U.S. patent application number 12/404132 was filed with the patent office on 2009-08-27 for use of selective chloride channel modulators to treat alcohol and/or stimulant substance abuse.
This patent application is currently assigned to Hythiam, Inc.. Invention is credited to Juan Jose Legarda Ibanez.
Application Number | 20090215751 12/404132 |
Document ID | / |
Family ID | 37215204 |
Filed Date | 2009-08-27 |
United States Patent
Application |
20090215751 |
Kind Code |
A1 |
Legarda Ibanez; Juan Jose |
August 27, 2009 |
Use of Selective Chloride Channel Modulators to Treat Alcohol
and/or Stimulant Substance Abuse
Abstract
The invention relates to methods of and treatments for using
pharmaceutical compositions from a class of compounds that directly
or indirectly selectively modulates GABA.sub.A chloride channel
activity to treat alcohol and/or stimulant substance abuse. The
present invention also relates to methods of, and protocols for,
relieving symptoms associated with alcohol and/or stimulant
substance abuse in a comprehensive treatment plan. More
specifically, the present invention relates to the use of a
selective chloride channel modulator, such as flumazenil, to treat
alcohol and/or psychostimulant dependency, the withdrawal symptoms
associated therewith, and the cravings associated therewith.
Inventors: |
Legarda Ibanez; Juan Jose;
(Madrid, ES) |
Correspondence
Address: |
JOHN S. PRATT, ESQ;KILPATRICK STOCKTON, LLP
1100 PEACHTREE STREET, SUITE 2800
ATLANTA
GA
30309
US
|
Assignee: |
Hythiam, Inc.
Los Angeles
CA
|
Family ID: |
37215204 |
Appl. No.: |
12/404132 |
Filed: |
March 13, 2009 |
Related U.S. Patent Documents
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Patent Number |
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11111435 |
Apr 21, 2005 |
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12404132 |
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10621229 |
Jul 15, 2003 |
7348321 |
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11111435 |
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10622068 |
Jul 15, 2003 |
7186711 |
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10621229 |
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Current U.S.
Class: |
514/220 ;
514/255.04; 514/561 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/195 20130101; A61P 43/00 20180101; A61K 31/551 20130101;
A61K 31/5517 20130101; A61P 25/30 20180101; A61P 25/36 20180101;
A61P 25/32 20180101; A61K 31/137 20130101; A61K 31/137 20130101;
A61K 2300/00 20130101; A61K 31/5517 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/220 ;
514/255.04; 514/561 |
International
Class: |
A61K 31/5517 20060101
A61K031/5517; A61P 25/32 20060101 A61P025/32; A61K 31/495 20060101
A61K031/495; A61K 31/195 20060101 A61K031/195 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 17, 2001 |
ES |
ES/P200100106 |
Feb 15, 2001 |
ES |
ES/P200100342 |
Jan 10, 2002 |
ES |
PCT/ES02/00008 |
Feb 8, 2002 |
ES |
PCT/ES02/00061 |
Claims
1-29. (canceled)
30. A method for the treatment of alcohol abuse in a patient
comprising the steps of: evaluating the patient; administering a
therapeutically effective amount of a composition comprising a
selective chloride channel modulator in a pharmaceutically
acceptable carrier to the patient; monitoring the patient during
treatment; prescribing the patient a therapeutic compound in
addition to the selective chloride channel modulator; and
prescribing the patient an outpatient regimen.
31. The method of claim 30 wherein the patient evaluation step
comprises at least one of the following: a complete physical
examination, a complete psychological examination, a CIWA
assessment, and a determination of required medications.
32. The method of claim 30 wherein the selective chloride channel
modulator is flumazenil.
33. The method of claim 32 wherein the therapeutically effective
amount of flumazenil is between about 1.0 and 3.0 mg/day.
34. The method of claim 32 wherein the therapeutically effective
amount of flumazenil is between about 1.5 and 2.5 mg/day.
35. The method of claim 30 wherein the therapeutic compound
includes at least one of the following: fortified vitamin B
complex, hydroxyzine, or gabapentin.
36. The method of claim 30 wherein the outpatient regimen includes
at least one of diet, exercise, and cognitive therapy.
37. The method of claim 30 wherein the selective chloride channel
modulator is a partial allosteric modulator at GABA.sub.A receptor
sites.
38. The method of claim 37 wherein the partial allosteric modulator
acts with high potency but low efficacy at the GABA.sub.A receptor
sites.
39. The method of claim 37 wherein the partial allosteric modulator
acts to reset the GABA.sub.A receptor receptivity and increase
chloride channel ion flow.
40. The method of claim 30 wherein the selective chloride channel
modulator acts to reset changes in GABA.sub.A subunits.
41. The method of claim 30 wherein the selective chloride channel
modulator is a partial agonist of the GABA.sub.A receptor.
42. The method of claim 30 wherein the selective chloride channel
modulator is at least one of a imidazobenzodiazepine or a
derivative of ethyl
8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-a][1,4]
benzodiazepine-3-carboxylate.
43. A method for treating alcohol abuse in a patient comprising the
steps of: evaluating the patient; administering a therapeutically
effective amount of a composition comprising flumazenil in a
pharmaceutically acceptable carrier to the patient wherein the
therapeutically effective amount of flumazenil is less than 3
mg/day and is delivered in individual doses of 0.4 mg or less over
a period of 20 minutes or less; monitoring the patient during
treatment; prescribing the patient a therapeutic compound in
addition to the flumazenil; and prescribing the patient an
outpatient regimen.
Description
CROSS REFERENCE
[0001] The present invention is a continuation in part of U.S.
patent application Ser. No. 10/621,229, entitled "Use of flumazenil
in the production of a drug for the treatment of alcohol
dependency", filed on Jul. 15, 2003.
FIELD OF THE INVENTION
[0002] The invention relates to methods of, and methodologies for,
using pharmaceutical compositions from a class of compounds that
directly or indirectly selectively modulates GABA.sub.A chloride
channel activity to treat alcohol and/or psychostimulant substance
abuse, including, but not limited to, the various physical and
psychological states that manifest an individual's impaired control
over substance use, addiction, continued substance use despite
harm, compulsive substance use, cravings, psychological dependence,
physical dependence, tolerance, a maladaptive pattern of substance
use, preoccupation with substance use, and/or the prevalence of
withdrawal symptoms upon cessation of use. The present invention
also relates to methods of, and systems for, relieving symptoms
associated with said alcohol and stimulant substance abuse in a
comprehensive treatment plan. More specifically, the present
invention relates to the use of a compound, such as flumazenil, to
treat alcohol and/or psychostimulant substance abuse, the
withdrawal symptoms associated therewith, and the cravings
associated therewith.
BACKGROUND OF THE INVENTION
[0003] Alcohol and stimulant substance abuse disorders have a
devastating economic and societal impact on the United States
population. Alcohol and stimulant substance dependency is a
multi-factorial neurological disease. The use of such drugs impacts
an array of neurotransmission circuits in the brain, with a
suggested final common pathway of activation of the mesolimbic
reward circuit that is mediated via enhanced dopamine release. Over
time, repeated exposure to these drugs causes modification of the
neurotransmission circuits and adaptations in post-receptor
signaling cascades. The effects of this neuronal modification are
twofold. First, a reduction in the ability of natural rewards to
activate the reward pathways leads to depressed motivation and
mood, and increased compulsion to take more drugs. Second, there is
a production of long-lasting memories related to the drug
experience that, when stimulated by stressful events or exposure to
drug-associated or mood-associated cues, act to stimulate cravings
for the drug.
[0004] For many individuals, an innate neurochemical anomaly
renders them susceptible to substance dependency or addictive
behavior, even before any long-term effects of alcohol on
neurological processing are evident. It is clear, however, that
excessive drinking over time can lead to the impairment of brain
function and result in structural brain changes in frontal and
prefrontal areas of the brain, which are associated with cognition.
Impaired cognition and judgment can therefore become permanent.
[0005] Alcohol affects the mesolimbic dopamine circuit by modifying
the activity of two key receptors in the dopamine circuit, the
GABA.sub.A receptor and NMDA receptor. GABA (gamma-aminobutryic
acid) is a neurotransmitter that is a predominant inhibitory
transmitter in areas of the brain such as the cortex and basal
ganglia. The NMDA (N-methyl-D-aspartate) receptor is a ligand-gated
ionic channel activated by and involved in the release of the
neurotransmitter glutamate, which is an important excitatory
transmitter in the brain. The positive affect on the mesolimbic
dopamine circuit creates a self-reinforcing cycle of
neuropathophysiological reward that drives individuals to become
alcohol dependent. Alcohol increases chloride channel ion flow,
relative to the post-synaptic chloride channel at rest, by engaging
a GABA.sub.A receptor site. Benzodiazepines have a similar
affect.
[0006] Acute exposure to alcohol results in the up regulation of
NMDA and down regulation of the GABA-ergic system. Repeated
exposure results in cross-tolerance and cross-dependence between
alcohol and benzodiazepines. Consequently, an alcohol dependent
person experiences stress, a down regulation of GABA.sub.A and an
increase in the severity of withdrawal symptoms when he or she
attempts to withdraw.
[0007] Therefore, when an alcoholic attempts to initiate abstinence
or stop consuming alcohol, he or she may experience withdrawal
symptoms, including cravings, which often result in a failure to
stop consuming alcohol. Traditional alcohol withdrawal symptoms
include anxiety, tremors, difficulty sleeping, elevated pulse and
blood pressure, nausea, and vomiting. In some cases, withdrawal
symptoms may be more severe and result in complications, including
seizures, hallucinosis, hallucinations with severe tremors (or
"delirium tremens", DTs) and difficulty regulating body
temperature. These complications may often be fatal. In an
exemplary case, withdrawal symptoms begin appearing 6 to 12 hours
after a prior consumption of alcohol. Alcohol withdrawal syndrome
may occur 6 to 48 hours after a prior consumption of alcohol.
[0008] Psychostimulants are a class of central nervous system
stimulants and include cocaine, crack cocaine, ephedrine,
amphetamines, such as dextroamphetamine (commonly referred to as
amphetamine), methamphetamine, and phenmetrazine,
methylenodioxyamphetamine (MDA), and methylenodioxymethamphetamine
(MDMA or "ecstasy"), and analogs thereof. Amphetamine-like drugs
are classified as indirect action agonists of noradrenergic,
dopaminergic, and serotonergic synapses which result from
inhibiting both neurotransmitters reuptake and the enzyme monoamine
oxidase (MAO). They are competitive inhibitors of noradrenaline and
dopamine transport and, in high doses, also inhibit serotonin
reuptake. They cause non-calcium dependent dopamine and
noradrenaline release.
[0009] Stimulants affect a number of neurological circuits,
including dopaminergic, beta-adrenergic, serotonergic,
glutamatergic, GABAergic circuits, and ultimately results in
impaired dopamine function. GABA.sub.A functionality is eventually
impaired.
[0010] At lower doses, stimulants result in a feeling of euphoria,
an increase in energy, a decrease in fatigue, and an increase in
mental acuity. As dosing increases, a person starts to experience
tremors, emotional instability, restlessness, irritability, and
feelings of paranoia and panic. At higher doses, a person
experiences intense anxiety, paranoia, hallucinations,
hypertension, tachycardia, hyperthermia, respiratory depression,
heart failure, and seizures.
[0011] Traditional withdrawal symptoms for those trying to end
their abuse of psychostimulants include: depressed mood, fatigue,
vivid and unpleasant dreams, difficulty sleeping or excessive
sleeping, increased appetite, anxiety, and agitation. Cravings for
the psychostimulant are particularly pronounced and may recur for
many months, if not years. A return of "normal" mood and the
ability to experience pleasure may take a significant amount of
time due to the depletion or modification of neurotransmitters.
[0012] Alcohol and psychostimulant substance abuse are often
associated with changes in food selection and intake that lead to
calorie and protein malnutrition and disruption of energy
expenditure. The resulting malnutrition is related to deficient
food intake, malabsorption, increased protein turnover, liver
disease, intensity of drug addiction, anorexia, and poor food and
drink consumption. Furthermore, the disturbance of social and
familial links can itself result in poor nutrition. Malnutrition,
in turn, is associated with impairment of immune function.
Therefore, restoration and maintenance of normal physiological
function can be regarded as an important objective when treating
substance dependencies. Effective treatment of alcohol substance
abuse should address the neurological, nutritional, and
psychosocial disturbances that both cause and exacerbate the
abuse.
[0013] The customary treatment of alcohol dependency includes the
administration of vitamin B and C complexes, benzodiazepines (to
calm agitation and blunt withdrawal symptoms), and, sometimes,
disulfuram (to prevent alcohol use). The traditional medical
detoxifications involve replacing alcohol with substances
pharmacologically similar to alcohol in order to reduce withdrawal
agitation. Detoxification can take 3-5 days, involves sedation with
potentially dependence forming drugs, and is generally
uncomfortable for the patient.
[0014] Traditional treatments for managing withdrawal and craving
for alcohol and/or psychostimulants (such as cocaine) may include
the administration of benzodiazepines (e.g. lorezepam) if agitation
or anxiety is present, antidepressants to treat persistent
depression and dopamine-agonists to increase brain dopamine. These
treatments, however, have limited success and have high dropout
rates. Dropout can refer to several different types of treatment
events related to the premature cessation of treatment, including
times when patients dropout during treatment and when patients
relapse following treatment.
[0015] A review of the various pharmacological treatments existing
for the treatment of alcohol dependency can be found in A Practice
Guideline for the Treatment of Patients With Substance Use
Disorders Alcohol, Cocaine and Opioids, produced by the Work Group
on Substance Use Disorders of the American Psychiatric Association
and published in Am. J. Psychiatry 152:11, November 1995
Supplement. An updated review of the treatment of alcohol
dependency was created by Mayo-Smith et al., JAMA Jul. 9, 1997,
Vol. 278, No. 2, who conclude by indicating that the
benzodiazepines (alprazolam, diazepam, halazepam, lorazepam or
oxazepam) are agents suitable for the treatment of alcohol
dependency, whereas beta-blockers (propranolol), neuroleptics
(chlorpromazine and promazine), clonidine and carbamazepine, may be
used in coadjuvant therapy, but their use is not recommended as a
monotherapy. A benzodiazepine is any of a group of chemically
similar psychotropic drugs with potent hypnotic and sedative
action, used predominantly as anti-anxiety (anxiolytic) and
sleep-inducing drugs. Side effects of these drugs may include
impairment of psychomotor performance; amnesia; euphoria;
dependence; and rebound (i.e., the return of symptoms) transiently
worse than before treatment, upon discontinuation of the drug.
[0016] In certain conventional uses, flumazenil, an
imidazobenzodiazepine derivative, antagonizes the actions of
benzodiazepines on the central nervous system. In conventional
doses, flumazenil [ethyl
8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-a][1,4]benzodiazepine-
-3-carboxylate] therefore acts as a benzodiazepine antagonist which
selectively blocks the effects exerted on the central nervous
system via the benzodiazepine receptors. This active principle is
indicated to neutralize the central sedative effect of the
benzodiazepines; consequently, it is conventionally used in
anesthesia to end the general anesthesia induced and maintained
with benzodiazepines in hospitalized patients, or to stop the
sedation produced with benzodiazepines in patients undergoing brief
diagnostic or therapeutic procedures on an inpatient or outpatient
basis.
[0017] Some clinical studies have examined the role of flumazenil
in the reversal of alcohol withdrawal syndrome. Gerra et al., 1991,
Current Therapeutic Research, Vol. 50, 1, pp 62-66, describe the
administration to 11 selected alcoholics (who did not have
cirrhosis, metabolic disorders, convulsions, addictions to other
substances or psychiatric disorders) of 2 mg/day of flumazenil
divided into 4 doses (0.5 mg), intravenously (IV) via a continuous
drip, in saline solution, every 6 hours for 48 hours. The use of
0.5 mg of flumazenil is based on the presentation of pharmaceutical
preparations that contain said active principle but not on studies
performed in humans concerning the level of occupation of the
receptors involved. The flumazenil was administered at the rate of
0.5 mg of flumazenil every 6 hours (i.e., 0.08 mg/hour of
flumazenil). The tests performed by Gerra et al. present some
characteristics that are far from the actual circumstances, for
example, the tests were performed on a small sample (11
individuals) of select patients not representative of the pathology
considered since it is relatively customary that these patients may
have cirrhosis, metabolic disorders, addictions to other substances
(cocaine, heroin, etc.) and/or psychiatric disorders. Moreover,
Gerra et al. do not present data concerning the evaluation of
dependency or craving either before or after administration of the
drug. Most importantly, however, Gerra et al. discloses the
administration of very small quantities of flumazenil over long
periods of time, which was not particularly effective at treating
alcohol dependency. Nutt et al. [Alcohol & Alcoholism, 1993,
Suppl. 2, pp 337-341. Pergamon Press Ltd.;
Neuropschychopharmacology, 1994, Vol. 10, 35, part 1, Suppl., p.
