AGONIST-AVERSIVE COMBINATION MEDICINES

ASSOCIATION DE MEDICAMENTS AGONISTE ET AVERSIF

English Abstract

ABSTRACT

Alcohol disorders have been treated with a variety of therapies, including
pharmaceutical. Benzodiazepines, are one type of pharmaceutical that has aided
in
treating the anxiety associated with alcohol disorders, however there are
serious risks
of abuse and dependence. Disulfiram is another pharmaceutical that provides a
deterrent against consuming alcohol since it causes a person to become very
ill when
combined with alcohol. The deterrent effect of disulfiram is only effective
when
taken and non-compliance is a major limitation. This invention relates to a
combination pharmaceutical medicine of disulfiram and a benzodiazepine that
acts in
an agonist-aversive manner for people with alcohol disorders. The combination
of
disultiram and a benzodiazepine acts to reduce anxiety and deter alcohol
consumption
at the same time. This invention also relates to other combinations of agonist
and
aversive medicines to reduce anxiety and deter alcohol consumption. This
invention
also relates to aversive medicines combined with other agents to treat medical
conditions, which medical conditions or agents' effectiveness are negatively
impacted
by the consumption of ethanol.

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Claims

WHAT IS CLAIMED IS:
1. A combination medicine comprising pharmaceutically effective amounts
of a first pharmaceutical and a second pharmaceutical, wherein the second
pharmaceutical causes illness when alcohol is ingested.

2. A combination medicine comprising pharmaceutically effective amounts
of a first pharmaceutical and a second pharmaceutical, wherein the second
pharmaceutical blocks the usual effects of alcohol ingestion.

3. A combination medicine comprising pharmaceutically effective amounts
of a first pharmaceutical and a second pharmaceutical, wherein the second
pharmaceutical is an aldehyde dehydrogenase inhibitor.

4. The combination medicine of claims 1, 2 and 3, wherein said first
pharmaceutical and second pharmaceutical are intimately co-mixed.

5. The combination medicine of claims 1, 2 and 3, wherein said combination
medicine is in the form of one of the following: capsule, tablet, oral
solution, suspension, water, suppository, transdermal patch, sublingual
tablet, buccal tablet.

6. The combination medicine of claims l, 2 and 3, wherein the first
pharmaceutical is chosen from the following group: anxiolytics, anti-
depressants, sedatives, hypnotics, opioids, histamine H2 receptor
antagonists, proton pump inhibitors.

7. The combination medicine of claims 1, 2 and 3, wherein the first
pharmaceutical treats one of the following: anxiety, depression, pain,
insomnia, alcohol abuse, drug abuse, gastric or duodenal ulcer, epilepsy.

8. The combination medicine of claims 1, 2 and 3, wherein the first
pharmaceutical is an anxiolytic.

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9. The combination medicine of claim 8, wherein the first pharmaceutical is a
benzodiazepine.

10. The combination medicine of claims 1 and 3, wherein the first
pharmaceutical is a benzodiazepine and the second pharmaceutical is
disulfiram or calcium carbimide.

11. The combination medicine of claim 2, wherein the first pharmaceutical is a
benzodiazepine and the second pharmaceutical is acamprosate or
naltrexone.

12. The combination medicine of claim 10, wherein the benzodiazepine is
chosen from the following: alprazolam, bromazepam, chlordiazepoxide,
clobazam, clonazepam, clorazepate, diazepam, flurazepam, halazepam,
lorazepam, nitrazepam, oxazepam, prazepam, temazepam, triazolam.

13. The combination medicine of claim 11, wherein the benzodiazepine is
chosen from the following: alprazolam, bromazepam, chlordiazepoxide,
clobazam, clonazepam, clorazepate, diazepam, flurazepam, halazepam,
lorazepam, nitrazepam, oxazepam, prazepam, temazepam, triazolam.

14. The combination medicine of claims l, 2 and 3, wherein the first
pharmaceutical is an anti-depressant.

15. The combination medicine of claim 14 wherein the said anti-depressant is
chosen from the following group: tricyclics, secondary amine tricyclics,
serotonin reuptake inhibitors, atypical antidepressants, monoamine
oxidase inhibitors.

