneously, or orally up to the adult dose,
every 3 or 4 hours as necessary. REMIFENTANIL During Induction of
Anesthesia: ULTIVA should be administered at an infusion rate of
0.5 to 1 mcg/kg/min with a hypnotic or volatile agent for the
induction of anesthesia. If endotracheal intubation is to occur
less than 8 minutes after the start of the infusion of ULTIVA, then
an initial dose of 1 mcg/kg may be administered over 30 to 60
seconds. For exact dosing for induction, maintenance and
continuation of general anesthesia, including special cases, please
refer to FDA Documents. SUFENTANIL Not more than 3 total doses.
Each dose must be at least one hour apart. THEBAINE Thebaine is not
used therapeutically, but is converted into a variety of compounds
including codeine, hydrocodone, hydromorphone, oxycodone,
oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and
etorphine. It is controlled in Schedule II of the Controlled
Substances Act as well as under international law. TRAMADOL
Tramadol is approximately 10% as potent as morphine, when given by
the IV/IM route. Oral doses range from 50-400 mg daily, with up to
600 mg daily when given IV/IM. TETRA- MARINOL Marinol: widely
available through prescription. It comes in the HYRDOC form of a
pill and is also being studied by researchers for suitability
ANNIBINOL/ via other delivery methods, such as an inhaler or patch.
The active THC ingredient of Marinol is synthetic THC, which has
been found to THC and some relieve the nausea and vomiting
associated with chemotherapy and other the loss of appetite
associated with various other disease states. cannibinoids, have
analgesic properties. THC - Herbal and Synthetic ILLICIT SUBSTANCE
- NO FDA-APPROVED DOSAGE KETAMINE Intravenous Route: The initial
dose of ketamine administered intravenously may range from 1 mg/kg
to 4.5 mg/kg (0.5 to 2 mg/lb). The average amount required to
produce five to ten minutes of surgical anesthesia has been 2 mg/kg
(1 mg/lb). Intramuscular Route: The initial dose of ketamine
administered intramuscularly may range from 6.5 to 13 mg/kg (3 to 6
mg/lb). A dose of 10 mg/kg (5 mg/lb) will usually produce 12 to 25
minutes of surgical anesthesia. BARBITURATES ALLOBARBITAL MRTD
(Maximum Recommended Therapeutic Dose) - 3.33000 mg/kg- body weight
(bw)/day based upon an average adult weighing 60 kg. AMOBARBITAL
Defined Daily Dose - 0.1 g, No data available from FDA.
APROBARBITAL MRTD (Maximum Recommended Therapeutic Dose) - 2.67000
mg/kg- body weight (bw)/day based upon an average adult weighing 60
kg. For trouble in sleeping: Adults-40 to 160 milligrams (mg) at
bedtime. For daytime sedation: Adults-40 mg three times a day.
BARBEXACLONE 100 mg of barbexaclone is equivalent to 60 mg of
phenobarbital. BARBITAL MRTD (Maximum Recommended Therapeutic Dose)
in mg/kg- (VERONAL) body weight (bw)/day based upon an average
adult weighing 60 kg - 10.00000 BUTABARBITAL Butabarbital Oral is
used to treat the following: Severe Anxiety, Additional Agent to
Induce General Anesthesia, Abnormal Trouble Sleeping MRTD (Maximum
Recommended Therapeutic Dose) in mg/kg- body weight (bw)/day based
upon an average adult weighing 60 kg - 2.000 BUTALBITAL MRTD
(Maximum Recommended Therapeutic Dose) in mg/kg- Butalbital,
5-allyl-5- body weight (bw)/day based upon an average adult
weighing isobutylbarbituric acid. 60 kg - 5.000 COMMON COMBINATIONS
INCLUDE: Butalbital and acetaminophen butalbital, acetaminophen,
and caffeine butalbital and aspirin butalbital, aspirin, and
caffeine BUTOBARBITAL 50 mg of Butobarbital is equivalent to 10 mg
of Diazepam; Acc. to (SONERYL) Nordic Statistics on Medicines, the
Defined Daily Dose of Butobarbital is 150 mg. No data available
from FDA. CYCLOBARBITAL MRTD (Maximum Recommended Therapeutic Dose)
in mg/kg- body weight (bw)/day based upon an average adult weighing
60 kg - 6.67000 ETHALLOBARBITAL N.A. HEPTABARBITAL Defined Daily
Dose - 0.2 g, No data available from FDA. HEXOBARBITAL MRTD
(Maximum Recommended Therapeutic Dose) in mg/kg- body weight
(bw)/day based upon an average adult weighing 60 kg - 8.33000
MEPHOBARBITAL Epilepsy: Average dose for adults: 400 mg to 600 mg
daily; children (METHYLPHENOBARBITAL) under 5 years: 16 mg to 32 mg
three or four times daily; children over 5 years: 32 mg to 64 mg
three or four times daily. Sedation: Adults: 32 mg to 100 mg
optimum dose, 50 mg three to four times daily. Children: 16 mg to
32 mg three to four times daily. METHARBITAL METHOHEXITAL For
induction of anesthesia, a 1% solution is administered at a rate of
about 1 mL/5 seconds. The dose required for induction may range
from 50 to 120 mg or more but averages about 70 mg. The usual
dosage in adults ranges from 1 to 1.5 mg/kg. Maintenance of
anesthesia may be accomplished by intermittent injections of the 1%
solution or, more easily, by continuous intravenous drip of a 0.2%
solution. Intermittent injections of about 20 to 40 mg (2 to 4 mL
of a 1% solution) may be given as required, usually every 4 to 7
minutes. For continuous drip, the average rate of administration is
about 3 mL of a 0.2% solution/minute (1 drop/second). PENTOBARBITAL
The usual adult dosage of NEMBUTAL Sodium Solution is 150 to 200 mg
as a single IM injection; the recommended pediatric dosage ranges
from 2 to 6 mg/kg as a single IM injection not to exceed 100 mg.
The rate of IV injection should not exceed 50 mg/min for
pentobarbital sodium. PHENOBARBITAL Pediatric Oral Dosage (as
recommended by the American
Academy of Pediatrics): Preoperative: 1 to 3 mg/kg. Adult Oral
Dosage: Daytime sedative: 30 to 120 mg daily in 2 to 3 divided
doses. Bedtime hypnotic: 100 to 320 mg. Anticonvulsant: 50 to 100
mg 2 to 3 times daily. PRIMIDONE Adult Dosage: Patients 8 years of
age and older who have received no previous treatment may be
started on primidone according to the following regimen using
Primidone 250 mg tablets. Days 1-3: 100 to 125 mg at bedtime; Days
4-6: 100 to 125 mg b.i.d.; Days 7-9: 100 to 125 mg t.i.d.; Day
10-maintenance; 250 mg t.i.d. For most adults and children 8 years
of age and over, the usual maintenance dosage is three to four 250
mg primidone tablets daily in divided doses (250 mg t.i.d. or
q.i.d.). If required, an increase to five or six 250 mg tablets
daily may be made but daily doses should not exceed 500 mg q.i.d.