85f) describe the administration to 8 alcoholics in the acute
withdrawal phase of 2 mg of flumazenil, by IV, for 1 minute. The
results obtained after the administration of flumazenil were not
completely satisfactory since in some cases, there was an immediate
worsening of the withdrawal symptoms, especially of sweats and
anxiety. In other cases, the withdrawal symptoms disappeared but
returned a few hours later. Since flumazenil is metabolized and
eliminated very rapidly, the IV administration of a relatively high
dose of flumazenil in a single dose of 2 mg, for 1 minute, has
several disadvantages since such dosing triggers undesired side
effects, and the bulk of flumazenil administered yields no
pharmacological response and results in unnecessary expense.
[0018] Moreover, the results obtained by Gerra et al. and by Nutt
et al. are not conclusive since in some cases, no significant
changes were observed in either the blood pressure or the heart
rate of patients after the administration of flumazenil, an
immediate worsening of the withdrawal symptoms was observed,
especially sweats and anxiety, and the tests were performed using a
very small non-representative patient sample.
[0019] In two articles by Sheryl S. Moy (Skipper Bowles Center for
Alcohol Studies, Department of Psychiatry and UNC Neuroscience
Center), investigators disclose the use of flumazenil to block
anxiety created by ethanol withdrawal in rats. According to Moy et
al. (2000), in rat models of the ethanol withdrawal syndrome,
flumazenil can reverse anxiogenic withdrawal effects such as
inhibition during a social interaction test (File et al. 1989,
1992) and reduced open arm exploration on an elevated plus maze
(Moy et al. 1997). Further in Moy et al. (2000) and Uzbay et al.
(1995) it was reported that flumazenil could prevent the agitation
and stereotyped behavior induced by withdrawal from long-term
ethanol exposure in rats. Doses, however, were provided for rat
models and cannot be readily translated to human dosage levels.
Moreover, the prior art teaches the use of flumazenil in a
conventional benzodiazepine treatment model, which requires the
substitution of ethanol usage with large quantities of
benzodiazepine to alleviate withdrawal symptoms.
[0020] However, all disclosed uses of flumazenil in the treatment
of alcohol withdrawal and addiction have relied on either the
single administration of large quantities of flumazenil or on-going
administrations of very low quantities of flumazenil over long
periods of time. Moreover, the disclosed administrative regimens
has not applied the use of flumazenil, or a class of compounds
represented by flumazenil, for treating psychostimulant substance
abuse at all. Furthermore, conventional treatments for alcohol
and/or psychostimulant dependency have had limited success and
often have undesirable side effects. New approaches are needed that
can improve treatment outcomes and reduce the risk of relapse.
Thus, an improved treatment methodology for treating alcohol and/or
psychostimulant substance abuse is desirable.
[0021] In addition, conventional treatments for controlling
withdrawal symptoms and cravings for alcohol and/or
psychostimulants have had limited success and often have
undesirable side effects. Thus, an improved treatment methodology
for controlling cravings and withdrawal symptoms caused by alcohol
and/or psychostimulant substance abuse would be desirable.
[0022] It would also be desirable to have an improved methodology
and protocol for treating alcohol and/or psychostimulant substance
abuse, which results in reduced patient dropout rates.
SUMMARY OF THE INVENTION
[0023] The present invention is directed towards various methods
and protocols for the treatment of alcohol and/or psychostimulant
substance abuse based on safe and effective administration of a
class of compounds that directly or indirectly selectively
modulates GABA.sub.A chloride channel activity, such as, but not
limited to flumazenil, and which requires a short period of time to
effectively eradicate symptoms of alcohol and/or psychostimulant
substance abuse. As defined herein, the class of compounds that
selectively modulates GABA.sub.A chloride channel activity
(referred to herein as Selective Chloride Channel Modulators) is
intended to cover the selective modulation of chloride channel
activity and does not encompass full agonists of the GABA.sub.A
receptor, such as fluoxetine benzodiazpenes. Additionally, as
defined herein, the term substance abuse is used to refer to the
various physical and psychological states that manifest an
individual's impaired control over alcohol and/or stimulant
substance use, continued alcohol and/or stimulant substance use
despite harm, addiction, compulsive alcohol and/or stimulant
substance use, cravings, psychological dependence, physical
dependence, tolerance, a maladaptive pattern of alcohol and/or
stimulant substance use, preoccupation with alcohol and/or
stimulant substance use, and/or the prevalence of withdrawal
symptoms upon cessation of use.
[0024] It is another object of the present invention to provide for
methods and protocols for the treatment of alcohol and/or
psychostimulant substance abuse that includes administration, to a
patient in need of said treatment, of a therapeutically effective
quantity of a compound that directly or indirectly selectively
modulates chloride channel activity, administered in multiple doses
at a predetermined rate, until said therapeutically effective
quantity to treat alcohol and/or psychostimulant substance abuse
has been reached.
[0025] It is another object of the present invention to provide for
methods and protocols that reduce cravings and withdrawal symptoms
from addiction to alcohol and/or psychostimulants that includes
administration, to a patient in need of said treatment, of a
therapeutically effective quantity of a compound that directly or
indirectly selectively modulates chloride channel activity,
administered in multiple doses at a predetermined rate, until said
therapeutically effective quantity administration reduces cravings
and withdrawal symptoms from addiction to alcohol and/or
psychostimulants.
[0026] It is another object of the present invention to provide a
methodology for controlling cravings, reducing withdrawal symptoms
and treating addiction to alcohol and/or psychostimulants. It is
yet another object of the present invention to administer a
compound that directly or indirectly selectively modulates chloride
channel activity, such as, but not limited to flumazenil, in a
therapeutically effective quantity so as to control cravings and
withdrawal symptoms. In addition, the methodology according to the
invention also results in improved cognitive function.
[0027] It is yet another object of the present invention to provide
a methodology and protocol for reducing patient dropout rates for
those patients undergoing treatment for alcohol and/or
psychostimulant addiction. The invention includes the
administration of a compound that directly or indirectly
selectively modulates chloride channel activity in a
therapeutically effective quantity resulting in higher patient
recovery rates compared to conventional treatments. This, in turn,
results in lower patient dropout rates.
[0028] Optionally, it is another object of the present invention to
provide for administration of therapeutically effective amounts of
flumazenil in multiple doses at a predetermined rate which results
in significantly lower patient dropout rates and fewer side effects
in the patient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] These and other features and advantages of the present
invention will be appreciated, as they become better understood by
reference to the following Detailed Description when considered in
connection with the accompanying drawings, wherein:
[0030] FIG. 1 is a flowchart depicting various pre-treatment,
co-treatment, and post-treatment phases of an exemplary methodology
for using pharmaceutical compositions from a class of compounds
that directly or indirectly selectively modulate GABA.sub.A
chloride channel activity to treat alcohol and/or psychostimulant
substance abuse;
[0031] FIG. 2 is a flowchart illustrating a first embodiment of an
exemplary methodology to treat alcohol substance abuse;
[0032] FIG. 3 is a flowchart illustrating a second embodiment of an
exemplary methodology to treat alcohol substance abuse;
[0033] FIG. 4 is a flowchart illustrating a third embodiment of an
exemplary methodology to treat alcohol substance abuse;
[0034] FIG. 5 is a flowchart illustrating a first embodiment of an
exemplary methodology to treat stimulant substance abuse; and
[0035] FIG. 6 is a flowchart illustrating a second embodiment of an
exemplary methodology to treat stimulant substance abuse.
DETAILED DESCRIPTION OF THE INVENTION
[0036] The present invention is directed towards methods and
protocols for the treatment of alcohol and/or psychostimulant
substance abuse based on safe and effective administration of a
class of compounds that directly or indirectly selectively
modulates chloride channel activity, such as, but not limited to
flumazenil, and which requires a short period of time to
effectively eradicate symptoms of alcohol and/or psychostimulant
substance abuse.
[0037] The present invention provides for a comprehensive treatment
approach for managing the recovery process for alcohol and/or
stimulant substance abuse. The methodology of the present invention
is also designed to reduce inpatient treatment time (2-3 days),
improve treatment completion rates, reduce cravings, and decrease
patient relapse rates versus current alcohol and/or stimulant abuse
treatment options.
[0038] 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 alcohol and/or
stimulant substance use, continued alcohol and/or stimulant
substance use despite harm, compulsive alcohol and/or stimulant
substance use, and/or cravings. The term is intended to include
psychological dependence, physical dependence, tolerance, a
maladaptive pattern of alcohol and/or stimulant substance use,
preoccupation with alcohol and/or stimulant substance use, and/or
the prevalence of withdrawal symptoms upon cessation of use.
[0039] 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.
[0040] In particular, the term drug is used to refer to a class of
compounds that directly or indirectly selectively modulates
chloride channel activity ("Selective Chloride Channel
Modulators"), e.g. chloride ion flow across the channel, with
respect to GABA.sub.A receptors in the brain. One of ordinary skill
in the art would appreciate that, as defined herein, the term
Selective Chloride Channel Modulators is intended to cover the
selective modulation of chloride channel activity and does not
encompass full agonists of the GABA.sub.A receptor, such as
benzodiazpenes.
[0041] In one embodiment, the Selective Chloride Channel Modulators
comprises a partial allosteric modulator that acts with high
affinity but low potency at GABA.sub.A receptor sites. The partial
allosteric modulators of the present invention are capable of
engaging a GABA.sub.A receptor site based upon a conformational
compatibility with the GABA.sub.A receptor site. In one embodiment,
the partial allosteric modulators of the present invention are
capable of displacing, modifying, or otherwise limiting the affects
of endogenous benzodiazepine inverse agonists by preventing their
engagement with a GABA.sub.A receptor site. In another embodiment,
the partial allosteric modulators of the present invention have a
mild inverse agonist affect on the GABA.sub.A receptor due to a
high affinity and low potency.
[0042] In another embodiment, the Selective Chloride Channel
Modulators comprises a partial allosteric modulator that acts to
reset GABA.sub.A receptivity and thereby increase receptivity and
chloride channel ion flow without requiring alcohol.
[0043] In another embodiment, the Selective Chloride Channel
Modulators comprise a composition that functions as a partial
agonist of the GABA.sub.A receptor by displacing, modifying or
otherwise limiting the affects of endogenous benzodiazepine inverse
agonists, such as diazepam binding inhibitor (DBI), and that
functions as an inverse agonist of the GABA.sub.A receptor if not
in the presence of an endogenous benzodiazepine inverse
agonist.
[0044] In another embodiment, Selective Chloride Channel Modulators
comprise a composition that functions as a partial agonist of the
GABA.sub.A receptor by displacing, modifying or otherwise limiting
the affects of benzodiazepine inverse agonists, such as diazepam
binding inhibitor (DBI), and that has substantially no affect on
the GABA.sub.A receptor in the absence of a benzodiazepine inverse
agonist.
[0045] In another embodiment, Selective Chloride Channel Modulators
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 in
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, Selective
Chloride Channel Modulators comprise flumazenil and carboxylic
acids, esters, acyl chlorides, acid anhydrides, amides, nitrites,
alkyls, alkanes, cycloalkanes, alkenes, alcohols, aldehydes,
ketones, benzenes, phenyls, and salts thereof.
[0046] 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.
[0047] It should be appreciated that the administration of a
Selective Chloride Channel Modulator may be achieved through any
appropriate route of administration, for example, orally, inhaled,
rectally, sublingually, bucally, transdermally, nasally, or
parenterally, for which it will be formulated using the appropriate
excipients for the form of administration. In one embodiment, the
Selective Chloride Channel Modulator is administered intravenously
(IV). In another embodiment, the Selective Chloride Channel
Modulator is administered using an infusion pump. In another
embodiment, the Selective Chloride Channel Modulator is
administered using a syringe pump that provides the continuous, or
physician-controlled, delivery of the drug. In another embodiment,
the Selective Chloride Channel Modulator is administered from
pre-filled syringes that automatically deliver a predetermined dose
over an infusion period.
[0048] 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 to determine which protocol steps should be
applied in accordance with the patient data. 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.
[0049] Reference will now be made in detail to specific embodiments
of the invention. While the invention will be described in
conjunction with specific embodiments, it is not intended to limit
the invention to one embodiment.
1. Introduction to an Exemplary Methodology
[0050] Referring to FIG. 1, the treatment methodology of the
present invention 100 is a system consisting of multiple components
administered on a pre-admittance, inpatient, outpatient, and
post-discharge basis for the treatment of alcohol dependence. The
methodology is designed to reduce cravings associated with and
following alcohol withdrawal, and to help the dependent patient
maintain abstinence and reduce harmful behavior during outpatient
and follow-up care. The methodology will largely be described with
reference to the alcohol dependence methodology in this section,
but is not limited to such methodology. A separate methodology may
be administered for psychostimulant, or combined alcohol and
psychostimulant, dependence. Additionally, separate methodologies
may be catered to outpatient vs. inpatient treatment settings.
[0051] As shown in FIG. 1, the treatment methodology 100 for
alcohol dependence has multiple phases and components that, in
combination, provide a comprehensive and integrated neurological,
physiological, and psychosocial approach for the alcohol-dependent
patient. Each component has been selected to address specific
effects of chronic alcohol consumption and the corresponding
symptoms of alcohol withdrawal, with the objective of restoring a
balance in neurological circuits. The methodology does not address
the specific physical injury, such as liver damage, that is often
associated with alcohol 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 drugs used for this treatment with
those used for the dependency treatment.
[0052] 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. It is also preferred that the patient meet at
least a portion of the DSM IV criteria for substance dependence on
stimulants or alcohol. The DSM IV criteria is known to those of
ordinary skill in the art and can be described as a maladaptive
pattern of alcohol and/or stimulant 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: [0053] (1) Tolerance, as defined by either of the
following: [0054] a. A need for markedly increased amounts of the
substance to achieve intoxication or desired effect. [0055] b.
Markedly diminished effect with continued use of the same amount of
the substance. [0056] (2) Withdrawal, as manifested by either of
the following: [0057] a. The characteristic withdrawal syndrome for
the substance. [0058] b. The same (or a closely related) substance
is taken to relieve or avoid withdrawal symptoms. [0059] (3) The
substance is often taken in larger amounts or over a longer period
than was intended (loss of control). [0060] (4) There is a
persistent desire or unsuccessful efforts to cut down or control
substance use (loss of control). [0061] (5) A great deal of time is
spent in activities necessary to obtain the substance, use the
substance, or recover from its effects (preoccupation). [0062] (6)
Important social, occupational, or recreational activities are
given up or reduced because of substance use (continuation despite
adverse consequences). [0063] (7) 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).
[0064] 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 alcohol or stimulant 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).
[0065] Similarly, it is preferred not to treat a patient on an
inpatient basis for alcohol 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 is currently taking tricyclic anti-depressants or
benzodiazepines.
[0066] Patients admitted for the methodology for alcohol (and/or
psychostimulant) dependence are initially treated with medications
for 2 days of neurostabilization (which may include detoxification)
along with nutritional supplements to ensure their supply does not
limit the body's ability to restore an appropriate metabolic
balance (such as physiological amino acid and protein turnover).
Subsequent patient management includes maintenance pharmacotherapy
with protocol components, combined with optional (but recommended)
psychosocial and/or behavioral therapies, which are described in
detail below. The combined effects of pharmacotherapy and
psychosocial support are designed to minimize withdrawal symptoms,
help prevent relapse, and reduce cravings for the dependent
substance. Ongoing psychosocial and/or behavioral treatment is
tailored to optimize the probability of long-term recovery.