16. The combination medicine of claims 1 and 3, wherein the first
pharmaceutical is chosen from the following group: tricyclics, secondary
amine tricyclics, serotonin reuptake inhibitors, atypical antidepressants,
monoamine oxidase inhibitors; and the second pharmaceutical is
disulfiram or calcium carbimide.

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17. The combination medicine of claim 2, wherein the first pharmaceutical is a
chosen from the following group: tricyclics, secondary amine tricyclics,
serotonin reuptake inhibitors, atypical antidepressants, monoamine
oxidase inhibitors; and the second pharmaceutical is acamprosate or
naltrexone.

18. The combination medicine of claims 1 and 3, wherein the first
pharmaceutical is chosen from the following group: amitriptyline,
clomipramine, doxepin, imipramine, amoxapine, desipramine, maprotiline,
nortriptyline, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine,
bupropion, nefazodone, trazodone, phenelzine, tranylcypromine,
selegiline; and the second pharmaceutical is disultiram or calcium
carbimide.

19. The combination medicine of claim 2, wherein the first pharmaceutical is a
chosen from the following group: amitriptyline, clomipramine, doxepin,
imipramine, amoxapine, desipramine, maprotiline, nortriptyline,
fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, bupropion,
nefazodone, trazodone, phenelzine, tranylcypromine, selegiline; and the
second pharmaceutical is acamprosate or naltrexone.

20. The combination medicine of claims 1, 2 and 3, wherein the first
pharmaceutical is a sedative.

21. The combination medicine of claim 20 wherein the said sedative is chosen
from the following group: benzodiazepine, cyclopyrrolone derivatives,
pyrazolopyrimidines, barbiturates, zopiclone, zaleplon, secobarbital.

22. The combination medicine of claims 1 and 3, wherein the first
pharmaceutical is chosen from the following group: benzodiazepine,
cyclopyrrolone derivatives, pyrazolopyrimidines, barbiturates, zopiclone,
zaleplon, secobarbital; and the second pharmaceutical is disulfiram or
calcium carbimide.

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23. The combination medicine of claim 2, wherein the first pharmaceutical is a
chosen from the following group: benzodiazepine, cyclopyrrolone
derivatives, pyrazolopyrimidines, barbiturates, zopiclone, zaleplon,
secobarbital; and the second pharmaceutical is acamprosate or naltrexone.

24. The combination medicine of claims 1, 2 and 3, wherein the first
pharmaceutical is a hypnotic.

25. The combination medicine of claim 24 wherein the said hypnotic is chosen
from the following group: benzodiazepine, cyclopyrrolone derivatives,
pyrazolopyrimidines, barbiturates, zopiclone, zaleplon, secobarbital.

26. The combination medicine of claims 1 and 3, wherein the first
pharmaceutical is chosen from the following group: benzodiazepine,
cyclopyrrolone derivatives, pyrazolopyrimidines, barbiturates, zopiclone,
zaleplon, secobarbital; and the second pharmaceutical is disulfiram or
calcium carbimide.

27. The combination medicine of claim 2, wherein the first pharmaceutical is a
chosen from the following group: benzodiazepine, cyclopyrrolone
derivatives, pyrazolopyritnidines, barbiturates, zopiclone, zaleplon,
secobarbital; and the second pharmaceutical is acamprosate or naltrexone.

28. The combination medicine of claims 1, 2 and 3, wherein the first
pharmaceutical is an opioid.

29. The combination medicine of claim 28 wherein the said opioid is chosen
from the following group: methadone, codeine, hydrocodone,
hydromorphone, morphine, oxycodone, oxymorphone, pentazocine,
meperidine, propoxyphene.

30. The combination medicine of claims 1 and 3, wherein the first
pharmaceutical is chosen from the following group: methadone, codeine,
hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone,

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pentazocine, meperidine, propoxyphene; and the second pharmaceutical is
disulfiram or calcium carbimide.