Pediatric Dosage: For children under 8 years of age, the following
regimen may be used: Days 1-3: 50 mg at bedtime; Days 4-6: 50 mg
b.i.d.; Days 7-9: 100 mg b.i.d.; Day 10-maintenance: 125. mg t.i.d.
to 250 mg t.i.d. For children under 8 years of age, the usual
maintenance dosage is 125 to 250 mg three times daily, or 10-25
mg/kg/day in divided doses. SECOBARBITAL For oral dosage form
(capsules): For trouble in sleeping: Adults-100 milligrams (mg) at
bedtime. Children-Dose must be determined by your doctor. For
daytime sedation: Adults-30 to 50 mg three or four times a day.
Children-Dose is based on body weight or size and must be
determined by your doctor. The usual dose is 2 mg per kilogram (kg)
(0.9 mg per pound) of body weight three times a day. For sedation
before surgery: Adults-200 to 300 mg one or two hours before
surgery. Children-Dose is based on body weight and must be
determined by your doctor. The usual dose is 2 to 6 mg per kg (0.9
to 2.7 mg per pound) of body weight one or two hours before
surgery. However, the dose is usually not more than 100 mg. For
injection dosage form: For trouble in sleeping: Adults-100 to 200
mg injected into a muscle, or 50 to 250 mg injected into a vein.
Children-Dose is based on body weight or size and must be
determined by your doctor. The usual dose is 3 to 5 mg per kg (1.4
to 2.3 mg per pound) of body weight, injected into a muscle.
However, the dose is usually not more than 100 mg. For sedation
before dental procedures: Adults-Dose is based on body weight and
must be determined by your doctor. The usual dose is 1.1 to 2.2 mg
per kg (0.5 to 1 mg per pound) of body weight, injected into a
muscle ten to fifteen minutes before the procedure. Children-Dose
must be determined by your dentist. For sedation before a nerve
block: Adults-100 to 150 mg, injected into a vein. For sedation
before surgery: Children-Dose is based on body weight and must be
determined by your doctor. The usual dose is 4 to 5 mg per kg (1.8
to 2.3 mg per pound) of body weight, injected into a muscle.
TALBUTAL MRTD (Maximum Recommended Therapeutic Dose) in mg/kg-
(Lotusate .RTM.), also called 5-allyl- body weight (bw)/day based
upon an average adult weighing 5-sec-butylbarbituric acid. 60 kg -
3.30000 THIOBARBITAL N.A. THIOPENTAL Use in Anesthesia: Moderately
slow induction can usually be Pentothal (Thiopental Sodium
accomplished in the "average" adult by injection of 50 to 75 mg for
Injection, USP). (2 to 3 mL of a 2.5% solution) at intervals of 20
to 40 seconds, depending on the reaction of the patient. Once
anesthesia is established, additional injections of 25 to 50 mg can
be given whenever the patient moves. Use in Convulsive States: For
the control of convulsive states following anesthesia (inhalation
or local) or other causes, 75 to 125 mg (3 to 5 mL of a 2.5%
solution) should be given as soon as possible after the convulsion
begins. Convulsions following the use of a local anesthetic may
require 125 to 250 mg of Pentothal given over a ten minute period.
Use in Psychiatric Disorders: For narcoanalysis and narcosynthesis
in psychiatric disorders, premedication with an anticholinergic
agent may precede administration of Pentothal. After a test dose,
Pentothal (Thiopental Sodium for Injection, USP) is injected at a
slow rate of 100 mg/mm (4 mL/min of a 2.5% solution) with the
patient counting backwards from 100. Shortly after counting becomes
confused but before actual sleep is produced, the injection is
discontinued. Allow the patient to return to a semidrowsy state
where conversation is coherent. Alternatively, Pentothal may be
administered by rapid I.V. drip using a 0.2% concentration in 5%
dextrose and water. At this concentration, the rate of
administration should not exceed 50 mL/min. VINBARBITAL MRTD
(Maximum Recommended Therapeutic Dose) in mg/kg- Vinbarbital
(5-Ethyl-5-(1- body weight (bw)/day based upon an average adult
weighing methyl-1-butenyl)barbituric 60 kg - 3.33000 acid).
VINYLBITAL Defined Daily Dose - 0.15 g, No data available from FDA.
Butylvinyl BENZODIAZEPINES ALPRAZOLAM Dosage Depends on Disorder:
Oral (For anxiety or nervous tension): Start: 0.25 mg to 0.5 mg 3
times daily. Maximum: 4 mg in 24 hours. Oral (For panic disorder):
Start: 0.5 mg 3 times daily. Increases: 1 mg daily in 3 to 4 day
intervals. Maximum: 10 mg in 24 hours. BROMAZEPAM Not commercially
available in the U.S. BROTIZOLAM Brotizolam is not approved for
sale in the United States or Canada. CAMAZEPAM Defined Daily Dose -
30 mg, No data available from FDA. CHLORDIAZEPOXIDE For relief of
mild and moderate anxiety disorders and symptoms of anxiety: 5 mg
or 10 mg, 3 or 4 times daily. For relief of server anxiety
disorders and symptoms of anxiety: 20 mg or 25 mg, 3 or 4 times
daily. Geriatric patients or in the presence of debilitating
disease: 5 mg, 2 to 4 times daily. CLONAZEPAM Seizure Disorders:
Adults: The initial dose for adults with seizure disorders should
not exceed 1.5 mg/day divided into three doses. Dosage may be
increased in increments of 0.5 to 1 mg every 3 days until seizures
are adequately controlled or until side effects preclude any
further increase. Maintenance dosage must be individualized for
each patient depending upon response. Maximum recommended daily
dose is 20 mg. Pediatric Patients: Klonopin is administered orally.