2. Exemplary Methodology Components (100)
[0067] Referring back to FIG. 1, the exemplary treatment
methodology 100 of the present invention comprises pre-treatment,
co-treatment, and post-treatment phases further comprising various
components of an exemplary methodology for using pharmaceutical
compositions from a class of compounds that directly or indirectly
selectively modulate GABA.sub.A chloride channel activity to treat
addiction to alcohol and/or psychostimulants. As described herein,
reference will be made to specific components of the individual
phases of the treatment methodology 100. It should be noted,
however, that the individual components comprising each phase of
the methodology--pre-treatment, co-treatment, and
post-treatment--may be performed in different orders and should be
determined on a per-patient basis. Thus, any reference to
administering the individual components of the phases of
methodology 100 in a particular order is exemplary and it should be
understood to one of ordinary skill in the art that the
administration of methodology 100 may vary depending on the
assessed needs of the patient.
[0068] a. Pre-Treatment (110)
[0069] Referring back to FIG. 1, prior to admittance into the
treatment program of the present invention, each patient should
undergo a pre-treatment analysis 110. The pre-treatment analysis
110 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 110 may be administered to
prepare a patient for admittance into the treatment methodology 100
of the present invention. The pre-treatment phase typically
includes, but is not limited to a complete physical examination
110a, a complete psychological examination 110b, a CIWA Assessment
110c, and a determination of required medications 110d. The
components of the pre-treatment phase of the methodology 100 of the
present invention are described in greater detail below.
[0070] i. Complete Physical Examination (110a)
[0071] Before starting the treatment, it is preferred that patient
undergo a complete medical examination. The patient is preferably
monitored to obtain a complete blood count, a biochemical profile
[for example, creatinine, glucose, blood urea nitrogen (BUN),
cholesterol (HDL and LDL), triglycerides, alkaline phosphatase, LDH
(lactic dehydrogenase) and total proteins], hepatic function tests
[GOT, GPT, GGT, bilirubin), electrocardiogram and, if need be,
pregnancy test and x-ray examination. Exclusion criteria is 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
flumazenil or another Selective Chloride Channel Modulator if being
used.
[0072] ii. Complete Psychological Examination (110b)
[0073] Before starting the treatment, it is also preferred that
patient undergo a complete psychological medical examination.
[0074] iii. Withdrawal Symptomatology (110c)
[0075] Before and after the administration of the Selective
Chloride Channel Modulator, the withdrawal symptomatology should be
measured using the CIWA-A evaluation (Adinoff et al., Medical
Toxicology 3:172-196 (1988)), as well as heart rate and blood
pressure.
[0076] iv. Determination of Required Medications (110d)
[0077] The physician in charge should make a determination, prior
to treatment, if a patient diagnosed with any symptom or disorder,
other than alcohol or psychostimulant addiction, should receive
medication for this disorder. For example, a patient diagnosed with
arterial hypertension should be prescribed with the appropriate
medication or continue with any existing medication.
[0078] b. During Treatment (120)
[0079] Referring back to FIG. 1, if a patient is admitted into the
treatment program of the present invention, the patient will then
begin the during treatment phase 120 of the treatment methodology
100 of the present invention. During treatment, a patient will
preferably be administered pharmaceutical compositions 120a, adhere
to a prescribed diet 120b, maintain an exercise regimen 120c, and
attend inpatient therapy sessions 120d. The exemplary components of
the during treatment phase of the treatment methodology 100 are
described in greater detail below, but are not limited to such
options.
[0080] i. Pharmaceutical Compositions (120a)
[0081] Various pharmaceutical compounds may be administered during
treatment with a benzodiazepine antagonist as with the methodology
of the present invention. These are listed below.
[0082] 1. Selective Chloride Channel Modulator
[0083] In one embodiment, the Selective Chloride Channel Modulator
flumazenil is used because it functions to effectively regulate
GABA.sub.A receptor activity and minimize the severity of
conventional withdrawal symptoms. The use of flumazenil may
normalize shifts in neuronal GABA.sub.A activity and subsequent
dopamine malfunctions resulting from chronic exposure to ethanol.
Specifically, when used in accordance with the novel invention
presented herein, flumazenil is anxiolytic, thereby ameliorating an
important withdrawal symptom, and decreases cravings.
[0084] 2. Gabapentin
[0085] a. Use of Gabapentin
[0086] 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. Gabapentin
compliments flumazenil in helping normalize GABA and glutamate
transmission, thus enhancing GABA tone.
[0087] Gabapentin was originally designed as a structural analog of
GABA. It likely operates as a calcium N-channel blocker. Gabapentin
also exhibits post-synaptic effects modulating NMDA-mediated
transmission by 1) reducing NMDA/Glutamatergic tone and 2)
indirectly helping compensate for reduced GABAergic tone due to
upregulated NMDA activity in the withdrawn state. Gabapentin
provides for an improved quality and quantity of sleep and an
improved anxiety state. As a result of its above-mentioned
qualities, gabapentin decreases withdrawal symptoms.
[0088] b. Key Pharmacologic Safety Considerations for the Use of
Gabapentin
[0089] 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.
[0090] 3. Hydroxyzine HCl
[0091] Hydroxyzine, an H1 histamine receptor antagonist, is
indicated for treatment of generalized anxiety disorder 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 that, for some patients, is
significantly associated with subsequent alcoholic relapse.
[0092] 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
might be synergistically enhanced with the administration of
hydroxyzine. Exemplary drugs include pharmacological compositions
having the trade names Atarax and Vistaril.
[0093] 4. Vitamin B
[0094] a. Fortified Vitamin B Complex
[0095] Chronic alcohol consumption depletes the levels of several
vitamins, particularly the B vitamins (also known as the stress
vitamins). These vitamins are required by the body to convert food
into energy, maintain the integrity of tissues such as the skin and
liver, and combat physical or emotional stress. Administration of
vitamin B complex as part of the management of the
alcohol-dependent patient may help to ameliorate the risk of
Wernicke-Korsakoff syndrome and alcoholism-induced cognitive
deficit. The present invention preferably includes the provision of
a nutritional supplement of fortified vitamin B-complex
(thiamine--B1, riboflavin--B2, niacin--B3, pyridoxine--B6, folic
acid--B9, cyanocobalamin--B12, pantothenic acid, and biotin) to
patients daily during stabilization with the methodology and
post-discharge for as long as medically beneficial.
[0096] b. IV Vitamin B Supplement
[0097] Alcohol abusers tend to have poor nutritional status,
exacerbated by poor diet, gastritis, duodenitis, frequent vomiting,
physical illness, and weight loss. Thus, there is a need for
parenteral vitamins. Thiamine absorption from oral treatment tends
to vary; alcohol in the gut interferes with absorption. Thus, there
is a potentially large thiamine deficiency in alcohol dependence.
Oral dosing is unlikely to meet maintenance requirements. Thiamine
decreases sodium transport in alcohol dependence. In addition, it
is a catalyzer of key metabolic actions of GABA.
[0098] 5. Protein Supplement Drink
[0099] Chronic alcohol consumption increases the body's overall
rate of metabolism, and alcohol-dependent subjects often have
reduced skeletal muscle synthesis and skeletal muscle mass. Alcohol
reduces protein synthesis in a range of tissues, including but not
limited to skeletal muscle. This can lead to a net loss of protein
from and impaired function in important organs and tissues such as
the heart, liver and kidneys. To counteract these effects, a
protein supplement drink is preferably provided daily to the
patient during inpatient stabilization with the methodology. In
addition, the increased levels of serum amino acids (such tyrosine
and tryptophan) provide the substrate to help re-establish alcohol-
and withdrawal-induced alterations in levels of neurotransmitters
such as dopamine and serotonin.
[0100] 6. Glutamine
[0101] Glutamine is the most abundant amino acid in the body and is
an essential nutrient for actively replicating cells, such as those
of the immune system. Glutamine is also a precursor for both
glutamate and GABA. In skeletal muscle glutamine is the most
abundant amino acid and its depletion is associated with loss of
muscle mass, a process that can be reversed by glutamine
supplementation.
[0102] Alcohol has direct effects on the innate immune system.
Alcohol predisposes dependent patients to infections and sepsis by
blunting the initial response to pathogens. Withdrawing alcohol
does not immediately reverse this effect. Glutamine, given as a
nutritional supplement, is an important part of the methodology.
Glutamine supplementation provides an immediate supply of fuel to
the immune system, possibly enhancing immune function. Glutamine
supplementation helps to restore the plasma and muscle levels of
glutamine, which may help reverse the loss of protein typically
seen in alcohol-dependent patients.
[0103] ii. Diet (120b)
[0104] Depending upon the results of the initial examination, a
universal or patient-specific diet plan may optionally be
administered in conjunction with the methodology.
[0105] iii. Exercise (120c)
[0106] Depending upon the results of the initial examination, a
universal or patient-specific exercise programs may optionally be
administered in conjunction with the methodology.
[0107] iv. Inpatient Therapy (120d)
[0108] A structured program for cognitive behavior therapy is
preferably implemented in the methodology. Individual psychotherapy
is focused on a plurality of interventions, such as cognitive
restructuring, work therapy, prevention of relapse, and stress
reduction aimed at rehabilitating the social, family, work,
personal and leisure life of the patient.
[0109] c. Post-Treatment (130)
[0110] Referring back to FIG. 1, after a patient successfully
completes the during treatment phase of the methodology of the
present invention 100, each patient will be prescribed a
post-treatment regimen 130 to follow, which includes, but is not
limited to, the administration of pharmaceutical compositions 130a,
a CIWA assessment 130b, outpatient therapy 130c, a diet program
130d, and an exercise regimen 130e. The components of the
post-treatment phase of the methodology of the present invention
100 are described in greater detail below.
[0111] i. Pharmaceutical Compositions (130a)
[0112] Before discharge from the hospital, one or more of the
following compositions or drugs are prescribed. 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.
[0113] 1. Vitamin B
[0114] a. Fortified Vitamin B Complex
[0115] Chronic alcohol consumption depletes the levels of several
vitamins, particularly the B vitamins (also known as the stress
vitamins). These vitamins are required by the body to convert food
into energy, maintain the integrity of tissues such as the skin and
liver, and combat physical or emotional stress. Administration of
vitamin B complex as part of the management of the
alcohol-dependent patient may help to ameliorate the risk of
Wernicke-Korsakoff syndrome and alcoholism-induced cognitive
deficit. The present invention preferably includes the provision of
a nutritional supplement of fortified vitamin B-complex
(thiamine--B1, riboflavin--B2, niacin--B3, pyridoxine--B6, folic
acid--B9, cyanocobalamin--B12, pantothenic acid, and biotin) to
patients daily during stabilization with the methodology and
post-discharge for as long as medically beneficial.
[0116] b. IV Vitamin B Supplement
[0117] Alcohol abusers tend to have poor nutritional status,
exacerbated by poor diet, gastritis, duodenitis, frequent vomiting,
physical illness, and weight loss. Thus, there is a need for
parenteral vitamins. Thiamine absorption from oral treatment tends
to vary; alcohol in the gut interferes with absorption. Thus, there
is a potentially large thiamine deficiency in alcohol dependence.
Oral dosing is unlikely to meet maintenance requirements. Thiamine
decreases sodium transport in alcohol dependence. In addition, it
is a catalyzer of key metabolic actions of GABA.
[0118] 2. Piracetam
[0119] Piracetam is a CNS (central nervous system) stimulant with
no known toxicity or addictive properties. Piracetam is used as a
supplement to improve cognitive functioning in patients suffering
from alcohol withdrawal. Piracetam is preferably prescribed in the
following dosages for this methodology: 3 grams every morning for
one week, followed by 800 mg twice daily for one month.
[0120] 3. Fluoxetine
[0121] Fluoxetine hydrochloride is an antidepressant for oral
administration; it is chemically unrelated to tricyclic,
tetracyclic, or other available antidepressant agents. It is
designated
(.+-.)-N-methyl-3-phenyl-3-[(a,a,a-trifluoro-p-tolyl)-oxy]propylamine
hydrochloride. As part of this methodology, it is used to treat
symptoms of anxiety and depression associated with alcohol and/or
psychostimulant dependence. The suggested dosage is 10 to 20 mg of
fluoxetine every morning for two months, but may be increased or
decreased on a per patient basis.
[0122] 4. Clomethiazole
[0123] The suggested dosage of clomethiazole (or chlormethiazole)
is about 200 mg, and more specifically about 192 mg, in both the
morning and evening for 1 week and eliminated during the second
week.
[0124] 5. Disulfuram
[0125] Disulfuram, an inhibitor of aldehyde dehydrogenase in the
liver, increases blood acetaldehyde concentrations and subsequently
induces symptoms of acetaldehyde syndrome, including (but not
limited to) vomiting, weakness, confusion, vasodilation in the
head, and throbbing headache. This agent is used in the methodology
for six months post-discharge to induce averse associations with
alcohol consumption, thus helping to sustain the recovery process.
In one embodiment, the dosage is 250 mg every morning as long as
medically beneficial.
[0126] 6. Gabapentin
[0127] a. Use of Gabapentin
[0128] Gabapentin is an anxiolytic and anticonvulsant medication
typically prescribed to patients suffering from epilepsy
(effectively lowers brain glutamate concentrations) and can be used
in the treatment of anxiety disorders such as social anxiety
disorder and obsessive-compulsive disorder. Gabapentin compliments
flumazenil in helping normalize GABA and glutamate transmission,
thus enhancing GABA tone.
[0129] Gabapentin was originally designed as a structural analog of
GABA. It likely operates as a calcium N-channel blocker. Gabapentin
also exhibits post-synaptic effects modulating NMDA-mediated
transmission by 1) reducing NMDA/Glutamatergic tone and 2)
indirectly helping compensate for reduced GABAergic tone due to
upregulated NMDA activity in the withdrawn state. Gabapentin can
provide for an improved quality and quantity of sleep and an
improved anxiety state. As a result of its above-mentioned
qualities, gabapentin decreases withdrawal symptoms.
[0130] b. Key Pharmacologic Safety Considerations for the Use of
Gabapentin
[0131] 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.
[0132] 7. Other Drugs
[0133] Optionally, after the final Selective Chloride Channel
Modulator administration, non-stimulant drugs can be administered.
Specifically, after the final flumazenil treatment,
non-benzodiazepine, barbiturate drugs or drugs with a direct
chloride channel effect can be administered.
[0134] ii. Withdrawal Symptomatology (130b)
[0135] Before and after the administration of flumazenil, the
withdrawal symptomatology should be measured using the CIWA-A
evaluation (Adinoff et al., Medical Toxicology 3:172-196 (1988)),
as well as heart rate and blood pressure.
[0136] iii. Outpatient Therapy (130c)
[0137] Psychotherapy/behavioral therapy and counseling may be
critical for the success of alcohol and/or stimulant
substance-dependency treatment when adopting a pharmacological
approach. 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. The methodology is not considered a replacement for
behavioral therapy and is not a cure. Due to the complexity of
alcohol and/or stimulant substance dependence, patients benefit
most from a combination of pharmacologic and behavioral
interventions.
[0138] As part of the treatment program, patients are preferably
instructed to attend the outpatient treatment center for 9 months
with decreasing frequency [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].
[0139] Likewise, a semi-structured follow-up of cognitive behavior
therapy is preferably 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.
[0140] iv. Diet (130d)
[0141] Depending upon the results of the initial examination, a
universal or patient-specific diet plan may optionally be
administered in conjunction with the methodology.
[0142] v. Exercise (130e)
[0143] Depending upon the results of the initial examination, a
universal or patient-specific exercise programs may optionally be
administered in conjunction with the methodology.
3. Methodology Embodiments
[0144] Reference will now be made in detail to specific embodiments
and examples of the methods and protocols of the present invention.
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.
[0145] In one specific embodiment, the present invention relates to
the use of a therapeutically effective quantity of a drug, namely a
Selective Chloride Channel Modulator, such as, but not limited to,
flumazenil, in a methodology for treatment of alcohol and/or
psychostimulant dependency. More specifically, the invention
relates to the use of 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 cravings for alcohol. The
methodology of the present invention also provides for the
administration of flumazenil without significant side effects.