31. The combination medicine of claim 2, wherein the first pharmaceutical is a
chosen from the following group: methadone, codeine, hydrocodone,
hydromorphone, morphine, oxycodone, oxymorphone, pentazocine,
meperidine, propoxyphene; and the second pharmaceutical is acamprosate
or naltrexone.

32. The combination medicine of claims 1, 2 and 3, wherein the first
pharmaceutical is a histamine H2 receptor antagonist.

33. The combination medicine of claim 32 wherein the said histamine H2
receptor antagonist is chosen from the following group: cimetidine,
ranitidine or famotidine.

34. The combination medicine of claims l and 3, wherein the first
pharmaceutical is chosen from the following group: cimetidine ranitidine
or famotidine; and the second pharmaceutical is disulfiram or calcium
carbimide.

35. The combination medicine of claim 2, wherein the first pharmaceutical is a
chosen from the following group: cimetidine ranitidine or famotidine; and
the second pharmaceutical is acamprosate or naltrexone.

36. The combination medicine of claims 1, 2 and 3, wherein the first
pharmaceutical is a proton pump inhibitor.

37. The combination medicine of claim 36 wherein the said proton pump
inhibitor is chosen from the following group: omeprazole, lansoprazole,
rabeprazole, pantoprazole or esomeprazole.

38. The combination medicine of claims 1 and 3, wherein the first
pharmaceutical is chosen from the following group: omeprazole ,

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lansoprazole, rabeprazole, pantoprazole or esomeprazole.; and the second
pharmaceutical is disulliram or calcium carbimide.

39. The combination medicine of claim 2, wherein the first pharmaceutical is a
chosen from the following group: omeprazole , lansoprazole, rabeprazole,
pantoprazole or esomeprazole; and the second pharmaceutical is
acamprosate or naltrexone.

40. The combination medicine of claims 1, 2 and 3, wherein the first
pharmaceutical has deleterious or reduced effects when alcohol is
ingested.

41. The combination medicine of claims 1 and 3, wherein the first
pharmaceutical has deleterious or reduced effects when alcohol is ingested
and the second pharmaceutical is disulliram or calcium carbimide.

42. The combination medicine of claim 2, wherein the first pharmaceutical has
deleterious or reduced effects when alcohol is ingested and the second
pharmaceutical is acamprosate or naltrexone.

43. The combination medicine of claims 10, 16, 18, 22, 26, 30, 34, 38 and 41,
wherein the pharmaceutically effective amount of disulfiram is between 10
mg and 1000 mg daily.

44. The combination medicine of claims 10, 16, 18, 22, 26, 30, 34, 38 and 41,
wherein the pharmaceutically effective amount of disulliram is between
250 mg and 500 mg daily.

45. The combination medicine of claims 10, 16, 18, 22, 26, 30, 34, 38 and 41,
wherein the pharmaceutically effective amount of calcium carbimide is
between 5 and 500 mg daily.

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Description

CA 02414500 2002-12-17
AGONIST-AVERSIVE COMBINATION MEDICINES
Field of the Invention
This invention relates to a combination pharmaceutical medicine that acts
in an agonist-aversive manner for people with alcohol related disorders. The
combination of an agonist such as a benzodiazepine combined with a medicine
such
as disulfiram or calcium carbimide or naltrexone or acamprosate is used to
treat
alcohol-associated anxiety and also acts to deter alcohol consumption. This
invention
also relates to aversive medicines combined with other agents to treat medical
conditions, which medical conditions or agents' effectiveness are negatively
impacted
by the consumption of ethanol.
Background of the Invention
Alcohol dependent patients with complaints of anxiety commonly
approach physicians for assistance. According to a 1990 study, those with an
anxiety
disorder had a 50% increase in the odds of being diagnosed with an alcohol
disorder.
~ 5 A 1997 study also indicated a doubting to quadrupling of risk for alcohol
and drug
dependence given the presence of an anxiety disorder.-' Rates of anxiety
disorders in
the alcohol dependent population range from 20-50%. While rates of anxiety
disorders in the general population are generally I 5-20°/~.
Anxiety is known to be the predominant complaint of alcohol dependent
2o patients in the first four weeks of early withdrawal from alcohol. Common
complaints include tension, difficulty concentrating, fear, fatigue,
restlessness and
irritability. Other withdrawal symptoms include headaches, insomnia, sweating,
tremor, anorexia and dizziness. ~ Many argue that a sub-acute alcohol
withdrawal
syndrome exists even beyond the four week acute withdrawal period and this
2S withdrawal is responsible for many ongoing complaints of anxiety, insomnia
and
irritability and depression in abstinent alcohol dependent patients.'
Alcohol seems to be anxiolytic while it is being consumed yet anxiogenic
over the long terms Reducing anxiety symptom in-patients improves alcoholism
treatment outcomes'', and ongoing problems with panic and anxiety predict
relapse.'