In order to minimize drowsiness, the initial dose for infants and
children (up to 10 years of age or 30 kg of body weight) should be
between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day
given in two or three divided doses. Dosage should be increased by
no more than 0.25 to 0.5 mg every third day until a daily
maintenance dose of 0.1 to 0.2 mg/kg of body weight has been
reached, unless seizures are controlled or side effects preclude
further increase. Whenever possible, the daily dose should be
divided into three equal doses. If doses are not equally divided,
the largest dose should be given before retiring. Panic Disorder:
Adults: The initial dose for adults with panic disorder is 0.25 mg
bid. An increase to the target dose for most patients of 1 mg/day
may be made after 3 days. The recommended dose of 1 mg/day is based
on the results from a fixed dose study in which the optimal effect
was seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day in that
study were less effective than the 1 mg/day dose and were
associated with more adverse effects. Nevertheless, it is possible
that some individual patients may benefit from doses of up to a
maximum dose of 4 mg/day, and in those instances, the dose may be
increased in increments of 0.125 to 0.25 mg bid every 3 days until
panic disorder is controlled or until side effects make further
increases undesired. To reduce the inconvenience of somnolence,
administration of one dose at bedtime may be desirable. Treatment
should be discontinued gradually, with a decrease of 0.125 mg bid
every 3 days, until the drug is completely withdrawn. CLOTIAZEPAM
Clotiazepam is not approved for sale in the United States or Canada
CLORAZEPATE ORAL: START: 15 mg/daily INCREASES: As needed. MAXIMUM:
60 mg in 24 hours CLOXAZOLAM Cloxazolam is not approved for sale in
the United States or Canada. DELORAZEPAM Defined Daily Dose - 3 mg,
No data available from FDA. DIAZEPAM Management of Anxiety
Disorders and Relief of Symptoms of Anxiety: Depending upon
severity of symptoms - 2 mg to 10 mg, 2 to 4 times daily.
Symptomatic Relief in Acute Alcohol Withdrawal: 10 mg, 3 or 4 times
during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as
needed. Adjunctively for Relief of Skeletal Muscle Spasm: 2 mg to
10 mg, 3 or 4 times daily. Adjunctively in Convulsive Disorders. 2
mg to 10 mg, 2 to 4 times daily. Geriatric Patients, or in the
presence of debilitating disease: 2 mg to 2.5 mg, 1 or 2 times
daily initially; increase gradually as needed and tolerated.
Pediatric patients: Because of varied responses to CNS-acting
drugs, initiate therapy with lowest dose and increase as required.
Not for use in pediatric patients under 6 months. 1 mg to 2.5 mg, 3
or 4 times daily initially; increase gradually as needed and
tolerated. ESTAZOLAM The recommended initial dose for adults is 1
mg at bedtime; however, some patients may need a 2 mg dose. In
healthy elderly patients, 1 mg is also the appropriate starting
dose, but increases should be initiated with particular care. In
small or debilitated older patients, a starting dose of 0.5 mg,
while only marginally effective in the overall elderly population,
should be considered. ETIZOLAM Etizolam is not approved for sale in
the United States or Canada. FLUDIAZEPAM Defined Daily Dose - 0.75
mg, No data available from FDA. FLUNITRAZEPAM Flunitrazepam has not
been approved by the Food and Drug Administration for medical use
in the United States. It is available only by private prescription
in the United Kingdom FLURAZEPAM Dosage should be individualized
for maximal beneficial effects. The usual adult dosage is 30 mg
before retiring. In some patients, 15 mg may suffice. In elderly
and/or debilitated patients, 15 mg is usually sufficient for a
therapeutic response HALAZEPAM For oral dosage form (tablets): For
anxiety: Adults-20 to 40 milligrams (mg) three or four times a day.
Children younger than 18 years of age-Use and dose must be
determined by your doctor. Older adults-20 mg one or two times a
day. HALOXAZOLAM Defined Daily Dose - 7.50 mg, No data available
from FDA. LOPRAZOLAM It is available in 1 mg tablets. The usual
adult dose is 1-2 mg at bedtime, the higher dose being recommended
for patients who have previously been treated with benzodiazepines
for severe persistent insomnia. An initial dose of 0.5 mg-1.0 mg is
recommended in elderly and debilitated patients. LOREZEPAM The
usual range is 2 to 6 mg/day given in divided doses, the largest
dose being taken before bedtime, but the daily dosage may vary from
1 to 10 mg/day. For anxiety, most patients require an initial dose
of 2 to 3 mg/day given b.i.d. or t.i.d. For insomnia due to anxiety
or transient situational stress, a single daily dose of 2 to 4 mg
may be given, usually at bedtime. For elderly or debilitated
patients, an initial dosage of 1 to 2 mg/day in divided doses is
recommended, to be adjusted as needed and tolerated. MEDAZEPAM
Defined daily dose as used in the Nordic Statistics on Medicines -
20 mg; No data available from FDA. MIDAZOLAM For preoperative
sedation/anxiolysis/amnesia. Intramuscular - The recommended
premedication dose of VERSED for good risk (ASA Physical Status I
& II) adult patients below the age of 60 years is 0.07 to 0.08
mg/kg IM (approximately 5 mg IM) administered up to 1 hour before
surgery. The dose must be individualized and reduced when IM VERSED
is administered to patients with chronic obstructive pulmonary
disease, other higher risk surgical patients, patients 60 or more
years of age, and patients who have received concomitant narcotics
or other CNS depressants. In a study of patients 60 years or older,
who did not receive concomitant administration of narcotics, 2 to 3
mg (0.02 to 0.05 mg/kg) of VERSED produced adequate sedation during
the preoperative period. The dose of 1 mg IM VERSED may suffice for
some older patients if the anticipated intensity and duration of
sedation is less critical. Intravenous - VERSED 1 mg/mL formulation
is recommended for sedation/anxiolysis/amnesia for procedures to
facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL
formulations may be diluted with 0.9% sodium chloride or 5%
dextrose in water. 1. Healthy Adults Below the Age of 60: Titrate
slowly to the desired effect (eg, the initiation of slurred
speech). Some patients may respond to as little as 1 mg. No more
than 2.5 mg should be given over a period of at least 2 minutes. A
total dose greater than 5 mg is not usually necessary to reach the
desired endpoint. If narcotic premedication or other CNS
depressants are used, patients will require approximately 30% less
VERSED than unpremedicated patients. 2. Patients Age 60 or Older,
and Debilitated or Chronically Ill Patients: Titrate slowly to the
desired effect (eg, the initiation of slurred speech). Some
patients may respond to as little as 1 mg. No more than 1.5 mg
should be given over a period of no less than 2 minutes. If
additional titration is necessary, it should be given at a rate of
no more than 1 mg over a period of 2 minutes, waiting an additional
2 or more minutes each time to fully evaluate the sedative
effect. Total doses greater than 3.5 mg are not usually necessary.