[0146] Thus, in one embodiment, a method is provided for the
treatment of alcohol and/or psychostimulant abuse that includes the
administration to a patient in need of said treatment of a
therapeutically effective quantity of flumazenil between 0.5 mg/day
and 10 mg/day, specifically between 1.0 and 3.0 mg/day, and even
more specifically between 1.5 and 2.5 mg/day, broken down into
multiple doses of flumazenil between 0.2 and 0.3 mg and intended
for administration during predetermined time periods or intervals,
until said therapeutically effective quantity of flumazenil to
treat alcohol and/or psychostimulant dependency 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.
[0147] 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 0.5 mg/day and 10.0 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 10.0 mg/day. The
present invention therefore provides for the delivery of multiple,
sequential doses, delivered at substantially consistent time
intervals.
[0148] Conventional uses of flumazenil comprise either singular
doses or much larger doses over shorter periods of time and are
directed toward addressing anesthesia, conscious sedation, or
benzodiazepine overdose. Further, Romazicon, a brand name for
flumazenil as marketed and sold 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, relative to
the present invention, this dosing regimen either fails to maintain
a presence of flumazenil in the bloodstream for extended periods of
time (over a 12 to 24 hour period) or presents excessive amounts of
flumazenil at any given time. Moreover, such conventional uses of
flumazenil are not directed toward the treatment of alcohol or
stimulant dependence.
[0149] In the treatment methodology of the present invention,
flumazenil can be safely administered to patients in small
quantities, applied in multiple doses during predetermined time
periods/intervals, until a therapeutically effective quantity of
flumazenil to treat alcohol and/or psychostimulant dependency has
been reached. Thus, it is possible to administer flumazenil in
smaller 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).
[0150] In addition, the administration method of the present
invention provides a better use of flumazenil to treat the symptoms
of alcohol and/or psychostimulant 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 alcohol and/or psychostimulant dependency in a very
short period of time.
[0151] The method for the treatment of alcohol dependency provided
by this invention is applicable to any patient who, when the
treatment is to begin, has no acute or uncompensated illness, or is
not taking medication contraindicated with the Selective Chloride
Channel Modulator, such as flumazenil. In general, the method of
treatment of alcohol and/or psychostimulant dependency provided by
this invention begins with a complete medical and psychological
examination, as described in detail above. Before and after
administration of flumazenil, the symptoms of alcohol withdrawal,
heart rate, and blood pressure are evaluated. If the patient
presents with mild to moderate anxiety, it is possible to
administer an appropriate therapeutic agent, for example,
clomethiazole, before administration of flumazenil, as described
above.
[0152] Once inpatient treatment has concluded, as part of the
therapeutic program, the patient must continue pharmacological
treatment and continue sessions with his therapist to evaluate his
progress. The treatment is supplemented by a semi-structured
therapy regime to monitor the cognitive behavior of the patient.
According to another embodiment, alcohol dependent patients may be
treated on an outpatient basis for 48 hours.
[0153] While references above have been made to inpatient
treatment, it should be appreciated that an outpatient treatment
regimen is possible, provided that the patient criteria is met, as
previously described. It should further be appreciated that in both
outpatient and inpatient treatment methodologies, Clinical
Inventory Withdrawal Assessments (CIWA-Ar) should be utilized for
assessment of withdrawal.
[0154] For example, for inpatient alcohol dependency treatment, the
following CIWA evaluation guide can be used:
TABLE-US-00001 TABLE 1 Inpatient Alcohol CIWA-Ar Evaluation Guide
Pre-admission CIWA-Ar Transfer to appropriate medical Screening
facility for detoxification if score is .gtoreq.15, and/or if acute
medical or psychiatric problems are present. Day 1 (a.m. of CIWA-Ar
Transfer to appropriate medical potential facility for
detoxification if score admission) is .gtoreq.15, and/or if acute
medical or psychiatric problems are present. Day 1 Pre- CIWA-Ar
Track CIWA-Ar scores to determine infusion direction and potential
acceleration of scores. Day 1 Post- CIWA-Ar Track CIWA-Ar scores to
determine infusion direction and potential acceleration of scores.
Day 1 9pm.sup.1. CIWA-Ar Day 3 required if CIWA .gtoreq.10 Day 2
Pre- CIWA-Ar Day 3 required if CIWA .gtoreq.10 infusion.sup.1. Day
2 Post- CIWA-Ar Day 3 required if CIWA >6. Also can
infusion.sup.1. serve as discharge evaluation. .sup.1A patient
meeting any one of these scores requires a 3.sup.rd treatment.
[0155] For outpatient alcohol dependency treatment, the following
CIWA evaluation guide can be used:
TABLE-US-00002 TABLE 2 Outpatient Alcohol CIWA-Ar Evaluation Guide
Screening CIWA-Ar Recommend in-patient treatment if score is
.gtoreq.6 but not greater than 15. Transfer to appropriate medical
facility for detoxification if score is .gtoreq.15, and/or if acute
medical or psychiatric problems are present. Day 1 CIWA-Ar Transfer
to appropriate medical (a.m. of facility for detoxification if
score potential is .gtoreq.15, and/or if acute medical or
admission) psychiatric problems are present. Day 1 Post- CIWA-Ar
Daily discharge criteria requires a infusion CIWA-Ar score of less
than 6. Day 2 Post- CIWA-Ar Daily discharge criteria requires a
infusion CIWA-Ar score of less than 6.
[0156] Now referring to FIG. 2, in a first exemplary methodology
200 for treating alcohol withdrawal, a patient undergoes the
aforementioned pre-treatment regimen 210, which may include a
complete physical examination 210a, a complete psychological
examination 210b, a CIWA assessment 210c, and determination of
required medications 210d.
[0157] On day 1 220a of treatment phase 220, the patient receives
pharmaceutical compositions 221a, including flumazenil via an
intravenous infusion, ultimately delivering a total amount of 2 mg
per dosing interval. The patient further receives 50 mg of
hydroxyzine twice daily plus or minus 25 mg as may be required. The
patient further receives fortified vitamin B complex daily and a
protein supplement drink daily in the morning.
[0158] On day 2 220b of treatment, the patient receives
pharmaceutical compositions 221b, including flumazenil via an
intravenous infusion, ultimately delivering a total amount of 2 mg
per dosing interval. The patient further receives 50 mg of
hydroxyzine twice daily plus or minus 25 mg as may be required. The
patient further receives fortified vitamin B complex daily and a
protein supplement drink daily in the morning.
[0159] Also during treatment, the patient may be prescribed a diet
plan 222, exercise regiment 223, and inpatient therapy 224.
[0160] In the post-treatment phase 230 after discharge, for one
week, the patient receives various pharmaceutical compositions
230a, including 50 mg of hydroxyzine at bedtime or for sleep and,
for a subsequent week, the patient receives 25 mg of hydroxzine at
bedtime or for sleep. For two weeks, the patient also receives
glutamine titrated up to 1500 mg per day and fortified vitamin B
complex daily. The patient may also receive additional
post-treatment options, including a CIWA Assessment 230b,
outpatient therapy 230c, and a diet and exercise regimen 230d,
230e.
[0161] Referring now to FIG. 3, in a second exemplary methodology
for treating alcohol withdrawal 300, a patient undergoes the
aforementioned pre-treatment regimen 310, which may include a
complete physical examination 310a, a complete psychological
examination 310b, a CIWA assessment 310c, and a determination of
required medications 310d.
[0162] On day 1 330a of treatment phase 330, the patient receives
various pharmaceutical compositions 321a, including flumazenil via
an intravenous infusion, ultimately delivering a total amount of 2
mg per dosing interval. The patient further receives 50 mg of
hydroxyzine during the day and 50 mg of hydroxyzine at bedtime or
in the evening. The patient further receives IV Vitamin B Complex
and oral Gabapentin at a dose of 300 mg.
[0163] On day 2 330b of treatment phase 330, the patient receives
various pharmaceutical compositions 321b, including flumazenil via
an intravenous infusion, ultimately delivering a total amount of 2
mg per dosing interval. The patient further receives 50 mg of
hydroxyzine during the day and 50 mg of hydroxyzine at bed or in
the evening. The patient further receives IV Vitamin B Complex and
oral Gabapentin at a dose of 300 mg in the afternoon and evening or
at bedtime.
[0164] In addition, during treatment phase 320, a patient may be
prescribed a diet plan 322, an exercise regimen 323, and inpatient
therapy 324.
[0165] After discharge, for days one and two of post-treatment
phase 330, the patient receives pharmaceutical compositions 330a,
including 50 mg of hydroxyzine at bedtime or in the evening. For 30
days, the patient receives Gabapentin at a dose of 900 mg in the
afternoon and evening or at bedtime then titrating down to 0. For
one week, the patient also receives vitamin B 100 daily. The
patient may also optionally receive a CIWA assessment 330b,
outpatient therapy 330c, a diet plan 330d, and an exercise regiment
330e.
[0166] Referring now to FIG. 4, in a third exemplary methodology
for treating alcohol withdrawal 400, a patient undergoes the
aforementioned pre-treatment regimen 410, which may include a
complete physical examination 410a, a complete psychological
examination 410b, a CIWA assessment 410c, and a determination of
required medications 410d.
[0167] During treatment phase 420, the patient undergoes a
pre-treatment procedure 421 that includes a CIWA assessment and the
administration of hydroxyzine at a dose of 50 mg. On day one 422a
of treatment phase 420, a first infusion 423a is administered to
the patient. The first infusion includes vitamin B1, vitamin B6,
vitamin B12, and vitamin B complex and 2 mg of flumazenil over a
period of 2 hours. After the first infusion, the patient undergoes
a post-treatment procedure 424, typically in the late afternoon to
evening that includes a CIWA assessment, the administration of
Gabapentin at a dose of 300 mg, and the administration of
hydroxyzine at a dose of 50 mg in the evening or bedtime.
[0168] On day two 422b of treatment phase 420, a patient undergoes
a pre-treatment procedure 421 that includes a CIWA assessment and
the administration of hydroxyzine at a dose of 50 mg. A second
infusion 423b is then administered to the patient. The second
infusion includes vitamin B1, vitamin B6, vitamin B12, and vitamin
B complex and 2 mg of flumazenil over a period of 2 hours. After
the second infusion, the patient undergoes a post-treatment
procedure 424, typically in the late afternoon to evening that
includes a CIWA assessment, the administration of Gabapentin at a
dose of 300 mg, and the administration of hydroxyzine at a dose of
50 mg in the evening or bedtime.
[0169] During treatment phase 420 may also optionally include a
diet plan 425, an exercise regimen 426, and inpatient therapy
427.
[0170] After discharge, the patient is monitored based on the CIWA
assessment 430b and the patient's medical condition. Optionally,
prior to discharge, the patient undergoes a third day 422c of
treatment 420 that is similar to day 2 422b, if warranted by the
patient's medical condition and/or CIWA assessment.
[0171] At discharge, in post-treatment phase 430, the patient is
given pharmaceutical compositions 430a, which include 50 mg of
hydroxyzine on days 1 and 2 at bedtime. The patient is also given
gabapentin in the following amounts: 300 mg on day 1; 600 mg on day
2; and on days 3-30, 900 mg titrated down to zero. The patient is
also given an Oral Vitamin B 100 complex daily for one week.
Optionally, the patient may be prescribed outpatient therapy 430c,
a diet plan 430d, and an exercise regimen 430e.
[0172] Referring now to FIG. 5, in a first exemplary methodology
for treating stimulant withdrawal 500, a patient undergoes the
aforementioned pre-treatment regimen 510. Pre-treatment regimen 510
may include a complete physical examination 510a, a complete
psychological examination 510b, a CIWA assessment 510c, and a
determination of required medications 510d.
[0173] On day 1 520a, day 2 520b and day 3 520c of treatment phase
520, the patient receives pharmaceutical compositions 521,
including flumazenil via an intravenous infusion, ultimately
delivering a total amount of 2 mg per dosing interval. The patient
further receives 50 mg of hydroxyzine twice daily plus or minus 25
mg as may be required. The patient further receives fortified
vitamin B complex daily and a protein supplement drink daily in the
morning.
[0174] This treatment regimen 520, preferably day 1 520a and day 2
520b only, is repeated after three weeks 522. During both phases of
the treatment phase 520, the patient may be prescribed a diet plan
523, an exercise regimen 524, and inpatient therapy 525.
[0175] In post-treatment phase 530, after discharge, the patient
receives pharmaceutical compositions 530a, which include 50 mg of
hydroxyzine at bedtime or for sleep for one week and, for a
subsequent week, 25 mg of hydroxyzine at bedtime or for sleep. For
two weeks, the patient also receives glutamine titrated up to 1500
mg per day and fortified vitamin B complex daily. The patient
further receives Gabapentin titrated up to 1200 mg per day for six
months. This regimen is interrupted for a second round of
treatments 522, as described above, after three weeks have elapsed
from the first round of treatments and restarted thereafter.
[0176] Now referring to FIG. 6, in a second exemplary methodology
for treating stimulant withdrawal 600, a patient undergoes the
aforementioned pre-treatment regimen 610. Pre-treatment regimen 610
may include a complete physical examination 610a, a complete
psychological examination 610b, a CIWA assessment 610c, and a
determination of required medications 610d.
[0177] On day 1 620a, day 2 620b and day 3 620c of treatment phase
620, the patient receives pharmaceutical compositions 621,
including flumazenil via an intravenous infusion, ultimately
delivering a total amount of 2 mg per dosing interval. The patient
further receives 50 mg of hydroxyzine. The patient further receives
fortified vitamin B complex daily and Gabapentin at a dose of 300
mg.
[0178] This treatment regimen 620, preferably day 1 620a and day 2
620b only, is repeated after three weeks 622. During both phases of
the treatment phase 620, the patient may be prescribed a diet plan
623, an exercise regimen 624, and inpatient therapy 625.
[0179] In post-treatment phase 630, after discharge, the patient
receives pharmaceutical compositions 630a, which include gabapentin
titrated up to 400 mg per day for 30 days, decreasing to 0. The
patient also receives fortified vitamin B 100 complex daily and a
plurality of amino acid supplements. This regimen is interrupted
for a second round of treatments, as described above, after three
weeks have elapsed from the first round of treatments and restarted
thereafter. During post-treatment 630, the patient may also undergo
CIWA assessment 630b as needed, outpatient therapy 630c, a diet
plan 630d, and an exercise regimen 630e.
[0180] In another exemplary methodology, a patient is treated on an
inpatient basis for alcohol dependence. Preferably, in this
treatment methodology, the interval between treatment episodes,
implemented in a series, should be no less than 12 hours and no
greater the 24 hours. Depending on a patient's progress with the
treatments, he or she may require an additional treatment requiring
that would take place on day three of his/her inpatient stay, as
described above in an exemplary CIWA-Ar Evaluation Guide.
[0181] On day one, the patient is administered 50 mg of hydroxyzine
HCL 50 p.o., unless otherwise contraindicated. After at least
one-hour, the Selective Chloride Channel Modulator, such as
flumazenil, is administered. Prior to Selective Chloride Channel
Modulator infusion, two infusion bags are prepared. The first
infusion bag comprises 500 cc 1/2 normal saline (NS) to which
thiamine, pyridoxine and other vitamin components are added and the
second infusion bag comprises 500 cc 1/2 NS for clearing the line
and for subsequent Selective Chloride Channel Modulator
administration. 100 mg of thiamine, 25 mg of pyridoxine, and 5 cc
of MVI is preferably added to the first infusion bag. The first
infusion bag is administered to the patient at 125 cc/hr (NTE 150
cc/hour) by placing the IV in the antecubital fossa. The IV line
should further include the use of a stopcock for clearing of the
line and subsequent administration of the Selective Chloride
Channel Modulator. Using the stopcock, the line should be washed
out with the 1/2 NS until no further color is seen in the line
going to the patient.