CA 02414500 2002-12-17
Even in prolonged periods of abstinence, alcohol dependent patients claim
incapacitating anxiety as a common reason for return to drinking.
Benzodiazepines
are the easiest way to relieve this anxiety. With their favourable side effect
profile
and wide therapeutic window, benzodiazepines are the treatment of choice for
early
withdrawal symptoms. Benzodiazepines also prevent and treat withdrawal
seizures
and withdrawal induced delirium tremens in patients.
There has been controversy over whether benzodiazepines should be used
to treat anxiety symptoms and withdrawal symptoms in alcoholic outpatients.''
The
dangers of dose escalation of the benzodiazepine and combination of the
t o benzodiazepine with alcohol prevent most physicians from using
benzodiazepines to
treat early alcohol withdrawal symptoms in outpatients. When benzodiazepines
are
mixed with alcohol, a severe form of intoxication occurs and the mixture of
these two
substances can lead to blackouts, coma and possibly even death.'°
Because of the risk of dual intoxication most experts feel that
~ 5 benzodiazepines should not be used to treat anxiety or withdrawal
complaints in
alcohol abusing outpatients. Alternative agents such as antidepressants and
buspirone
are recommended as the therapeutic agents of choice for the complaints of
anxiety and
insomnia that occur in early withdrawal. These alternative agents are thought
to have
less of a risk for abuse. Current standards of care indicate that if a patient
has been
2o treatment resistant to these alternative agents and has ongoing complaints
of anxiety a
benzodiazepine can still be considered as long as the patient is abstinent
from alcohol
and stable in their recovery." If a benzodiazepine is used to treat the
anxiety the
physician should closely monitor the dose. It is often useful if a family
member is
included in the therapeutic alliance so that they can provide the alcohol
dependent
25 patient with the medicine.''
The hesitancy to use benzodiazepines in the substance using population is
understandable yet unfortunate. Anxiety disorders in the substance using
population
are notoriously difficult to treat. Anxiety tends to be chronic, with high
rates of
morbidity and mortality and many agents such as antidepressants, buspirone,
30 neuroleptics or mood stabilizers otter only partial relief." 'there is
strong evidence