Epileptic fit: 10 mg intranasally or as buccal. NIMETAZEPAN MRTD
(Maximum Recommended Therapeutic Dose) in mg/kg- body weight
(bw)/day based upon an average adult weighing 60 kg - 0.08330
NITRAZEPAM Nitrazepam shortens the time required to fall asleep and
lengthens the duration of this sleep. Typically, it may work within
an hour and allow the individual to maintain sleep for 4 to 6
hours. It is no longer available in the United States. NORDAZEPAM
Defined Daily Dose - 15 mg, No data available from FDA. OXAZEPAM
Mild to moderate anxiety, with associated tension, irritability,
agitation or related symptoms of functional origin or secondary to
organic disease: 10 to 15 mg, 3 or 4 times daily. Severe anxiety
syndromes, agitation, or anxiety associated with depression: 15 to
30 mg, 3 or 4 times daily. Older patients with anxiety, tension,
irritability, and agitation: Initial dosage - 10 mg, 3 times daily.
If necessary, increase cautiously to 15 mg, 3 or 4 times daily.
Alcoholics with acute inebriation, tremulousness, or anxiety on
withdrawal: 15 to 30 mg, 3 or 4 times daily. OXAZOLAM 20 mg is
equivalent to 10 mg of Diazepam. MRTD (Maximum Recommended
Therapeutic Dose) in mg/kg- body weight (bw)/day based upon an
average adult weighing 60 kg - 1.0000 PINAZEPAM MRTD (Maximum
Recommended Therapeutic Dose) in mg/kg- body weight (bw)/day based
upon an average adult weighing 60 kg - 0.33300 PRAZEPAM MRTD
(Maximum Recommended Therapeutic Dose) in mg/kg- body weight
(bw)/day based upon an average adult weighing 60 kg - 1.00000
QUAZEPAM The recommended initial dose is 15 milligrams daily. Your
doctor may later reduce this dosage to 7.5 milligrams. TEMAZEPAM
While the recommended usual adult dose is 15 mg before retiring,
7.5 mg may be sufficient for some patients, and others may need 30
mg. In transient insomnia, a 7.5 mg dose may be sufficient to
improve sleep latency. In elderly and/or debilitated patients it is
recommended that therapy be initiated with 7.5 mg until individual
responses are determined. TETRAZEPAM Defined Daily Dose - 100 mg,
No data available from FDA. TOFISOPAM Tofisopam is not approved for
sale in the US or Canada. However, Vela Pharmaceuticals of New
Jersey is developing the D- enantiomer (dextofisopam) as a
treatment for IBS. TRIAZOLAM The recommended dose for most adults
is 0.25 mg before retiring. A dose of 0.125 mg may be found to be
sufficient for some patients (e.g., low body weight). A dose of 0.5
mg should be used only for exceptional patients who do not respond
adequately to a trial of a lower dose since the risk of several
adverse reactions increases with the size of the dose administered.
A dose of 0.5 mg should not be exceeded. In geriatric and/or
debilitated patients the recommended dosage range is 0.125 mg to
0.25 mg. Therapy should be initiated at 0.125 mg in this group and
the 0.25 mg dose should be used only for exceptional patients who
do not respond to a trial of the lower dose. A dose of 0.25 mg
should not be exceeded in these patients. HORMONES/ ESTROGENS See
other columns. Hormone-Containing Contraceptives General Dosing
Information: CONTRACEPTIVES include: ethinyl Combination
contraceptives are those containing both estrogen and estradiol and
progesterone. mestranol. Several types of combination birth control
pills exist, including PRO- monophasic pills, biphasic pills,
triphasic pils, and 91-day cycle GESTERONES pills. include: USE:
Starting at the beginning of the pill pack, take one each day at
Norethynodrel, approximately the same time every day to increase
efficacy. norethindrone, WHEN TO BEGIN: The following regimens may
be used when norethindrone first starting on birth control pills:
acetate, Taking one pill each day, starting on the fifth day after
the norgestimate, onset of menses and continuing for 21 or 28 days.
desogestrel, Beginning pills on the first day of the menstrual
period. ethyndiol Beginning on the first Sunday after the menstrual
period diacetate, starts. norgestrel, 21-DAY PILL CONTAINER: Take
one pill daily for 21 days, stop levonorgestrel, for 7 days, then
resume taking the pills with a new container of pills.
drospirenone. 28-DAY PILL CONTAINER: Start with the first pill in
the container and swallow one daily for 28 days. Do not stop taking
the pills. The last 7 ae usually placebos. 91-DAY PILL CONTAINER:
One pill is taken daily for 12 weeks, followed by one week of
inactive pills. A menstrual period occurs during the week of
inactive pills, so women on this regimen have a period only once
every three months. Monophasic Pills: Alesse, Brevicon, Demulen,
Desogen, Levlen, Levlite, Loestrin, Microgestin, Modicon, Necon,
Nelova, Nordette, Norinyl, Ortho-Cept, Ortho-Cyclen, Ortho-Novum,
Ovcon, Ovral, Yasmin, Zovia. Monophasic pills have a constant dose
of estrogen and progestin in each of the hormonally active pills
through the entire cycle (21 days of ingesting active pills).
Several of the brands listed above may be available in several
strengths of estrogen or progesterone, from which doctors choose
according to a woman's individual needs. Biphasic Pills: Jenest,
Mircette, Necon 10/11, Nelova 10/11, and Ortho-Novum 10/11 Biphasic
Pills typically contain two different progesterone doses. The
progesterone dose is increased about halfway through the cycle.
Triphasic Pills: Cyclessa, Estrostep, Ortho-Novum 7/7/7, Ortho Tri-
Cyclen, Ortho Tri-Cyclen LO, Tri-Levlen, Tri-Norinyl, Triphasil,
Trivora Triphasic pills gradually increase the dose of estrogen
during the cycle (some pills also increase the progesterone dose).
Three different increasing pill doses are contained in each cycle.
Ninety-One Day BCP: Levonorgestrel/ethynl estradiol (Seasonale)
These pills are monophasic birth control pills that have been
approved for use on a daily basis for 84 days without interruption.
Users have fewer schedules menstrual cycles (only 1 period every 3
months). Topical Contraceptive Patch: Norelgestromin/ethinyl
estradiol (Ortho Evra) A new patch is applied on the same day of
the week, each week for three weeks in a row. The first patch is
applied on either the first day of the menstrual period or on the
Sunday following menses. On the fourth week, no patch is applied.