[0182] Once the line is washed, the Selective Chloride Channel
Modulator administration can be initiated. Where the Selective
Chloride Channel Modulator is flumazenil, a total dose of 2 mg is
given at each treatment episode. The medication should be given by
IV bolus as follows: a) 0.1 mg every 3 minutes for two doses, b)
0.2 mg every 3 minutes for two doses; and c) 0.3 mg every 2 minutes
until the total dose of 2 mg has been given. If, when increasing
dose or decreasing time between doses, discomfort of any kind is
observed or reported, the drug administration should be returned to
the pre-discomfort level or even returned to initial levels. In one
embodiment, the total dose of flumazenil administration is 4 mg for
alcohol dependence (two treatment episodes) and 6 mg for patients
requiring an additional treatment (e.g. on inpatient day # 3).
Parameters of flumazenil administration could be modified in some
cases. Quantities can be higher than the 2 mg dose or can be higher
than 0.3 mg per administration. Additionally, time periods between
administrations can be increased or decreased slightly. Once the
flumazenil administration is complete, the vitamin infusion can be
reinitiated once the line is cleared with 1/2 NS. The patient
should be monitored for 3 hours post flumazenil administration
during which time repeat CIWA-Ar assessments should be
performed.
[0183] Provided in Tables 3 and 4 below are further details on this
specific methodology example.
TABLE-US-00003 TABLE 3 Alcohol Dependence Treatment Methodology
During 2 Day In-Patient Stay Day 1 Day 1 Day 2 Day 2 Post-discharge
Time (Admission Day) Time (Discharge) medications 30 minutes
Negative Urine 1 hour Hydroxyzine HCL 50 mg Hydroxyzine HCL: 50 mg
po hs toxicology. po for one Week Pre-treatment Medical Continue
Observation Gabapentin: Begin day Assessment & Monitoring for
AWS following discharge 900 mg po MVI/12, Thiamine, hs for 30 days
then titrate Pyridoxine IV down to 0 days 31-37 ((600 mg 150 cc,
NTE 150 cc/hr. for 3 days, 300 mg for 3 days) Fortified Vitamin B
Complex: 100 mg po for one Week 1 hour Hydroxyzine HCL 50 mg 30
mins. Flumazenil 2 mg IVP po per administration MVI/12, Thiamine,
schedule Pyridoxine IV NTE 150 cc/hr. 30 mins. Flumazenil 2 mg IVP
3 hours MVI/12, Thiamine, per administration Pyridoxine IV schedule
NTE 150 cc/hr. (Total vitamin infusion of 250 cc-500 cc) Continue
Observation & Monitoring Gabapentin 600 mg po 3 hours MVI/12,
Thiamine, May discharge if Pyridoxine IV CIWA-AR <6 NTE 150
cc/hr. (Total Discharge w/ vitamin infusion of medication 250
cc-500 cc) instructions and Continue Observation continuing care
& Monitoring recommendations Bedtime Gabapentin 300 mg po If
day 3 needed: no later than 21:00 hrs. See inpatient alcohol but
after CIWA- CIWA-Ar Evaluation Ar assessment Guide to determine
Hydroxyzine HCL 50 mg need for 3.sup.rd day. If po @ bedtime may
3.sup.rd day needed, refer repeat with 25 mg as to Table 4 below
needed for sleep
TABLE-US-00004 TABLE 4 Alcohol Dependence Treatment Methodology
During 3 day In-Patient Stay Day 1 Day 1 (Admission Day 2 Day 3 Day
3 Post-discharge Time Day) Time Day 2 Time (Discharge) medications
30 mins. Negative 1 hour Hydroxyzine 1 hour Hydroxyzine Hydroxyzine
HCL: Urine HCL 50 mg po HCL 50 mg po 50 mg po hs for toxicology
Continue Continue one week Pre- Observation & Observation &
Gabapentin: treatment Monitoring for Monitoring Begin day Medical
AWS for AWS following Assessment MVI/12, MVI/12, discharge 900 mg
Thiamine, Thiamine, po hs for 30 Pyridoxine IV Pyridoxine IV days
then 150 cc, NTE 150 cc/hr. 150 cc, NTE titrate down to 150 cc/hr.
0 days 31-37 ((600 mg for 3 days, 300 mg for 3 days) Fortified
Vitamin B Complex: 100 mg po for One Week 1 hour Hydroxyzine 30
mins. Flumazenil 2 mg 30 mins. Flumazenil 2 mg HCL 50 mg po IVP IVP
MVI/12, per per Thiamine, administration administration Pyridoxine
schedule schedule IV NTE 150 cc/hr. 30 mins. Flumazenil 2 mg 3
hours MVI/12, 3 hours MVI/12, IVP per Thiamine, Thiamine,
administration Pyridoxine IV Pyridoxine IV schedule NTE 150 cc/hr.
NTE 150 cc/hr. (Total vitamin (Total infusion of vitamin 250 cc-500
cc) infusion of Continue 250 cc-500 cc) Observation & Continue
Monitoring Observation & Monitoring Gabapentin 900 mg po 3
hours MVI/12, Discharge w/ Thiamine, medication Pyridoxine
instructions IV and NTE 150 cc/hr. continuing (Total care vitamin
recommendations infusion of 250 cc-500 cc) Continue Observation
& Monitoring Bedtime Gabapentin Bedtime Gabapentin 600 mg 300
mg po no po no later later than than 21:00 hrs. 21:00 hrs. but
after but after CIWA-Ar CIWA-Ar assessment assessment Hydroxyzine
Hydroxyzine HCL 50 mg po @ HCL 50 mg po bedtime may @ bedtime
repeat with 25 mg may repeat as needed with 25 mg for sleep as
needed for sleep
[0184] In another exemplary methodology, a patient is treated on an
outpatient basis for alcohol dependence. Preferably, in this
treatment methodology, the interval between treatment episodes,
implemented in a series, should be no less than 12 hours and no
greater the 24 hours.
[0185] On day one, the patient is administered 50 mg of hydroxyzine
HCL 50 p.o., unless otherwise contraindicated. After at least
one-hour, the Selective Chloride Channel Modulator, such as
flumazenil, is administered. Prior to Selective Chloride Channel
Modulator infusion, two infusion bags are prepared. The first
infusion bag comprises 500 cc 1/2 normal saline (NS) to which
thiamine, pyridoxine and other vitamin components are added and the
second infusion bag comprises 500 cc 1/2 NS for clearing the line
and for subsequent Selective Chloride Channel Modulator
administration. 100 mg of thiamine, 25 mg of pyridoxine, and 5 cc
of MVI is preferably added to the first infusion bag. The first
infusion bag is administered to the patient at 125 cc/hr (NTE 150
cc/hour) by placing the IV in the antecubital fossa. The IV line
should further include the use of a stopcock for clearing of the
line and subsequent administration of the Selective Chloride
Channel Modulator. Using the stopcock, the line should be washed
out with the 1/2 NS until no further color is seen in the line
going to the patient.
[0186] Once the line is washed, the Selective Chloride Channel
Modulator administration can be initiated. Where the Selective
Chloride Channel Modulator is flumazenil, a total dose of 2 mg is
given at each treatment episode. The medication should be given by
IV bolus as follows: a) 0.1 mg every 3 minutes for two doses, b)
0.2 mg every 3 minutes for two doses; and c) 0.3 mg every 2 minutes
until the total dose of 2 mg has been given. If, when increasing
dose or decreasing time between doses, discomfort of any kind is
observed or reported, the drug administration should be returned to
the pre-discomfort level or even returned to initial levels. In one
embodiment, the total dose of flumazenil administration is 4 mg for
alcohol dependence (two treatment episodes). Parameters of
flumazenil administration could be modified in some cases.
Quantities can be higher than the 2 mg dose or can be higher than
0.3 mg per administration. Additionally, time periods between
administrations can be increased or decreased slightly. Once the
flumazenil administration is complete, the vitamin infusion can be
reinitiated once the line is cleared with 1/2 NS. The patient
should be monitored for 3 hours post flumazenil administration
during which time repeat CIWA-Ar assessments should be
performed.
[0187] Provided in Table 5 below are further details on this
specific methodology example.
TABLE-US-00005 TABLE 5 Alcohol Dependence Treatment Methodology
During 2 Day Out-Patient Stay Day 1 Day 2 Final discharge Time Day
1 Time Day 2 medications 30 mins. Negative Urine 1 hour Hydroxyzine
HCL Hydroxyzine HCL: toxicology. 50 mg po 50 mg po hs for One
Pre-treatment Continue Week Medical Assessment Observation &
Gabapentin: Begin Monitoring day following final MVI/12, Thiamine,
discharge 900 mg po Pyridoxine IV hs for 30 days then 150 cc, NTE
150 cc/hr. titrate down to 0 days 31-37 ((600 mg for 3 days, 300 mg
for 3 days) Fortified Vitamin B Complex: 100 mg po for One Week 1
hour Hydroxyzine HCL 30 mins. Flumazenil 2 mg IVP 50 mg po per
administration MVI/12, Thiamine, schedule Pyridoxine IV NTE 150
cc/hr. 30 mins. Flumazenil 2 mg IVP 3 hours MVI/12, Thiamine, per
administration Pyridoxine IV schedule NTE 150 cc/hr. (Total vitamin
infusion of 250 cc-500 cc) Continue Observation & Monitoring
Gabapentin 600 mg po 3 hours MVI/12, Thiamine, May discharge if
Pyridoxine IV CIWA-AR <6 NTE 150 cc/hr. Discharge w/ (Total
vitamin medication infusion of 250 cc-500 cc) instructions and
Continue continuing care Observation & recommendations
Monitoring May discharge if CIWA-AR <6 Discharge w/ medication
instructions and scheduled time for day 2 treatment Bedtime
Gabapentin 300 mg po no later than 21:00 hrs. Hydroxyzine HCL 50 mg
po @ bedtime may repeat with 25 mg as needed for sleep
[0188] In another exemplary methodology, a patient is treated on an
inpatient or outpatient basis for stimulant dependence. Preferably,
in this treatment methodology, the interval between treatment
episodes, implemented in a series, should be no less than 12 hours
and no greater the 24 hours.
[0189] On day one, the patient is administered 50 mg of hydroxyzine
HCL 50 p.o., unless otherwise contraindicated. After at least
one-hour, the Selective Chloride Channel Modulator, such as
flumazenil, is administered. Prior to Selective Chloride Channel
Modulator infusion, two infusion bags are prepared. The first
infusion bag comprises 500 cc 1/2 normal saline (NS) to which
thiamine, pyridoxine and other vitamin components are added and the
second infusion bag comprises 500 cc 1/2 NS for clearing the line
and for subsequent Selective Chloride Channel Modulator
administration. 100 mg of thiamine, 25 mg of pyridoxine, and 5 cc
of MVI is preferably added to the first infusion bag. The first
infusion bag is administered to the patient at 125 cc/hr (NTE 150
cc/hour) by placing the IV in the antecubital fossa. The IV line
should further include the use of a stopcock for clearing of the
line and subsequent administration of the Selective Chloride
Channel Modulator. Using the stopcock, the line should be washed
out with the 1/2 NS until no further color is seen in the line
going to the patient.
[0190] Once the line is washed, the Selective Chloride Channel
Modulator administration can be initiated. Where the Selective
Chloride Channel Modulator is flumazenil, a total dose of 2 mg is
given at each treatment episode. The medication should be given by
IV bolus as follows: a) 0.1 mg every 3 minutes for two doses, b)
0.2 mg every 3 minutes for two doses; and c) 0.3 mg every 2 minutes
until the total dose of 2 mg has been given. If, when increasing
dose or decreasing time between doses, discomfort of any kind is
observed or reported, the drug administration should be returned to
the pre-discomfort level or even returned to initial levels. In one
embodiment, the total dose of flumazenil administration is 6 mg for
the first treatment cycle (three treatment episodes) and 4 mg for
the second treatment cycle (two treatment episodes). Parameters of
flumazenil administration could be modified in some cases.
Quantities can be higher than the 2 mg dose or can be higher than
0.3 mg per administration. Additionally, time periods between
administrations can be increased or decreased slightly. Once the
flumazenil administration is complete, the vitamin infusion can be
reinitiated once the line is cleared with 1/2 NS. The patient
should be monitored for 3 hours post flumazenil administration
during which time repeat CIWA-Ar assessments should be
performed.
[0191] Provided in Tables 6 and 7 below are further details on this
specific methodology example.
TABLE-US-00006 TABLE 6 Stimulant Dependence Treatment Methodology
Cycle 1 - During 3 day In-Patient/Out-Patient Stay Day 1 Day 1
(Admission Day 2 Day 3 Post-discharge Time Day) Time Day 2 Time Day
3 medications 30 mins. Negative 1 hour Hydroxyzine 1 hour
Hydroxyzine Hydroxyzine HCL: Urine HCL 50 mg po HCL 50 mg po 50 mg
po hs for one toxicology. Continue Continue week Pre- Observation
& Observation & Gabapentin: Begin treatment Monitoring
Monitoring day following Medical MVI/12, MVI/12, discharge 900 mg
po Assessment Thiamine, Thiamine, hs for 2 days and Pyridoxine IV
Pyridoxine days 3 to evening 150 cc, NTE IV before treatment 150
cc/hr. 150 cc, NTE cycle 2 1200 mg 150 cc/hr. po hs Fortified
Vitamin B Complex: 100 mg po for One Week 1 hour Hydroxyzine 30
mins. Flumazenil 2 mg 30 mins. Flumazenil HCL 50 mg po IVP 2 mg IVP
MVI/12, per admin. per admin. Thiamine, schedule schedule
Pyridoxine IV NTE 150 cc/hr. 30 mins. Flumazenil 2 mg 3 hours
MVI/12, 3 hours MVI/12, IVP per Thiamine, Thiamine, admin.
Pyridoxine IV Pyridoxine schedule NTE 150 cc/hr. IV (Total NTE 150
cc/hr. vitamin (Total infusion of vitamin 250 cc-500 cc) infusion
of Continue 250 cc-500 cc) Observation & Continue Monitoring
Observation & Gabapentin Monitoring 600 mg po Gabapentin 600 mg
po 3 hours MVI/12, Discharge Thiamine, w/ Pyridoxine medication IV
instruction NTE 150 cc/hr. and (Total continuing vitamin care
infusion of recommend. 250 cc-500 cc) Continue Observation &
Monitoring Bedtime Gabapentin 300 mg po no later than 21:00 hrs.
Hydroxyzine HCL 50 mg po @ bedtime may repeat with 25 mg as needed
for sleep
TABLE-US-00007 TABLE 7 Stimulant Dependence Treatment Methodology
Cycle 2 - During 2 day In-Patient/Out-Patient Stay Day 1 Day 1
(Admission Day 2 Day 2 Time Day) Time (Discharge) Post-discharge
medications 30 mins. Negative 1 hour Hydroxyzine HCL 50 mg
Gabapentin: Continue Urine po 1200 mg po hs for one week toxicology
Continue Observation then titrate down to 0 Pre- & Monitoring
days 8-16 (900 mg for 3 treatment MVI/12, Thiamine, days, 600 mg
for 3 days, Medical Pyridoxine IV 300 mg for 3 days) Assessment 150
cc, NTE 150 cc/hr. 1 hour Hydroxyzine 30 mins. Flumazenil 2 mg IVP
HCL 50 mg po per administration MVI/12, schedule Thiamine,
Pyridoxine IV NTE 150 cc/hr. 30 mins. Flumazenil 2 mg 3 hours
MVI/12, Thiamine, IVP per Pyridoxine IV admin. NTE 150 cc/hr.
(Total schedule vitamin infusion of 250 cc-500 cc) Continue
Observation & Monitoring 3 hours MVI/12, Thiamine, Pyridoxine
IV NTE 150 cc/hr. (Total vitamin infusion of 250 cc-500 cc)
Continue Observation & Monitoring Bedtime Gabapentin Bedtime
Gabapentin 600 mg po 300 mg po no no later than 21:00 hrs. later
than Hydroxyzine HCL 50 mg 21:00 hrs. po @ bedtime may Hydroxyzine
repeat with 25 mg as HCL 50 mg po needed for sleep @ bedtime may
repeat with 25 mg as needed for sleep
[0192] In another exemplary methodology, a patient is treated on an
inpatient or outpatient basis for stimulant abuse or on an
inpatient or outpatient basis for stimulant and alcohol abuse.