CA 02414500 2002-12-17
suggesting that anxiety is associated with craving and relapse. And those
negative
affective states serve as powerful internal cues that frequently precede
relapse.
Benzodiazepines are highly effective anxiolytics and patients may benefit
greatly
from a short course of treatment with subgroups of chronically anxious
patients
needing long term treatment."
Unfortunately benzodiazepines can be used by patients to intoxicate
themselves just as the patient used alcohol to intoxicate himself or
herself.'S Short-
term side effects include sedation, ataxia, psychomotor slowing, poor
concentration
and anterograde amnesia. Other side effects include impaired driving,
increased risk
of falls by the elderly and paradoxical effects of increased anger and
hostility." When
benzodiazepines are consumed with alcohol a more impaired state and possibly
lethal
state can arise. As most alcohol using patients are treated as outpatients,
they are at
risk to drink alcohol during treatment with all the subsequent potential
dangers a
possibility. As alcohol and benzodiazepines have equivalent intoxicating
effects, the
~ 5 co-morbid overuse of the two substances is prevalent. "'
Physicians are used to giving disultiram to aid patients in their quest to
refrain from alcohol. Although 250-SOOmg of disulfiram is recommended in North
America, it appears that some patients may need up to one gram of disulfiram
to get a
proper aversive reaction to alcohol.'' Although disultiram is a deterrent
medicine that
?o was approved 50 years ago for the treatment of alcoholism, it has
unfortunately not
consistently been shown to be efficacious.~~ Disulliram inhibits aldehyde
dehydrogenase, the enzyme that catalyzes the oxidation of acetylaldehyde, a
metabolite formed when the body breaks down alcohol. If alcohol is ingested
while
this enzyme is inhibited by disulfiram, blood acetylaldehyde rises causing an
aversive
z5 reaction. This aversive reaction includes facial flush, hot flashes,
conjunctiva
injection, palpitations, headache, and hypotension. It is these negative
reactions that
are responsible fox a patient's aversion to drinking when he or she has
ingested
disulfiram. The most common side effects of the disulliram without any alcohol
having been consumed are drowsiness, headaches and GI discomfort.
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CA 02414500 2002-12-17
Abstinence occurs when using disulfiram only if there is medication
compliance.''' It is well known to practitioners that patients often do not
take their
disulfiram so that they can continue drinking alcohol. Compliance rates as low
as
20% have been reported.'"
One must weigh carefully the risks and benefits of initiating or not
initiating a benzodiazepine treatment in the alcohol dependent population,
particularly
for outpatients. The effectiveness of disulfiram treatment depends on
compliance.
Alcohol use and abuse complicates many disease states and interferes with
treatment and rehabilitation.'' Men and women who fullfill the criteria for
alcohol use
disorders decrease their life span by approximately 15 years, with abuse and
dependence responsible for almost 25% of premature deaths in men and 15% in
women, figures that represent a three- to sixfold odds ratio of early death
even among
people with higher levels of education and socio-economic functioning.'-
Alcohol use is a common co-morbid psychiatric disorder of depression.
~ 5 For example elderly depressed patients are three to four times more likely
to have an
alcohol use disorder compared with non-depressed elderly subjects, with a
prevalence
of 15 to 30% in patients with late life major depression. Successful treatment
of
depression with reducing alcohol use leads to the best possible outcomes."
Viewed
from a different vantage point, depressive symptoms can be found in as many as
30%
of those who abuse alcohol so that abstinence is crucial to treatment.'
Summary of the Invention
This invention relates to a combination medicine comprising pharmaceutically
effective amounts of a first pharmaceutical and a second pharmaceutical,
wherein the
second pharmaceutical causes illness when alcohol is ingested.
This invention also relates to a combination medicine comprising
pharmaceutically
effective amounts of a first pharmaceutical and a second pharmaceutical,
wherein the
second pharmaceutical blocks the usual effects of alcohol ingestion.
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CA 02414500 2002-12-17
This invention also relates to a combination medicine comprising
pharmaceutically
effective amounts of a first pharmaceutical and a second pharmaceutical,
wherein the
second pharmaceutical is an aldehydc dehydrogenase inhibitor.
The first and second pharmaceuticals of the combination medicine are
intimately co-
mixed and may be in any form, such as, capsule, tablet, oral solution,
suppository,
transdermal patch, sublingual tablet. buccal tablet.
The first pharmaceutical of the combination medicine is chosen from the
following
group: anxiolytics, anti-depressants, sedatives, hypnotics, opioids ,
histamine H2
receptor antagonists, proton pump inhibitors or is chosen to treat the
following:
anxiety, depression, pain, insomnia, alcohol abuse, drug abuse, epilepsy
gastric or
duodenal ulcer.
The invention relates to a combination medicine comprising: benzodiazepine and
disulfiram or calcium carbimide; benzodiazepine and acamprosate or naltrexone;