Another 4-week cycle is started by applying a new patch following
the 7-day patch free period. Long-Acting, Injectable,
Progesterone-Only Contraceptives: Medroxyprogesterone acetate
(Depo-Provera) The first injection is given within five days
following the onset of menstruation. After that, an injection is
needed every 11-13 weeks. Unlike pills, the injection works right
away. Progesterone-Only Pills: Norethindrone (Nor-QD)
Progesterone-only pills, also known as mini-pills, are not used
widely in the US. POPs are ingested once daily, every day. They may
be started on any day, and there are no pill-free days or different
colored pills to track. Since progesterone is the only hormonal
ingredient, estrogen-related side effects are avoided. Vaginal
Ring: Etonogestrel/ethinyl estradiol (NuvaRing) The ring is
self-inserted into the vagina. Exact positioning is not required
for it to be effective. The vaginal ring must be inserted within 5
days of the onset of the menstrual period, even if bleeding is
still occurring. During the first cycle, an additional method of
contraception is recommended. The ring remains in place
continuously for three weeks. It is removed for one week. The next
ring is then inserted one week after the last ring was removed.
NON- CHLORAL HYDRATE The usual hypnotic dose is 500 mg to 1 g,
taken 15 to 30 minutes BENZODIAZEPINE before bedtime or 1/2 hour
before surgery. The usual sedative dose is ANXIOLYTICS 250 mg three
times daily after meals. Generally, single doses or SEDATIVES daily
dosage should not exceed 2 g. HYPNOTICS CHLORAL BETAINE Chloral
betaine 707 mg (chloral hydrate 414 mg) TRANQUILIZERS Dose: 1-2
tablets with water or milk at bedtime, max. 5 tablets (2 g chloral
hydrate) daily CLOMETHIAZOLE (or MRTD (Maximum Recommended
Therapeutic Dose) in mg/kg- CHLOMETHIAZOLE) body weight (bw)/day
based upon an average adult weighing 60 kg - 6.40000
DIPHENHYDRAMINE Adults: 25 to 50 mg three or four times daily.
Children (over 20 lb): 12.5 to 25 mg three to four times daily.
Maximum daily dosage not to exceed 300 mg. ETHCHLORVYNOL Due to the
problems it can cause, it is unusual for ethchlorvynol to be
prescribed for periods exceeding seven days. PROMETHIAZINE.
Administration of 12.5 to 25 mg Phenergan by the oral route or by
rectal suppository at bedtime will provide sedation in children.
Adults usually require 25 to 50 mg for nighttime, presurgical, or
obstetrical sedation. ZALPELON The recommended dose of Sonata for
most nonelderly adults is 10 mg. (imidazopyridine) For certain low
weight individuals, 5 mg may be a sufficient dose. Although the
risk of certain adverse events associated with the use of Sonata
appears to be dose dependent, the 20 mg dose has been shown to be
adequately tolerated and may be considered for the occasional
patient who does not benefit from a trial of a lower dose. ZOLPIDEM
The recommended dose for adults is 10 mg immediately before
(pyrazolopyrimidine) bedtime, indicated for the short-term
treatment of insomnia. ZOPICLONE The usual dose is 7.5 mg at
bedtime. This dose should not be exceeded. Depending on clinical
response and tolerance, the dose may be lowered to 3.75 mg.
Geriatrics: In the elderly and/or debilitated patient an initial
dose of 3.75 mg at bedtime is recommended. The dose may be
increased to 7.5 mg if the starting dose does not offer adequate
therapeutic effect. STIMULANTS CAFFEINE Caffeine Oral is used to
treat the following: Absence of Breathing in the Newborn Caffeine
Oral may also be used to treat: Drowsiness, Low Energy Caffeine
citrate is indicated for the short term treatment of apnea of
prematurity in infants between 28 and <33 weeks gestational age.
Caffeine Citrate: Loading Dose - 20 mg/kg Maintenance Dose - 5
mg/kg NICOTINE NICOTROL Inhaler is indicated as an aid to smoking
cessation for the relief of nicotine withdrawal symptoms. NICOTROL
Inhaler therapy is recommended for use as proof of a comprehensive
behavioral smoking cessation program. It it supplied as 42
cartridges each containing 10 mg (4 mg is delivered) nicotine.
Initial Treatment: Up to 12 Weeks: 6-16 cartridges/day Gradual
Reduction (if needed) - 6-12 Weeks: No tapering strategy has been
shown to be superior to any other in clinical studies. OTC
DEXTROMETHORPHAN Now prescription only in the United States.
MEDICATIONS MRTD (Maximum Recommended Therapeutic Dose) in mg/kg-
body weight (bw)/day based upon an average adult weighing 60 kg -
2.00000 MISCELLANEOUS GHB It has been used as a general anesthetic,
and a hypnotic in the Gamma-hydroxybutyrate treatment of insomnia.
GHB has also been used to treat clinical depression, and improve
athletic performance. In the US, the FDA permits the use of GHB to
reduce the number of cataplexy attacks in patients with narcolepsy.
In Italy, GHB is used for the treatment of alcoholism (50 to 100 mg
per kg per day, in 3 or more divided doses), both for acute alcohol
withdrawal and medium to long term detoxification. LD50 of GHB is
estimated to be between 1100 mg/kg and 2000 mg/kg in rodents and is
almost certainly lower in humans. MEPROBROMATE Meprobromate is
available in 200 mg and 400 mg tablets for oral administration.
Symptoms of meprobromate overdose include coma, drowsiness, loss of
muscle control, severly impaired breathing, shock, sluggishness,
and unresponsiveness. Death has been reported with ingestion of as
little as 12 g of meprobromate and survival with as much as 40 g.
METHQUALONE In the United States, the marketing of methaqualone
pharmaceutical products stopped in 1984, and methaqualone was
transferred to Schedule I of the CSA. NITROUS OXIDE Nitrous Oxide
is a weak general anesthetic, and is generally not used alone. It
has a very low short-term toxicity and is an excellent analgesic.
In general anesthesia it is often used in a 2:1 ratio with oxygen
in addition to more powerful general anesthetic agents. Possession
of nitrous oxide is illegal in most localities in the United States
for the purposes of inhaling or ingesting if not under the care of
a physician or dentist. PCP Not available for medicinal use.
Phencyclidine HERBAL VALERIAN ROOT Dosing not regulated/approved by
FDA. MEDICINALS (Valeriana officinalis, Large doses are known to
cause
withdrawal symptoms when Valerianaceae) stopped, as it is mildly
addictive. Those with liver disease are advised not to use
valerian. Valerian is the source of valeric acid. SALVINORIN A N.A.