[0193] After a patient has been properly screened and admitted to a
treatment facility for in-patient treatment, a patient undergoes a
first treatment cycle which comprises a series of treatments over a
period of three days. On the first day, the patient is administered
hydroxyzine and a selective chloride channel modulator, preferably
flumazenil. In one embodiment, the patient is administered
hydroxyzine HCL 50 mg p.o. one hour before flumazenil infusion. A
medical practitioner records the time of hydroxyzine HCL
administration and all subsequent medication administrations.
[0194] Two infusion bags are prepared. A first infusion bag
comprises a 500 cc Ringers Lactate Solution to which thiamine and
multivitamin components are added, and a second infusion bag
comprises a 500 cc Ringers Lactate Solution for clearing of the
line following flumazenil administration. To the first infusion bag
is added thiamine 250 mg and a 5 cc MVI vial. An IV is inserted
using a stopcock for clearing of the line following each dose of
flumazenil and subsequent administration of flumazenil. A
heparin-lock may be placed in patients admitted on an in-patient
status. The intravenous vitamin infusion is administered at a rate
between 200 and 250 cc/hour. A medical practitioner preferably
obtains and records the patient's pulse, blood pressure and
respiratory rate before infusion and every 3-5 minutes following
flumazenil administration.
[0195] The medical practitioner should use the stopcock, stop the
flow of vitamins and washout out the line going to the patient with
the Ringer's Lactate Solution until no further color is seen in the
line going to the patient. Flumazenil should then be administered,
as described below, clearing the line with the Ringer's Lactate
Solution after each dose of flumazenil.
[0196] In a freely flowing intravenous infusion, flumazenil should
be administered via IV over about 1 minute as follows: [0197] 0.1
mg every 3 minutes for two doses. [0198] 0.2 mg every 3 minutes for
two doses. [0199] 0.3 mg every 2 minutes until the total dose of 2
mg has been given.
[0200] If, when increasing dose or decreasing time between doses,
discomfort of any kind is observed or reported, the drug
administration should be returned to the pre-discomfort level or
even returned to initial levels. The standard total dose of
flumazenil administration is 6 mg for the first treatment cycle and
4 mg for second treatment cycle giving a total dose of 10 mg.
[0201] Once the flumazenil administration is complete, the vitamin
infusion can continue. The patient is to be medically monitored for
three hours post flumazenil administration. During the monitoring
process, CIWA-Ar assessment should be repeated if treating for
combination stimulant and alcohol dependence.
[0202] At bedtime, the patient is administered gabapentin 300 mg
orally and hydroxyzine HCL at bedtime if a medical practitioner
determines a patient needs it for sleep.
[0203] On the second day, the patient is administered, as detailed
above, hydroxyzine and flumazenil. At bedtime, the patient is
administered gabapentin 600 mg p.o and hydroxyzine HCL 50 mg orally
if needed for sleep.
[0204] On the third day, the patient is administered, as detailed
above, hydroxyzine and flumazenil. The patient is instructed to
take 900 mg of gabapentin at bedtime and hydroxyzine HCL 50 mg
orally if needed for sleep. Thereafter, the patient is instructed
to take 1200 mg of gabapentin at bedtime if needed and hydroxyzine
HCL 50 mg orally if needed for sleep. Before discharge, patients
are prescribed the following medication: hydroxyzine HCL (50 mg
p.o. hs for one week), gabapentin (beginning the day following the
first treatment cycle, 1200 mg is to be taken at bedtime for until
the next treatment cycle and continued at 1200 mg for one week
following the second treatment cycle and then tapered to zero),
multivitamin (once daily p.o. for one month), and thiamine (250 mg
p.o. daily for one month).
[0205] After a period of time, preferably between 21 and 28 days,
the patient is reassessed in a second treatment cycle. In one
embodiment, patients who cannot engage in treatment a
pre-designated period, such as 28 days, the patient will be
restarted on the first treatment cycle. The reassessment is
conducted using CIWA-Ar in cases where the patient is being treated
for a combination of stimulant and alcohol dependence. If
appropriate, the patient is then instructed to gabapentin 1200 mg
per day is continued through this second treatment cycle.
[0206] In a case where a patient is being treated on an out-patient
basis, after a patient has been properly screened, a patient
undergoes a first treatment cycle which comprises a series of
treatments over a period of three days. On the first day, the
patient is administered hydroxyzine and a Selective Chloride
Channel Modulator, preferably flumazenil. In one embodiment, the
patient is administered hydroxyzine HCL 50 mg p.o. one hour before
flumazenil infusion in a manner as described above. After
completing the infusion, the patient is administered gabapentin 300
mg orally and the CIWA-Ar assessment is repeated if treating for a
combination of stimulant and alcohol dependence. The patient may be
released when the CIWA-AR score is <6. The patient is provided
with 50 mg hydroxyzine HCL and instructions to take before bedtime
if needed for sleep.
[0207] On the second day, the patient is administered hydroxyzine
and a Selective Chloride Channel Modulator, preferably flumazenil.
In one embodiment, the patient is administered hydroxyzine HCL 50
mg p.o. one hour before flumazenil infusion in a manner as
described above. After completing the infusion, the patient is
administered gabapentin 600 mg p.o. and the CIWA-Ar assessment is
repeated if treating for a combination of stimulant and alcohol
dependence. The patient may be released when the CIWA-AR score is
<6. The patient is provided with 50 mg hydroxyzine HCL and
instructions to take before bedtime if needed for sleep.
[0208] On the third day, the patient is administered hydroxyzine
and a Selective Chloride Channel Modulator, preferably flumazenil.
In one embodiment, the patient is administered hydroxyzine HCL 50
mg p.o. one hour before flumazenil infusion in a manner as
described above. After completing the infusion, the patient is
administered gabapentin 900 mg p.o. and the CIWA-Ar assessment is
repeated if treating for a combination of stimulant and alcohol
dependence. The patient may be released when the CIWA-AR score is
<6.
[0209] At the end of the third day of treatment, patients are
prescribed the following medication: hydroxyzine HCL (50 mg p.o. hs
for one week), gabapentin (beginning the day following the first
treatment cycle, 1200 mg is to be taken at bedtime for until the
next treatment cycle and continued at 1200 mg for one week
following the second treatment cycle and then tapered to zero),
multivitamin (once daily p.o. for one month), and thiamine (250 mg
p.o. daily for one month).
[0210] After a period of time, preferably between 21 and 28 days,
the patient is reassessed in a second treatment cycle. In one
embodiment, patients who cannot engage in treatment a
pre-designated period, such as 28 days, the patient will be
restarted on the first treatment cycle. The reassessment is
conducted using CIWA-Ar in cases where the patient is being treated
for a combination of stimulant and alcohol dependence.
[0211] Provided in Tables 8 and 9 below are further details on this
specific methodology example.
TABLE-US-00008 TABLE 8 Procedures during Treatment Cycle 1 Post-
Day 1 Day 1 Day 2 Day 3 Day 3 discharge Time (Admission) Time Day 2
Time (Discharge) medications 30 Negative 30 Negative 30 Negative
Hydroxyzine min. Urine min. Urine min. Urine HCL: 50 mg po
toxicology toxicology toxicology hs for one Pre- (out-patient
(out-patient Week treatment only) only) Gabapentin Medical 300 mg
day 1, Assessment 600 mg day 2, 1 Hydroxyzine 1 Hydroxyzine 1
Hydroxyzine 900 mg day 3, hour HCL 50 mg po hour HCL 50 mg po hour
HCL 50 mg po 1200 mg days Continue Continue Continue 4-30, 900 mg
Observation & Observation & Observation & days 31-33,
Monitoring Monitoring Monitoring 600 mg days MVI/12, MVI/12,
MVI/12, 34-36, and Thiamine, Thiamine, Thiamine, 300 mg days IV
200-250 IV 200-250 IV 200-250 37-39 cc/hr. cc/hr. cc/hr.
Multivitamin 30 Flumazenil 30 Flumazenil 30 Flumazenil and Thiamine
min. IVP per min. IVP per min. IVP per 100 mg: po admin.
administration admin. for one month schedule schedule schedule
(cumulative (cumulative (cumulative dose of 2 mg) dose of 2 mg)
dose of 2 mg) 3 Complete 3 Complete 3 Complete hours MVI/12, hours
MVI/12, hours MVI/12, Thiamine, IV Thiamine, IV Thiamine, IV 150
cc-200 150 cc-200 150 cc-200 cc/hr. cc/hr. cc/hr. Continue Continue
Continue Observation Observation & Observation & &
Monitoring Monitoring Monitoring Gabapentin 900 mg po Bed-
Gabapentin 300 Bed- Gabapentin 600 Discharge time mg po no later
time mg po no later w/medication, than 21:00 than 21:00 continuing
hrs. but after hrs. but after care CIWA-Ar CIWA-Ar recommen-
assessment assessment dations and Hydroxyzine Hydroxyzine
appointment HCL 50 mg po @ HCL 50 mg po @ for treatment bedtime may
bedtime may cycle 2 repeat with 25 repeat with 25 mg as needed mg
as needed for sleep for sleep
TABLE-US-00009 TABLE 9 Procedures during Treatment Cycle 2 Day 1
Day 1 Day 2 Day 2 Post-discharge Time (Admission) Time (Discharge)
medications 30 Negative Urine 30 Negative Urine Gabapentin 300 mg
min. toxicology min. toxicology day 1, 600 mg Pre-treatment (screen
out- day 2, 900 mg Medical patient only) day 3, 1200 mg Assessment
days 4-30, 900 1 Hydroxyzine HCL 1 Hydroxyzine HCL mg days 31-33,
hour 50 mg po hour 50 mg po 600 mg days 34- Continue Continue 36,
and 300 mg Observation & Observation & days 37-39
Monitoring Monitoring MVI/12, Thiamine, MVI/12, Thiamine, IV
200-260 cc/hr. IV 200-250 cc/hr. 30 Flumazenil IVP 30 Flumazenil
IVP min. per administration min. per schedule administration
(cumulative schedule dose of 2 mg) (cumulative dose of 2 mg) 3
MVI/12, Thiamine, 3 MVI/12, Thiamine, hours IV 200-250 cc/hr. hours
IV 200-250 cc/hr. Continue Continue Observation & Observation
& Monitoring Monitoring Bed- Gabapentin 1200 Discharge w/ time
mg po no later medication than 21:00 hrs. instructions and
continuing care recommendations
[0212] In another exemplary methodology, a patient is treated on an
inpatient basis for alcohol abuse. After a patient has been
properly screened and admitted to a treatment facility for
in-patient treatment, a patient undergoes a first treatment cycle,
which comprises a series of treatments over a period of two to
three days. Preferably the interval between treatment episodes
should be no less than 12 hours and no greater than 30 hours.
[0213] On the first day, the patient is administered hydroxyzine
and a Selective Chloride Channel Modulator, preferably flumazenil.
In one embodiment, the patient is administered hydroxyzine HCL 50
mg p.o. one hour before flumazenil infusion. A medical practitioner
records the time of hydroxyzine HCL administration and all
subsequent medication administrations.
[0214] Two infusion bags are prepared. A first infusion bag
comprises a 500 cc Ringers Lactate Solution to which thiamine and
multivitamin components are added, and a second infusion bag
comprises a 500 cc Ringers Lactate Solution for clearing of the
line following flumazenil administration. To the first infusion bag
is added thiamine 100 mg and a 5 cc MVI vial. An IV is inserted
using a stopcock for clearing of the line following each dose of
flumazenil and subsequent administration of flumazenil. A
heparin-lock may be placed in patients admitted on an in-patient
status. The intravenous vitamin infusion is administered at a rate
between 150 and 200 cc/hour. A medical practitioner preferably
obtains and records the patient's pulse, blood pressure and
respiratory rate before infusion and every 3-minutes following
flumazenil administration.
[0215] The medical practitioner should use the stopcock, stop the
flow of vitamins and washout out the line going to the patient with
the Ringer's Lactate Solution until no further color is seen in the
line going to the patient. Flumazenil should then be administered,
as described below, clearing the line with the Ringer's Lactate
Solution after each dose of flumazenil.
[0216] In a freely flowing intravenous infusion, flumazenil should
be administered via IV over about 1 minute as follows: [0217] 0.1
mg every 3 minutes for two doses. [0218] 0.2 mg every 3 minutes for
two doses. [0219] 0.3 mg every 2 minutes until the total dose of 2
mg has been given.
[0220] If, when increasing dose or decreasing time between doses,
discomfort of any kind is observed or reported, the drug
administration should be returned to the pre-discomfort level or
even returned to initial levels. The standard total dose of
flumazenil administration is 4 mg for two treatment episodes
(treatment days one and two) and 6 mg for three treatment episodes
(treatment days one, two and three).
[0221] Once the flumazenil administration is complete, the vitamin
infusion can continue. The patient is to be medically monitored for
three hours post flumazenil administration. During the monitoring
process, CIWA-Ar assessment should be repeated.
[0222] At bedtime, such as around 9 p.m., the patient is
administered gabapentin 300 mg p.o. and 50 mg p.o. hs of
hydroxyzine HCL. The patient is also assessed with the CIWA-Ar.
[0223] On the second day, the patient is administered, as detailed
above, hydroxyzine and flumazenil. The patient is administered
gabapentin 600 mg p.o prior to discharge and 50 mg p.o. hs
hydroxyzine HCL. Depending on a patients'CIWA-Ar score, some
patients may need a third day of treatment. If a third treatment
episode, i.e. a third day, is required, the patient is administered
600 mg p.o. gabapentin prior to 9 p.m. and 900 mg gabapentin p.o.
prior to discharge.
[0224] At the end of the final day of treatment, patients are
prescribed the following medication: hydroxyzine HCL (50 mg p.o. hs
for one week), gabapentin (beginning the day following the first
treatment cycle, 900 mg p.o. hs for 30 days, 600 mg p.o. hs for
days 31-33, and 300 mg p.o. hs for days 34-37), multivitamin (once
daily p.o. for one month), and thiamine (100 mg p.o. daily for one
month).
TABLE-US-00010 TABLE 10 Treatment for Alcohol Dependence
Administration during 2 day in-patient stay Day 1 Day 1 Day 2 Day 2
Post-discharge Time (Admission Day) Time (Discharge) Medications 30
min. Negative Urine 1 hour Hydroxyzine HCL Hydroxyzine HCL:
toxicology. 50 mg po 50 mg po hs for Pre-treatment Continue One
week Medical Assessment Observation & Gabapentin: Monitoring
Begin day MVI/12, Thiamine, following IV discharge 900 mg 125
cc-150 cc/hr po hs for 30 1 hour Hydroxyzine HCL 30 min. Flumazenil
2 mg IVP days then 50 mg po per administration titrate down to
MVI/12, Thiamine, schedule 0 days 31-37 IV (600 mg for 3 125 cc-150
cc/hr. days, 300 mg for 30 min. Flumazenil 2 mg IVP 3 hours MVI/12,
Thiamine, 3 days) per administration IV Multivitamin and schedule
125 cc-150 cc/hr. Thiamine 100 mg: (Total vitamin po for One month
infusion of 250 cc-500 cc) Continue Observation & Monitoring
Gabapentin 600 mg po 3 hours MVI/12, Thiamine IV May discharge if
125 cc-150 cc/hr. CIWA-AR <6 (Total vitamin Discharge w/
infusion of 250 cc-500 cc) medication Continue instructions and
Observation & continuing care Monitoring recommendations Bed-
Gabapentin 300 mg If day 3 needed: time po no later than See Table
11 21:00 hrs. but after CIWA-Ar assessment Hydroxyzine HCL 50 mg po
@ bedtime may repeat with 25 mg as needed for sleep
TABLE-US-00011 TABLE 11 Treatment for Alcohol Dependence During 3
day in- patient stay (Day 3 required if CIWA .gtoreq.10 on day 1 or
day 2 or CIWA >6 post infusion on day 2) Post- Day 1 Day 1 Day 2
Day 3 Day 3 discharge Time (Admission) Time Day 2 Time (Discharge)
medications 30 min. Negative 1 hour Hydroxyzine 1 hour Hydroxyzine
Hydroxyzine Urine HCL 50 mg po HCL 50 mg po HCL: 50 mg toxicology
Continue Continue po hs for Pre- Observation & Observation
& One Week treatment Monitoring Monitoring Gabapentin: Medical
MVI/12, MVI/12, Begin day Assessment Thiamine, IV Thiamine, IV
following 125 cc-150 cc/hr. 125 cc-150 cc/hr. discharge 1 hour
Hydroxyzine 30 min. Flumazenil 2 mg 30 min. Flumazenil 2 mg 900 mg
po HCL 50 mg po IVP IVP hs for 30 MVI/12, per per admin. days then
Thiamine, IV administration schedule taper days 125-150 cc/hr.
schedule 31-37 (600 mg 30 min. Flumazenil 2 mg 3 hours MVI/12, 3
hours MVI/12, for 3 IVP per Thiamine, IV Thiamine, IV days, 300 mg
admin. 125 cc-150 cc/hr. 125 cc-150 cc/hr. for 3 schedule (Total
(Total days) vitamin vitamin Multivitamin infusion of infusion of
and 250 cc-500 cc) 250 cc-500 cc) Thiamine Continue Continue 100
mg: po Observation & Observation & for One Monitoring
Monitoring Month Gabapentin 900 mg po 3 hours MVI/12, Discharge w/
Thiamine, medication IV 125 cc-150 cc/hr. instructions Continue and
Observation continuing & Monitoring care recommendations Bed-
Gabapentin Bed- Gabapentin 600 mg time 300 mg po no time po no
later later than than 21:00 hrs. 21:00 hrs. but after but after
CIWA-Ar CIWA-Ar assessment assessment Hydroxyzine Hydroxyzine HCL
50 mg po @ HCL 50 mg po bedtime may @ bedtime repeat with 25 mg may
repeat as needed with 25 mg for sleep as needed for sleep
[0225] In another exemplary methodology, a patient is treated on an
outpatient basis for alcohol abuse. After a patient has been
properly screened, a patient undergoes a first treatment cycle,
which comprises a series of treatments over a period of two days.