anxiolytic and disulfiram or calcium carbimide; anxiolytic and acamprosate or
~ 5 naltrexone; anti-depressant and disulfiram or calcium carbimide; anti-
depressant and
acamprosate or naltrexone; sedative and disulfiram or calcium carbimide;
sedative and
acamprosate or naltrexone; hypnotic and disulfiram or calcium carbimide;
hypnotic
and acamprosate or naltrexone; opioid and disulfiram or calcium carbimide;
opioid
and acamprosate or naltrexone; histamine H2 receptor antagonist and disulfiram
or
2o calcium carbimide; histamine H2 receptor antagonist and acamprosate or
naltrexone;
proton pump inhibitor and disulliram or calcium carbimide; and proton pump
inhibitor and acamprosate or naltrexone.
This invention relates to a combination medicine comprising a pharmaceutical
that
has deleterious or reduced effects when alcohol is ingested and disulfiram or
calcium
?s carbimide; and a pharmaceutical that has deleterious or reduced effects
when alcohol
is ingested and acamprosate or naltrexone.
The combination medicine comprising disulfiram has a quantity of disulfiram of
between 10 mg and 1000 mg daily. The combination medicine comprising calcium
carbimide has a quantity of calcium carbimide of between 5 mg and 500 mg
daily.
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CA 02414500 2002-12-17
Detailed Description of the Invention
The inventor determined that by combining disulfiram with a
benzodiazepine one will improve compliance with the ingestion of disultiram.
The
patient knows that disulfiram ingestion will result in an aversion reaction.
The desire
to avoid this aversion reaction will encourage the patients to refrain from
drinking
alcohol. The benzodiazepine in turn will treat any underlying anxiety and thus
be
rewarding in and of itself and also serve to lessen the need for the
anxiolytic activity
of ethanol. If the combined preparation is taken regularly even missing a dose
will
create some benzodiazepine withdrawal anxiety that will result in more regular
taking
of the benzodiazepine-disultiram combination medicine in order to avoid this
withdrawal anxiety. Increased compliance ensures that the patient has a
sufficient
concentration of disulliram in the body so as to induce an aversion reaction
should the
patient ingest ethanol. 'The desire to avoid the negative experience
associated with the
aversion reaction will discourage the patient from ingesting ethyl alcohol
~ 5 The combination medicine of disulfiram combined with a benzodiazepine
would be the ideal compound to treat the alcohol dependent patients that
complain of
anxiety symptoms for which a benzodiazepine is a clinically appropriate
treatment.
This combination medicine could be used to treat early alcohol withdrawal
symptoms
and chronic anxiety symptoms, provide prophylaxis against seizures and prevent
2o delirium tremens. As the combination medicine also contains disulfiram it
would
prevent the patient from drinking alcohol while taking the benzodiazepine.
Thus
preventing the toxicity that occurs when benzodiazepines are mixed with
alcohol,
such as, severe intoxication, blackouts, coma, and possibly even death. A
combination of a benzodiazepine with disulfiram treats the underlying
condition and
25 reduces the probability of relapse to drinking alcohol.
Prescriptions of small quantities of the combination medicine and frequent
contact between the patient and the clinician are also essential to good
therapeutic
management. Judicious prescribing and careful monitoring can minimize the risk
of
abuse of the benzodiazepine and allow physicians to educate the patient about
risks to
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CA 02414500 2002-12-17
their health if they attempt to drink while taking the disulfiram containing
combination medicine.
One has to ensure an adequate dose of both medicines is achieved. Even
though 250-SOOmg of disultiram is recommended in North America, it appears
that
some patients may need up to one gram of disulfiram to get a proper aversive
reaction
to alcohol. The proper dose of benzodiazepine is also a contentious subject.
Too
much benzodiazepine causes over sedation, memory impairment and decreased
ability
to function cognitively. This includes impaired ability to operated mechanical
and
electronic equipment, such as motor vehicles etc. Combining disulfiram with
various
amounts of a benzodiazepine allows the physician to use a benzodiazepine to
treat
early withdrawal symptoms at the same time as the disulfiram prevents a return
to
drinking. Thus, there is no risk of the benzodiazepine being mixed with
alcohol.
The actual ratio of the benzodiazepine to disulfiram will depend on the
specific benzodiazepine chosen as well as the severity of the underlying
condition for
~ 5 which the benzodiazepine is being used as a treatment. See the table below
for a list
of benzodiazepines and the probable daily dose. 'Che ratio of benzodiazepine
to
disulfiram is dependent on the benzodiazepine chosen and the daily dose of
disulfiram. The ratio can range from as little a 0.00025 milligram of a
benzodiazepine
to 1 milligram of disultiram to as much as 4.5 milligram of a benzodiazepine
to I
?o milligram of disultiram. Ratios higher or lower than this may also be of
therapeutic
benefit since the list in the table is not exhaustive of all available
benzodiazepines or
the daily doses that might be used.
Ratio of Benzodiazepine
to Disulfiram