Salvinorin A is the main active Salvinorin A is a dissociative
hallucinogenic compound that is psychotropic constituent of the
active at the extremely low doses of 0.2-0.5 mg, second only to
plant Salvia divinorum LSD in quantitative potency, making it the
most potent naturally (diviner's sage, Mexican mint). occurring
drug known to date. A dose of 200 to 500 micrograms produces
profound hallucinations when smoked. Its' effects in the open field
test in mice and loco motor activity tests in rats are similar to
mescaline. ST. JOHN'S WORT The dosage of St John's wort
preparations vary greatly between Refers to the species Hypericum
formulations, due to variability in the plant source and
preparation perforatum. processes. The doses of St. John's wort
extract used in clinical trials generally range from 350 to 1800 mg
daily (equivalent to 0.4 to 2.7 mg hypericin depending on the
preparation). The recommended dosage for various forms of St John's
wort as recommended by the British Herbal Medicine Association
Scientific Committee (1983) are as follows: dried herb: 2-4 g or by
infusion three times daily liquid extract 2-4 mL (1:1 in 25%
alcohol) three times daily tincture 2-4 mL (1:10 in 45% alcohol)
three times daily ANTI- CITALOPRAM HBR Celexa (citalopram HBr) is
indicated for the treatment of DEPRESSION (CELEXA) depression.
DRUGS Celexa (citalopram HBr) should be administered at an initial
dose of 20 mg once daily, generally with an increase to a dose of
40 mg/ day. Dose increases should usually occur in increments of 20
mg at intervals of no less than one week ESCITALOPRAM OXALATE
LEXAPRO (escitalopram) is indicated for the treatment of major
LEXAPRO .TM. depressive disorder and Generalized Anxiety Disorder
(GAD). The recommended dose of LEXAPRO is 10 mg once daily.
FLUOXETINE Prozac is indicated for the treatment of: Major
Depressive Disorder: HYDROCHLORIDE a dose of 20 mg/day,
administered in the morning, is recommended as the initial dose.
The maximum fluoxetine dose should not exceed 80 mg/day. Obsessive
Compulsive Disorder: a dose of 20 mg/day, administered in the
morning, is recommended as the initial dose. The maximum fluoxetine
dose should not exceed 80 mg/day. Bulimia Nervosa: the recommended
dose is 60 mg/day, administered in the morning. Panic Disorder:
Treatment should be initiated with a dose of 10 mg/day. After 1
week, the dose should be increased to 20 mg/day. PAROXETINE Major
Depressive Disorder: The recommended initial dose is HYDROCHLORIDE
20 mg/day. Some patients not responding to a 20-mg dose may benefit
from dose increases, in 10-mg/day increments, up to a maximum of 50
mg/day. Obsessive Compulsive Disorder: The recommended dose of
PAXIL in the treatment of OCD is 40 mg daily. Patients should be
started on 20 mg/day and the dose can be increased in 10-mg/day
increments. The maximum dosage should not exceed 60 mg/day. Panic
Disorder: The target dose of PAXIL in the treatment of panic
disorder is 40 mg/day. The maximum dosage should not exceed 60
mg/day. Social Anxiety Disorder: The recommended and initial dosage
is 20 mg/day. Generalized Anxiety Disorder: The recommended
starting dosage and the established effective dosage is 20 mg/day.
Posttraumatic Stress Disorder: The recommended starting dosage and
the established effective dosage is 20 mg/day. FLUVOXAMINE MALEATE
Fluvoxamine is indicated in the treatment of depression and for
(LUVOX). Obsessive Compulsive Disorder (OCD). The recommended
starting dose for LUVOX Tablets in adult patients is 50 mg,
administered as a single daily dose at bed time. The maximum
therapeutic dose should not to exceed 300 mg per day. SERTRALINE
Major Depressive Disorder and Obsessive-Compulsive Disorder:
HYDROCHLORIDE ZOLOFT treatment should be administered at a dose of
50 mg once daily. Panic Disorder, Posttraumatic Stress Disorder and
Social Anxiety Disorder: ZOLOFT treatment should be initiated with
a dose of 25 mg once daily. After one week, the dose should be
increased to 50 mg once daily. Premenstrual Dysphoric Disorder:
ZOLOFT treatment should be initiated with a dose of 50 mg/day,
either daily throughout the menstrual cycle or limited to the
luteal phase of the menstrual cycle, depending on physician
assessment. AMITRIPTYLINE For the relief of symptoms of depression.
Endogenous depression is more likely to be alleviated than are
other depressive states. Oral Dosage: 75 mg of amitriptyline HCl a
day in divided doses. If necessary, this may be increased to a
total of 150 mg per day. Intramuscular Dosage: Initially, 20 to 30
mg (2 to 3 ml) four times a day. DESIPRAMINE Desipramine
hydrochloride is indicated for relief of symptoms in HYDROCHLORIDE
various depressive syndromes, especially endogenous depression. The
usual adult dose is 100 to 200 mg per day. Dosages above 300 mg/day
are not recommended. Not recommended for use in children.
NORTRIPTYLINE Nortriptyline HCl is indicated for the relief of
symptoms of depression. Endogenous depressions are more likely to
be alleviated than are other depressive states. It is not
recommended for children. Usual Adult Dose - 25 mg three or four
times daily. Doses above 150 mg/day are not recommended. Elderly
and Adolescent Patients - 30 to 50 mg/day, in divided doses, or the
total daily dosage may be given once a day. DULOXETINE Cymbalta is
indicated for the treatment of major depressive disorder
HYDROCHLORIDE (MDD) and pain associated with diabetic peripheral
neuropathy. Major Depressive Disorder: Cymbalta should be
administered at a total dose of 40 mg/day Diabetic Peripheral
Neuropathic Pain: Cymbalta should be administered at a total dose
of 60 mg/day given once a day VENLAFAXINE Effexor (venlafaxine
hydrochloride) is indicated for the treatment of Effexor major
depressive disorder. The recommended starting dose for Effexor is
75 mg/day, up to a maximum of 375 mg/day, generally in three
divided doses PHENELZINE SULFATE The usual starting dose of Nardil
is one tablet (15 mg) three times a day. Maintenance dose may be as
low as one tablet, 15 mg, a day or every other day, and should be
continued for as long as is required. TRANYLCYPROMINE For the
treatment of Major Depressive Episode Without (Parnate)
Melancholia. The usual effective dosage is 30 mg per day, usually
given in divided doses; may be extended to a maximum of 60 mg per
day. When tranylcypromine is withdrawn, monoamine oxidase activity
is recovered in 3 to 5 days, although the drug is excreted in 24
hours. MIRTAZEPINE Indicated for the treatment of major depressive
disorder. The recommended starting dose for REMERON .RTM.
(mirtazapine) Tablets is 15 mg/day, up to a maximum of 45 mg/day.
NEFAZODONE SERZONE (nefazodone hydrochloride) is indicated for the
HYDROCHLORIDE treatment of depression. When deciding among the
alternative SERZONE .RTM. treatments available for this condition,
the prescriber should consider the risk of hepatic failure
associated with SERZONE treatment. The recommended starting dose
for SERZONE (nefazodone hydrochloride) is 200 mg/day TRAZODONE
DESYREL is indicated for the treatment of depression. HYDROCHLORIDE
An initial dose of 150 mg/day in divided doses is suggested, up to
DESYREL but not in excess of 600 mg/day in divided doses. BUPROPION
WELLBUTRIN is indicated for the treatment of depression.