Preferably the interval between treatment episodes should be no
less than 12 hours and no greater than 30 hours.
[0226] On the first day, the patient is administered hydroxyzine
and a Selective Chloride Channel Modulator, preferably flumazenil.
In one embodiment, the patient is administered hydroxyzine HCL 50
mg p.o. one hour before flumazenil infusion. A medical practitioner
records the time of hydroxyzine HCL administration and all
subsequent medication administrations.
[0227] Two infusion bags are prepared. A first infusion bag
comprises a 500 cc Ringers Lactate Solution to which thiamine and
multivitamin components are added, and a second infusion bag
comprises a 500 cc Ringers Lactate Solution for clearing of the
line following flumazenil administration. To the first infusion bag
is added thiamine 100 mg and a 5 cc MVI vial. An IV is inserted
using a stopcock for clearing of the line following each dose of
flumazenil and subsequent administration of flumazenil. A
heparin-lock may be placed in patients admitted on an in-patient
status. The intravenous vitamin infusion is administered at a rate
between 150 and 200 cc/hour. A medical practitioner preferably
obtains and records the patient's pulse, blood pressure and
respiratory rate before infusion and every 3-5 minutes following
flumazenil administration.
[0228] The medical practitioner should use the stopcock, stop the
flow of vitamins and washout out the line going to the patient with
the Ringer's Lactate Solution until no further color is seen in the
line going to the patient. Flumazenil should then be administered,
as described below, clearing the line with the Ringer's Lactate
Solution after each dose of flumazenil.
[0229] In a freely flowing intravenous infusion, flumazenil should
be administered via IV over about 1 minute as follows: [0230] 0.1
mg every 3 minutes for two doses. [0231] 0.2 mg every 3 minutes for
two doses. [0232] 0.3 mg every 2 minutes until the total dose of 2
mg has been given.
[0233] If, when increasing dose or decreasing time between doses,
discomfort of any kind is observed or reported, the drug
administration should be returned to the pre-discomfort level or
even returned to initial levels. The standard total dose of
flumazenil administration is 4 mg for two treatment episodes
(treatment days one and two).
[0234] Once the flumazenil administration is complete, the vitamin
infusion can continue. The patient is to be medically monitored for
three hours post flumazenil administration. During the monitoring
process, CIWA-Ar assessment should be repeated.
[0235] Prior to releasing the patient after treatment cycle one,
the patient assessed with the CIWA-Ar and released if the score is
less than 6. The patient is administered gabapentin 300 mg p.o. The
patient is also instructed to take 50 mg p.o. hs of hydroxyzine HCL
before bedtime.
[0236] On the second day, the patient is administered, as detailed
above, hydroxyzine and flumazenil. The patient is assessed using
CIWA-Ar and administered gabapentin 600 mg p.o prior to
discharge.
[0237] At the end of the final day of treatment, patients are
prescribed the following medication: hydroxyzine HCL (50 mg p.o. hs
for one week), gabapentin (beginning the day following the first
treatment cycle, 900 mg p.o. hs for 30 days, 600 mg p.o. hs for
days 31-33, and 300 mg p.o. hs for days 34-37), multivitamin (once
daily p.o. for one month), and thiamine (100 mg p.o. daily for one
month).
TABLE-US-00012 TABLE 13 Treatment for Alcohol Dependence
Administration during 2 day out-patient treatment Day 1 Day 2 Final
Discharge Time Day 1 Time Day 2 Medications 30 min. Negative Urine
30 min. Negative Urine Hydroxyzine HCL: toxicology toxicology 50 mg
po hs for Pre-treatment one week Medical Assessment Gabapentin: 1
hour Hydroxyzine HCL 1 hour Hydroxyzine HCL Begin day 50 mg po 50
mg po following Continue Continue discharge 900 mg Observation
& Observation & po hs for 30 Monitoring Monitoring days
then taper MVI/12, Thiamine, MVI/12, Thiamine, to 0 days 31-37 IV
IV (600 mg for 3 125 cc-150 cc/hr. 150 cc-200 cc/hr days, 300 mg
for 30 min. Flumazenil IVP per 30 min. Flumazenil IVP 3 days)
administration per administration Multivitamin and schedule
schedule Thiamine 100 mg: (cumulative dose of (cumulative dose of
po for One month 2 mg) 2 mg) 3 hours Complete MVI/12, 3 hours
Complete MVI/12, Thiamine IV 150 cc-200 cc/hr. Thiamine, IV
Continue 150 cc-200 cc/hr. Observation & Continue Monitoring
Observation & Gabapentin 300 mg Monitoring po Gabapentin 600 mg
po Release May discharge if May discharge if to CIWA-AR <6
CIWA-AR <6 accompanying Discharge w/ Discharge w/ person
medication medication instructions and instructions and scheduled
time for continuing care day 2 treatment recommendations Bedtime
Hydroxyzine HCL 50 mg po @ bedtime may repeat with 25 mg as needed
for sleep
[0238] In another exemplary methodology, a patient is treated for
alcohol dependence. Preferably, in this treatment methodology, the
interval between treatment episodes, implemented in a series,
should be no less than 12 hours and no greater the 24 hours.
[0239] On day one, the patient is administered 50 mg of hydroxyzine
HCL 50 p.o., unless otherwise contraindicated. After at least
one-hour, the Selective Chloride Channel Modulator, such as
flumazenil, is administered. Prior to Selective Chloride Channel
Modulator infusion, two infusion bags are prepared. The first
infusion bag comprises 500 cc 1/2 normal saline (NS) to which
thiamine, pyridoxine and other vitamin components are added and the
second infusion bag comprises 500 cc 1/2 NS for clearing the line
and for subsequent Selective Chloride Channel Modulator
administration. 100 mg of thiamine, 25 mg of pyridoxine, and 5 cc
of MVI is preferably added to the first infusion bag. The first
infusion bag is administered to the patient at 125 cc/hr (NTE 150
cc/hour) by placing the IV in the antecubital fossa. The IV line
should further include the use of a stopcock for clearing of the
line and subsequent administration of the Selective Chloride
Channel Modulator. Using the stopcock, the line should be washed
out with the 1/2 NS until no further color is seen in the line
going to the patient.
[0240] Once the line is washed, the Selective Chloride Channel
Modulator administration can be initiated. Where the Selective
Chloride Channel Modulator is flumazenil, a total dose of 2 mg is
given at each treatment episode. The medication should be given by
IV bolus as follows: a) 0.1 mg every 3 minutes for two doses, b)
0.2 mg every 3 minutes for two doses; and c) 0.3 mg every 2 minutes
until the total dose of 2 mg has been given. If, when increasing
dose or decreasing time between doses, discomfort of any kind is
observed or reported, the drug administration should be returned to
the pre-discomfort level or even returned to initial levels. In one
embodiment, the total dose of flumazenil administration is 6 mg for
the first treatment cycle (three treatment episodes) and 4 mg for
the second treatment cycle (two treatment episodes). Parameters of
flumazenil administration could be modified in some cases.
Quantities can be higher than the 2 mg dose or can be higher than
0.3 mg per administration. Additionally, time periods between
administrations can be increased or decreased slightly. Once the
flumazenil administration is complete, the vitamin infusion can be
reinitiated once the line is cleared with 1/2 NS. The patient
should be monitored for 3 hours post flumazenil administration
during which time repeat CIWA-Ar assessments should be
performed.
[0241] Provided in Tables 7 and 8 below are further details on this
specific methodology example.
[0242] In another embodiment of the present invention, a
methodology is provided for the use and administration of a
Selective Chloride Channel Modulator, such as flumazenil, for the
treatment of cravings for alcohol and stimulants. If administered
in accordance with the general methodology described above, a
therapeutically effective amount of the compound is maintained in
the patient, thereby significantly reducing cravings for alcohol
and stimulants. The invention also provides for the administration
of flumazenil without significant side effects.
[0243] In another embodiment of the present invention a methodology
is provided that relates to the use and administration of a
therapeutically effective quantity of a Selective Chloride Channel
Modulator, such as flumazenil, for the treatment of cravings of
psychostimulants, reducing withdrawal symptoms during
detoxification and treating addiction of psychostimulants and with
improvement of cognitive ability, mental clarity, and focus. If
administered in accordance with the methodology of the present
invention, a therapeutically effective amount of the drug is
maintained in the patient thereby significantly reducing cravings
for psychostimulants.
[0244] The invention also provides for the administration of a
Selective Chloride Channel Modulator so as to reduce, and in some
cases, eliminate withdrawal symptoms and to generally treat
addiction to psychostimulants. Preferably, a drug in the class of
Selective Chloride Channel Modulator, such as flumazenil, is
administered in multiple dosages for a predetermined time period
until a therapeutically effective quantity is administered for the
reduction of cravings for psychostimulants.
[0245] In another embodiment of the present invention a methodology
is described for the use and administration of a therapeutically
effective quantity of a Selective Chloride Channel Modulator, such
as flumazenil, for the reduction in patient dropout rates both
during the administration of the treatment and after the treatment.
When administered in accordance with the methodology of the present
invention, a therapeutically effective amount of the compound is
maintained in the patient, thereby significantly reducing cravings
for alcohol and certain stimulants, resulting in lower patient
dropout rates. Such dosing also provides for administration of
flumazenil with fewer side effects. At these low dosage levels, the
treatment is still effective for reducing patient dropout rates
while also being therapeutically effective.
[0246] The following examples demonstrate the invention and must
not be considered to limit the scope thereof.
Example 1
Treatment of Patients With Flumazenil in Multiple Dosages at
Predetermined Time Periods
1.1 Experimental Protocol
[0247] 64 alcoholics (51 males and 13 females) voluntarily entered
a treatment program to discontinue the use of alcohol. The patients
were provided the appropriate information and the corresponding
informed consent form was obtained from them. The patients were
warned not to drink alcohol the morning on which the treatment was
to be carried out to enable better evaluation of the withdrawal
symptoms. Table 14 summarizes the characteristics of the patients
treated associated with alcohol use.
TABLE-US-00013 TABLE 14 Characteristics of Patients Associated with
Alcohol Use (note: 85% consumed alcohol daily and 39.1% consumed
benzodiazepines daily). STANDARD CHARACTERISTICS MEAN DEVIATION
MINIMUM MAXIMUM AGE (YEARS) 42.7 10.2 20 75 AGE AT BEGINNING 24.6
10.2 6 71 OF DAILY ALCOHOL USE (YEARS) DAILY UNITS OF 24.9 15.4 4
73 ALCOHOL INTAKE GAMMA-GLUTAMYL 159.1 227.2 12 1.230
TRANSPEPTIDASE (GGT) CORPUSCULAR 97.8 6.4 72 111 VOLUME (RBC)
NUMBER OF 1.6 1.2 0 5 PREVIOUS DETOXIFICATIONS
[0248] Before starting the treatment, the patients underwent a
complete medical and psychological examination. The monitoring of
the patients throughout the morning included a complete blood
count, a biochemical profile [creatinine, glucose, blood urea
nitrogen (BUN), cholesterol (HDL and LDL), triglycerides, alkaline
phosphatase, LDH (lactic dehydrogenase) and total proteins],
hepatic function tests [GOT, GPT, GGT, bilirubin),
electrocardiogram and, if need be, pregnancy test and x-ray
examination. The exclusion criteria applied included acute or
uncompensated illnesses, as well as the taking of any drug
contraindicated with flumazenil. No patient was excluded after the
pre-admission interview and the tests performed. Admission of one
patient was postponed until his cardiac pathology was checked.
[0249] Before and after the administration of flumazenil, the
withdrawal symptomatology was measured using the CIWA-A evaluation
(Adinoff et al., Medical Toxicology 3:172-196 (1988)), as well as
heart rate and blood pressure. Table 15 presents the treatment
protocol followed during hospitalization.
TABLE-US-00014 TABLE 15 Treatment Protocol Followed During
Hospitalization. TIME DAY OF ADMISSION DAY 2 DAY 3 (DISCHARGE) 9:00
a.m. Clomethiazole 192 mg Clomethiazole 192 mg Vitamin B Complex
Vitamin B Complex Piracetam 3 g (oral) Piracetam 3 g (oral) Drink
with vitamins, Drink with vitamins, minerals, proteins, and
minerals, proteins, amino acids and amino acids 11:00 a.m.
Flumazenil 2 mg per day 1:00 p.m. Clomethiazole 192 mg Vitamin B
Complex Piracetam 3 g (oral) 4:30 p.m. Flumazenil 2 mg per day 7:30
p.m. Vitamin B Vitamin B Complex Complex Disulfiram 250 mg 9:30
p.m. Clomethiazole Clomethiazole 384 mg 384 mg
[0250] Flumazenil was administered at a dose of 0.2 mg every 3
minutes (up to a total of 2 mg/day). This quantity per dose was
established to minimize the adverse side effects associated with
withdrawal or interactions with other pharmaceuticals or
psychopathologies.
[0251] Patients who presented marked anxiety were administered an
additional dose of 192 mg of clomethiazole 30 minutes before
administration of flumazenil.
[0252] Before discharge from the hospital, the following
medications were prescribed: [0253] Vitamin B complex: 1 month with
one dose during breakfast and one dose during lunch. [0254]
Piracetam, or a medicament that is pharmacologically equivalent, 3
g for 1 week with one dose during breakfast and 800 mg for 1 month
with one dose during breakfast and one dose during lunch; [0255]
Fluoxetine 20 mg for 2 months with one dose during breakfast;
[0256] Clomethiazole 192 mg for 1 week with one dose during
breakfast and one dose during dinner and a subsequent elimination
of dose during the second week; [0257] Disulfuram 250 mg with one
dose during breakfast.
[0258] As part of the treatment program, the patients were
instructed to attend the outpatient treatment center for 9 months
with decreasing frequency [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].
[0259] Likewise, a semi-structured follow-up of cognitive behavior
therapy was implemented. Individual and family psychotherapy was
focused on 4 major interventions (cognitive restructuring, work
therapy, prevention of relapse, and stress reduction) aimed at
rehabilitating the social, family, work, personal and leisure life
of the patient.
1.2 Results
[0260] Of the 64 patients treated, in 3 cases, the first
administration of flumazenil was interrupted and postponed to the
following day: one of them, who was obviously intoxicated with
alcohol, demonstrated a distressing increase in confusion, another
had a significant increase in distal tremors, and the other, who
was also addicted to benzodiazepines, demonstrated a significant
increase in anxiety. Another group of 3 patients received the first
dose of flumazenil under sedation with propofol in the intensive
care unit.