HYDROCHLORIDE The usual adult dose is 300 mg/day, given 3 times
daily. WELLBUTRIN (bupropion WELLBUTRIN should be discontinued in
patients who do not hydrochloride) demonstrate an adequate response
after an appropriate period of treatment at 450 mg/day. When
Wellbutrin is used in combination with an SSRI to offset sexual
side effects, the usual dose is 75 mg per day. Isocarboxazid The
maximum daily dose of isocarboxazid is 60 mg. Moclobemide
Depression: The initial dose is 300 mg daily in 2 or 3 divided
doses. Social Phobia: The recommended dose is 600 mg daily in 2 or
3 divided doses. A single 300 mg dose of moclobemide inhibits 80%
of monoamine oxidase A (MAO-A) and 30% of monoamine oxidase B
(MAO-B), blocking the decomposition of norepinephrine, serotonin
and, to a lesser extent, dopamine. No reuptake inhibition on any of
the neurotransmitters occurs. Selegiline 10 mg per day administered
as divided doses of 5 mg each. NEUROSTEROID 5-ALPHA- INHIBITORS
REDUCTASE INHIBITORS FINASTERIDE The recommended dosage is 1 mg
orally once per day. It may be administered with or without meals.
An alternate dosage of 5 mg orally once per day is also included.
It may be administered with or without meals. In general, daily use
for three months or more is necessary before benefit is observed.
Continued use is recommended to sustain benefit, which should be
re-evaluated periodically. Withdrawal of treatment leads to
reversal of effect within 12 months. In clinical studies, single
doses of finasteride up to 400 mg and multiple doses of finasteride
up to 80 mg/day for three months did not result in adverse
reactions. DUTASTERIDE The recommended therapeutic dose of
dutasteride is 0.5 mg taken orally once per day. Dutasteride
pharmacokinetics has not been investigated in subjects less than 18
years of age. No dose adjustment is necessary in the elderly. In
volunteer studies, single doses of dutasteride up to 40 mg (80
times the therapeutic dose) for 7 days have been administered
without significant safety concerns. In a clinical study, daily
doses of 5 mg (10 times the therapeutic dose) were administered to
60 subjects for 6 months with no additional adverse effects to
those seen at therapeutic does of 0.5 mg. SAW PALMETTO
Tablets/Capsules. A dose of 160 mg twice daily or 320 milligrams
daily (containing 80% to 90% liposterolic content) for up to 11
months has been taken by mouth. Higher doses may be used under
medical supervision. Berries. A dose of one to two grams of ground,
dried, or whole berries daily has been taken by mouth. Tincture. A
dose of two to four milliliters (1:4) three times daily has been
taken by mouth. Fluid Extract of Berry Pulp. A dose of one to two
milliliters (1:1) three times daily has been taken by mouth. Rectal
Suppositories. A dose of 640 milligrams once daily has been used.
Rectal use of saw palmetto is no better than taking saw palmetto by
mouth. Tea. Tea made from berries may not be effective because the
proposed active ingredient does not dissolve in water.
SPIRONOLACTONE Treatment protocols may involve continuous
spironolactone use at 50 mg to 200 mg per day or cyclic use; for
example, 50 mg or 100 mg twice daily from the 4.sup.th to the
22.sup.nd day of the menstrual cycle. Numerous treatment protocols
involving spironolactone have been used in different studies, but
no particular treatment approach has been shown to be significantly
superior. 3-ALPHA REDUCTASE INHIBITORS INDOMETHACIN Indomethacin
can be administered in the form of capsules (25 mg and 50 mg);
sustained-release capsules (75 mg); a suspension (25 mg/ml); or a
suppository (50 mg). The recommended dose for adults is 50-200 mg
per day split into 2-3 doses. CLASS OF FLUMAZENIL ROMAZICON is
indicated for the complete or partial reversal of COMPOUNDS
(Romazicon) the sedative effects of benzodiazepines in cases where
general THAT anesthesia has been induced and/or maintained with
SELECTIVELY benzodiazepines, where sedation has been produced with
MODULATES benzodiazepines for diagnostic and therapeutic
procedures, and for GABA.sub.A the management of benzodiazepine
overdose. Reversal of RECEPTORS Conscious Sedation: The recommended
initial dose of ROMAZICON is 0.2 mg (2 mL) administered
intravenously over 15 seconds. If the desired level of
consciousness is not obtained after waiting an additional 45
seconds, a second dose of 0.2 mg (2 mL) can be injected and
repeated at 60-second intervals where necessary (up to a maximum of
4 additional times) to a maximum total dose of 1 mg (10 mL).
Reversal of General Anesthesia in Adult Patients: The recommended
initial dose of ROMAZICON is 0.2 mg (2 mL) administered
intravenously over 15 seconds. If the desired level of
consciousness is not obtained after waiting an additional 45
seconds, a further dose of 0.2 mg (2 mL) can be injected and
repeated at 60-second intervals where necessary (up to a maximum of
4 additional times) to a maximum total dose of 1 mg (10 mL).
Management of Suspected Benzodiazepine Overdose in Adult Patients:
the recommended initial dose of ROMAZICON is 0.2 mg (2 mL)
administered intravenously over 30 seconds. If the desired level of
consciousness is not obtained after waiting 30 seconds, a further
dose of 0.3 mg (3 mL) can be administered over another 30 seconds.
Further doses of 0.5 mg (5 mL) can be administered over 30 seconds
at 1-minute intervals up to a cumulative dose of 3 mg. MILTIRONE
The below doses are based on scientific research, publications,
traditional use, or expert opinion. Many herbs and supplements have
not been thoroughly tested, and safety and effectiveness may not be
proven. You should read product labels, and discuss doses with a
qualified healthcare provider before starting therapy.