[0261] Approximately 10% of the patients suffered headache during
or immediately following the administration of flumazenil, which
disappeared after a few minutes, or after administration of
metamizole magnesium.
1.3 Results after the First Administration of Flumazenil
[0262] The CIWA-A scoring of 55 patients showed that: 47.3% had a
significant reduction (t: -7.713; p<0.000); 40.0% experienced no
change; and 12.7% had a significant increase (t: 2.511; p<0.046)
[in the three cases presenting the greatest increase, the treatment
was discontinued].
[0263] The heart rate values of 55 patients showed that: 50.9% had
a significant reduction (t: -8.820; p<0.000); 40.0% experienced
no change; and 9.1% had a significant increase (t: 4.750;
p<0.009).
[0264] The systolic blood pressure values of 53 patients showed
that: 47.2% had a significant reduction (t: -9.908; p<0.000);
37.7% experienced no change; and 15.1% had a significant increase
(t: 4.314; p<0.004).
[0265] The diastolic blood pressure values of 53 patients showed
that: 34% had a significant reduction (t: -9.220; p<0.000);
47.2% experienced no change; and 18.9% had a significant increase
(t: 5.511; p<0.000).
1.4 Results After the Second Administration of Flumazenil
[0266] The CIWA-A scoring of 58 patients showed that: 36.2% had a
significant reduction (t: -5.363; p<0.000); 55.2% experienced no
change; and 8.6% had a significant increase (t: 4.000;
p<0.016).
[0267] The heart rate values of 55 patients showed that: 41.8% had
a significant reduction (t: -8.523; p<0.000); and 58.2%
experienced no change.
[0268] The systolic blood pressure values of 56 patients showed
that: 28.6 had a significant reduction (t: -7.596; p<0.000);
55.4% experienced no change; and 16.1% had a significant increase
(t: 4.612; p<0.002).
[0269] The diastolic blood pressure values of 56 patients showed
that: 28.6% had a significant reduction (t: -6.325; p<0.000);
51.8% experienced no change (n=29); and 19.6% had a significant
increase (t: 6.640; p<0.000).
Table 16 statistically summarizes the results obtained before and
after the treatment (at the end of 18 hours). Table 17 summarizes
the follow-up data.
TABLE-US-00015 TABLE 16 Statistical Summary of Results Obtained
Before and After Treatment Standard No. of Deviation Mean Student's
Mean (M) Samples (SD) Error T Factor Significance BT* AT** BT AT BT
AT BT AT BT AT BT AT CIWA-A 4.13 .76 54 54 4.28 1.52 0.58 0.21 6.19
.002 Systolic 135.2 126.67 51 51 18.22 13.99 2.55 1.96 5.256 0.0
Blood Pressure Diastolic 86.27 82.75 51 51 10.76 9.13 1.51 1.28
3.273 .002 Blood Pressure Heart 81.42 75.02 53 53 13.83 9.93 1.9
1.36 4.273 0.0 Rate *Before Treatment, **After Treatment
TABLE-US-00016 TABLE 17 Summary of Follow-Up Data TIME Month 1
Month 3 Month 6 Month 9 (% N) 67.2/43 34.4/22 18.8/12 12.5/8
Therapy and 95.3% 86.4% 75% 75% Disulfiram Therapy without 4.5%
12.5% Disulfiram Dropouts 4.7% 9.1% 25% 12.5%
[0270] The psychophysiological functions such as appetite and sleep
were regained very rapidly during hospitalization. The second day
of hospitalization, the patients were permitted to spend a few
hours outside the clinic during the afternoon. Some patients had
dinner outside the clinic. The most striking result is the
spontaneous verbal report from the majority of the patients
concerning the absence of anxiety and of the desire to drink
alcohol.
Example 2
Improved Methodology for the Administration of Flumazenil to Treat
Alcohol Dependency
[0271] Before starting the protocol, the patients underwent a
complete medical and psychological examination. The monitoring of
the patients included a complete blood count, a biochemical profile
[creatinine, glucose, blood urea nitrogen (BUN), cholesterol (HDL
and LDL), triglycerides, alkaline phosphatase, LDH (lactic
dehydrogenase) and total proteins], hepatic function tests [GOT,
GPT, GGT, bilirubin), electrocardiogram and, if need be, pregnancy
test and x-ray examination. The exclusion criteria applied included
acute or uncompensated illnesses, as well as the taking of any drug
contraindicated with flumazenil. No patient was excluded after the
pre-admission interview and the tests performed.
[0272] In addition, patients diagnosed with a psychotic disorder
received anti-psychotic medication. Patients diagnosed with
arterial hypertension are prescribed the appropriate medication or
instructed to continue with any existing medication.
[0273] Patients were then intravenously administered 0.1 mg of
flumazenil every 3 minutes for two administrations. If the patient
did not experience any discomfort, then the dosage was increased up
to 0.3 mg every 2 minutes. The total dosage of flumazenil
administered was up to 3.0 mg per day for alcohol dependency over
the course of the treatment.
[0274] Patients were also administered amino acids, nutrients, and
vitamins. Non-addictive sedatives were also administered in order
to reduce patient stress and/or discomfort.
[0275] Following administration of the protocol, patients underwent
6 to 24 months of outpatient therapy (for the first two months,
once a week; the next four months, every two weeks; the next six
months, once a month; and the last twelve months, once every two
months). Depending on the patient, the outpatient treatment
included cognitive behavioral semi-structured follow-up, such as
individual and family psychotherapy that may include cognitive
restructuring, network therapy, relapse prevention and stress
reduction.
Example 3
Improved Methodology for the Administration of Flumazenil to Treat
Alcohol Dependency
[0276] In accordance with this embodiment of the present invention,
as related to such example, a protocol for the treatment of alcohol
cravings is described in the table below:
TABLE-US-00017 Time Day 3 - Admission Day Day 2 Discharge
Pre-Procedure Atarax Atarax Fortified (AM) (sedative) - (sedative)
- Vitamin B 50 mg (1-2 hour 50 mg (1-2 hour complex.
pre-procedure). pre-procedure). Protein May repeat with May repeat
with Drink. 25 mg for 25 mg for anxiety if anxiety if needed.
needed. Fortified Fortified Vitamin B Vitamin B complex. complex.
Protein Drink. Protein Drink. Procedure Flumazenil 2 mg Flumazenil
2 mg per day per day Post-Procedure Atarax 50 mg. at Atarax 50 mg.
at (PM) bedtime may bedtime may repeat with 25 mg. repeat with 25
mg. as needed as needed for sleep. for sleep.
At discharge, the following may be administered: disulfuram 250
mg., daily for six months; glutamic acid, 500 mg., once daily for
one day, twice daily for one day, then three times daily for two
weeks; vitamin B complex daily; and Atarax, 50 mg. at bedtime for
one week and then 25 mg. at bedtime for a week.
Example 4
Improved Methodology for the Administration of Flumazenil to Treat
Cocaine Dependency
[0277] Before starting the protocol, the patients underwent a
complete medical and psychological examination. The monitoring of
the patients included a complete blood count, a biochemical profile
[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 warranted, pregnancy test and x-ray
examination. The exclusion criteria applied included acute or
uncompensated illnesses, as well as the taking of any drug
contraindicated with flumazenil. No patient was excluded after the
pre-admission interview and the tests performed.
[0278] In addition, patients diagnosed with a psychotic disorder
received anti-psychotic medication. Patients diagnosed with
arterial hypertension were prescribed with the appropriate
medication or instructed to continue with any existing
medication.
[0279] Patients were administered 0.1 mg of flumazenil every 3
minutes for two administrations. If the patient did not experience
any discomfort, the dosage was increased up to 0.3 mg every 2
minutes. The total dosage of flumazenil administered was up to 3 mg
per day over the course of the treatment.
[0280] Patients were also selectively administered amino acids,
nutrients, and vitamins. Non-addictive sedatives were also
administered in order to reduce patient stress and/or discomfort.
Following administration of the protocol, patients underwent 6 to
24 months of outpatient therapy (for the first two months, once a
week; the next four months, every two weeks; the next six months,
once a month; and the last twelve months, once every two months).
Depending on the patient, the outpatient treatment included
cognitive behavioral semi-structured follow, such as individual and
family psychotherapy that may include cognitive restructuring,
network therapy, relapse prevention and stress reduction.
Example 5
Improved Methodology for the Administration of Flumazenil to Treat
Cocaine Dependency
[0281] In accordance with this embodiment of the present invention,
as related to such example, a protocol for the treatment of
cravings for cocaine is described in the table below:
TABLE-US-00018 Day 3 - Time Admission Day Day 2 Discharge
Pre-Procedure Atarax Atarax Fortified (AM) (sedative) - (sedative)
- Vitamin B 50 mg (1-2 hour 50 mg (1-2 hour complex.
pre-procedure). pre-procedure). Protein May repeat with May repeat
with Drink. 25 mg for 25 mg for anxiety if anxiety if needed.
needed. Fortified Fortified Vitamin B Vitamin B complex. complex.
Protein Drink. Protein Drink. Procedure Flumazenil 2 mg Flumazenil
2 mg per day per day Post-Procedure Atarax 50 mg. at Atarax 50 mg.
at (PM) bedtime may bedtime may repeat with 25 mg. repeat with 25
mg. as needed as needed for sleep. for sleep.
[0282] At discharge, the following may be administered: Neurontin
400 mg. daily for one day (at morning), then two times daily for
one day (morning and bedtime), then three times daily and
continuing for six months (decrease by 400 mg. weekly in order to
discontinue); glutamic acid, 500 mg., once daily for one day, twice
daily for one day, then three times daily for two weeks; vitamin B
complex daily; and Atarax, 50 mg. at bedtime for one week and then
25 mg. at bedtime for a week.
Example 6
Enhanced Methodology for the Administration of Flumazenil for the
Treatment of Alcohol Withdrawal
[0283] The following example is of an embodiment of an enhanced
protocol for the administration of flumazenil for the treatment of
alcohol dependency. The enhanced protocol is implemented to
concentrate targeting of GABA.sub.A Receptor Ionophore Complex. The
embodiment employs a CIWA-based algorithm for 1) triage of patients
in need of acute medical detoxification and 2) to provide
symptom-based tracking throughout acute phase of the protocol
treatment. The enhanced protocol also alleviates withdrawal related
sleep disturbance and anxiety. In addition, the enhanced protocol
supplies key co-factors that synergistically enhance GABA tone and
transmission.
[0284] In the exemplary enhanced protocol for treating alcohol
withdrawal, a patient undergoes the aforementioned pre-treatment
regimen. On day 1 of treatment, the patient receives flumazenil via
an intravenous infusion, ultimately delivering a total amount of 2
mg per dosing interval. The patient further receives 50 mg of
hydroxyzine during the day and 50 mg of hydroxyzine at bedtime or
in the evening. The patient further receives fortified vitamin B
complex and Gabapentin at a dose of 300 mg.
[0285] On day 2 of treatment, the patient receives flumazenil via
an intravenous infusion, ultimately delivering a total amount of 2
mg per dosing interval. The patient further receives 50 mg of
hydroxyzine during the day and 50 mg of hydroxyzine at bed or in
the evening. The patient further receives fortified vitamin B
complex daily and Gabapentin at a dose of 300 mg in the afternoon
and evening or at bedtime.
[0286] After discharge, for days one and two, the patient receives
50 mg of hydroxzine at bedtime or in the evening. For 30 days, the
patient receives Gabapentin at a dose of 900 mg in the afternoon
and evening or at bedtime then titrating down to 0. For one week,
the patient also receives vitamin B complex daily.
Example 7
Enhanced Methodology for the Administration of Flumazenil for the
Treatment of Alcohol Withdrawal
[0287] In a third exemplary methodology for treating alcohol
withdrawal, a patient undergoes a pre-treatment procedure that
includes a CIWA assessment and the administration of hydroxyzine at
a dose of 50 mg. On day one of treatment, a first infusion is
administered to the patient. The first infusion includes vitamin
B1, vitamin B6, vitamin B12, and vitamin B complex and 2 mg of
flumazenil over a period of 2 hours. After the first infusion, the
patient undergoes a post-treatment procedure, typically in the late
afternoon to evening that includes a CIWA assessment, the
administration of Gabapentin at a dose of 300 mg, and the
administration of hydroxyzine at a dose of 50 mg in the evening or
bedtime.
[0288] On day two of treatment, a patient undergoes a pre-treatment
procedure that includes a CIWA assessment and the administration of
hydroxyzine at a dose of 50 mg. A second infusion is then
administered to the patient. The second infusion includes vitamin
B1, vitamin B6, vitamin B12, and vitamin B complex and 2 mg of
flumazenil over a period of 2 hours. After the second infusion, the
patient undergoes a post-treatment procedure, typically in the late
afternoon to evening that includes a CIWA assessment, the
administration of Gabapentin at a dose of 300 mg, and the
administration of hydroxyzine at a dose of 50 mg in the evening or
bedtime.
[0289] After discharge, the patient is monitored based on the CIWA
assessment and the patient's medical condition. Optionally, prior
to discharge, the patient undergoes a third day of treatment that
is similar to day 2, if warranted by the patient's medical
condition and/or CIWA assessment.
[0290] At discharge, the patient is given 50 mg of hydroxyzine on
days 1 and 2 at bedtime. The patient is also given gabapentin in
the following amounts: 300 mg on day 1; 600 mg on day 2; and on
days 3-30, 900 mg titrated down to zero. The patient is also given
an Oral Vitamin B 100 complex daily for one week.
Example 8
Enhanced Methodology for the Administration of Flumazenil for the
Treatment of Stimulant Withdrawal
[0291] The following example is of an embodiment of an enhanced
methodology for the administration of flumazenil for the treatment
of psychostimulant dependency. The enhanced methodology is
implemented to concentrate targeting of GABA.sub.A Receptor
Ionophore Complex. The embodiment allows for streamlining of
nutritional components. In addition, the enhanced methodology also
alleviates withdrawal related sleep disturbance and anxiety. The
enhanced methodology also supplies key co-factors that
synergistically enhance GABA tone and transmission.
[0292] In a first exemplary enhanced methodology for treating
stimulant withdrawal, a patient undergoes the aforementioned
pre-treatment regimen. On days 1, 2 and 3 of treatment, the patient
receives flumazenil via an intravenous infusion, ultimately
delivering a total amount of 2 mg per dosing interval. The patient
further receives 50 mg of hydroxyzine twice daily plus or minus 25
mg as may be required. The patient further receives fortified
vitamin B complex daily and a protein supplement drink daily in the
morning. This regimen, preferably days 1 and 2 only, is repeated
after three weeks.
[0293] After discharge, for one week, the patient receives 50 mg of
hydroxyzine at bedtime or for sleep and, for a subsequent week, the
patient receives 25 mg of hydroxyzine at bedtime or for sleep. For
two weeks, the patient also receives glutamine titrated up to 1500
mg per day and fortified vitamin B complex daily. The patient
further receives Gabapentin titrated up to 1200 mg per day for six
months. This regimen is interrupted for a second round of
treatments, as described above, after three weeks have elapsed from
the first round of treatments and restarted thereafter.
Example 9
Enhanced Methodology for the Administration of Flumazenil for the
Treatment of Stimulant Withdrawal
[0294] In a second exemplary methodology for treating stimulant
withdrawal, a patient undergoes the aforementioned pre-treatment
regimen. On days 1, 2 and 3 of treatment, the patient receives
flumazenil via an intravenous infusion, ultimately delivering a
total amount of 2 mg per dosing interval. The patient further
receives 50 mg of hydroxyzine. The patient further receives
fortified vitamin B complex daily and Gabapentin at a dose of 300
mg. This regimen, preferably days 1 and 2 only, is repeated after
three weeks.
[0295] After discharge, the patient receives Gabapentin titrated up
to 400 mg per day for 30 days, decreasing to 0. The patient also
receives fortified vitamin B 100 complex daily and a plurality of
amino acid supplements. This regimen is interrupted for a second
round of treatments, as described above, after three weeks have
elapsed from the first round of treatments and restarted
thereafter.
[0296] 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.
* * * * *