Standardization: There is no widely accepted standardization or
well-studied dosing of miltirone, and many different doses are used
traditionally. Adults (18 years and older): By mouth: Oral dosing
has not been studied in well-conducted trials in humans, and
therefore no specific dose can be recommended. By injection: In
research from the 1970s, an 8 milliliter injection of miltirone (16
grams of the herb) was given intravenously (diluted in 500
milliliters of a 10% glucose solution) for up to four weeks for
ischemic stroke. Safety and effectiveness have not been established
for this route of administration and it cannot not recommended at
his time. Children (younger than 18 years): There is not enough
scientific evidence to recommend the safe use of danshen in
children, and it should be avoided due to potentially serious side
effects. FLAVONOIDS They have been classified N.A. according to
their chemical structure, and are usually subdivided into 6
subgroups: Flavonols, including Quercetin, Kaempferol, Myricetin,
Isorhamnetin Flavones, including Luteolin, Apigenin Flavanones,
including Hesperetin, Naringenin, Eriodictyol Flavan-3-ols,
including (+)- Catechin, (+)-Gallocatechin, (-)- Epicatechin, (-)-
*Epigallocatechin, (-)- Epicatechin 3-gallate, (-)-
Epigallocatechin 3-gallate, Theaflavin, Theaflavin 3- gallate,
Theaflavin 3'-gallate, Theaflavin 3,3' digallate, Thearubigins
Isoflavones, including Genistein, Daidzein, Glycitein
Anthocyanidins, including Cyanidin, Delphinidin, Malvidin,
Pelargonidin, Peonidin, Petunidin DOPAMINE ERGOT The dose of
bromocriptine will be different for different patients. change your
dose over several weeks as needed. Teenagers less than 15 years of
age and children-Use and dose must be determined by your doctor.
For pituitary tumors: Adults and teenagers 15 years of age or
older-At first, 1.25 milligrams (mg) two or three times a day taken
with meals. Then your doctor may change your dose over several
weeks as needed. Teenagers less than 15 years of age and
children-Use and dose must be determined by your doctor.
PRESCRIPTION METHYLPHENIDATE Methylphendiate comes in 5 mg, 10 mg
and 20 mg tablets. STIMULANTS ADULTS Tablets: Administer in divided
doses, 2 or 3 times daily, preferably 30 to 45 minutes before
meals. Average dosage is 20 to 30 mg daily. Some patient may
require 40 to 60 mg daily. In others, 10 to 15 mg daily will be
adequate. FOR CHILDREN, DOSAGES SHOULD BE INITIATED IN INCREMENTS
Days 1-3: One 5 mg tablet per day Days 4-6: Two 5 mg tablets per
day Add one pill every fourth day until a dosage of 20 mg per day
is achieved. Daily dosage above 60 mg is not recommended. ADDERALL.
Attention Deficit Disorder with Hyperactivity: Not recommended for
children under 3 years of age. In children from 3 to 5 years of
age, start with 2.5 mg daily; daily dosage may be raised in
increments of 2.5 mg at weekly intervals until optimal response is
obtained. In children 6 years of age and older, start with 5 mg
once or twice daily; daily dosage may be raised in increments of 5
mg at weekly intervals until optimal response is obtained. Only in
rare cases will it be necessary to exceed a total of 40 mg per day.
Give first dose on awakening; additional doses (1 or 2) at
intervals of 4 to 6 hours. Where possible, drug administration
should be interrupted occasionally to determine if there is a
recurrence of behavioral symptoms sufficient to require continued
therapy. Narcolepsy: Usual dose 5 mg to 60 mg per day in divided
doses, depending on the individual patient response. Narcolepsy
seldom occurs in children under 12 years of age; however, when it
does, dextroamphetamine sulfate may be used. The suggested initial
dose for patients aged 6-12 is 5 mg daily; daily dose may be raised
in increments of 5 mg at weekly intervals until optimal response is
obtained. In patients 12 years of age and older, start with 10 mg
daily; daily dosage may be raised in increments of 10 mg at weekly
intervals until optimal response is obtained. If bothersome adverse
reactions appear (e.g., insomnia or anorexia), dosage should be
reduced. Give first dose on awakening; additional doses (1 or 2) at
intervals of 4 to 6 hours. DEXEDRINE Narcolepsy. Usual dose 5 to 60
mg per day in divided doses, depending on the individual patient
response. Narcolepsy seldom occurs in children under 12 years of
age; however, when it does Dexedrine (dextroamphetamine sulfate)
may be used. The suggested initial dose for patients aged 6 to 12
is 5 mg daily; daily dose may be raised in increments of 5 mg at
weekly intervals until optimal response is obtained. In patients 12
years of age and older, start with 10 mg daily; daily dosage may be
raised in increments of 10 mg at weekly intervals until optimal
response is obtained. If bothersome adverse reactions appear (e.g.
insomnia or anorexia), dosage should be reduced. Spansule capsules
may be used for once-a-day dosage wherever appropriate. With
tablets give first dose on awakening, additional doses (1 or 2) at
intervals of 4 to 6 hours. AGONISTS ALKALOIDS Follow your doctor's
orders or the directions on the label. The following information
includes only the average doses of bromocriptine. If your dose is
different, do not change it unless your doctor tells you to do so.
The number of capsules or tablets that you take depends on the
strength of the medicine. Also, the number of doses you take each
day, the time allowed between doses, and the length of time you
take the medicine depend on the medical problem for which you are
taking bromocriptine. For oral dosage forms (capsules and tablets):
For infertility, male hormone problem (male hypogonadism), starting
the menstrual cycle (amenorrhea), or stopping abnormal milk
secretion from nipples (galactorrhea): Adults and teenagers 15
years of age or older-At first, 1.25 to 2.5 milligrams (mg) once a
day taken at bedtime with a snack. Then your doctor may change your
dose by 2.5 mg every three to seven days as needed. Doses greater
than 5 mg a day are taken in divided doses with meals or at bedtime
with a snack. Teenagers less than 15 years of age and children-Use
and dose must be determined by your doctor. For lowering growth
hormone (acromegaly): Adults and teenagers 15 years of age or
older-At first, 1.25 to 2.5 milligrams (mg) once a day taken at
bedtime with a snack for three days. Then your doctor may change
your dose by 1.25 or 2.5 mg every three to seven days as needed.
Doses greater than 5 mg are divided into smaller doses and taken
with meals or at bedtime with a snack. Teenagers less than 15 years
of age and children-Use and dose must be determined by your doctor.
For Parkinson's disease: Adults and teenagers 15 years of age or
older-At first, 1.25 milligrams (mg) one or two times a day taken
with meals or at bedtime with a snack. Then your doctor may
Attention Deficit Disorder with Hyperactivity. Not recommended for
pediatric patients under 3 years of age. In pediatric patients from
3 to 5 years of age, start with 2.5 mg daily, by tablet daily
dosage may be raised in increments of 2.5 mg at weekly intervals
until optimal response is obtained. In pediatric patients 6 years
of age and older, start with 5 mg once or twice daily, daily dosage
may be raised in increments of 5 mg at weekly intervals until
optimal response is obtained. Only in rare cases will it be
necessary to exceed a total of 40 mg per day. Spansule capsules may
be used for once-a-day dosage wherever appropriate. With tablets,
give first dose on awakening additional doses (1 or 2) at intervals
of 4 to 6 hours.
* * * * *