Benzodiazepine A Probable Disulfiram Daily
~ Daily Dose



Dose
10 mg
000 mg
I


Alprazolam _ 0. ; 0.003
I 3 mg i



CA 02414500 2002-12-17
Bromazepam 12 mg 1.2 0.012


Chlordiazepoxide30 mg 3 0.03


Clobazam 30 mg 3 0.03


Clonazepam 5 mg ~ 0.5 0.005
I


Clorazepate '- 3 -
30 mg 0.03


i Diazepam 20 mg ? 0.02


Flurazepam 30 mg ~ 3 0.03


Halazepam 100 mg 10 0.1


Lorazepam 3 mg 0.3 0.003


Nitrazepam 10 mg 1 0.01


Oxazepam 45 mg ~ 4.5 0.045


Prazepam 30 mg 3 0.03


Temazepam ' 30 mg 3 0.03


Triazolam 0.25 0.025 0.00025


For example a young patient may be treated with a high dose of
clonazepam during the initial withdrawal from alcohol in order to avoid
delirium
tremens. This patient may be given a combination of 6 mg of clonazepam and 250
mg of disultiram (ratio of 6/250 or 0.024 mg of clonazepam for every mg of
disulfiram) As the patient gets better 2 mg of clonazepam is sufficient to
control their
anxiety but the amount of disulf ram stays the same (ratio 2/250 or 0.008 mg
of
clonazepam to 1 mg of disulliram). In the treatment of an elderly low body
weight
patient 0.5 mg of clonazepam and 62.5 mg of disultiram may be enough (ratio
0.5/62.5 or 0.004 mg oFclonazepam to 1 mg of disulliram). The absolute amounts
of
each drug differ under different clinical circumstances, as do the ratios of
the two
ingredients with respect to each other.
_g_

CA 02414500 2002-12-17
To avoid the risk of the patient over-using this combination medicine the
prescription should be only given on a bi-weekly basis. A limitation in the
prescription availability lessens the chance of the patient consuming a
dangerously
high amount of disulfiram in order to consume a large amount of the
benzodiazepine.
Dispensing the combination medicine in a weekly amount ameliorates the risk of
benzodiazepine overuse.
The combination medicine must be given in a presentation such that the
disulfiram should not be capable of being separated from the benzodiazepine,
or at
least not be visible to the patient as two separate substances, that is,
intimately co-
mixed. For example, a combination medicine could have both disulfiram and a
benzodiazepine present as a finely ground powder of the same colour so that
the
patient is not capable of separating the disultiram powder from the
benzodiazepine
powder. If the powders are of different colour, dyes can be used to mask this
difference and make the powders indistinguishable. These powders can then be
mixed
15 with excipients so as to be formed into a tablet, caplet or filled into a
capsule.
The combination medicine can also be formulated by dissolving both in a
suitable solvent. This solution can then have added to it appropriate types
and
amounts of excipients to make a pleasant tasting and aesthetically pleasing
oral
solution. A solution containing both ingredients can also be placed in soft
gelatine
2o capsules. Other presentations could include suppositories, sublingual or
buccal
tablets, transdermal patches or any other presentation that is capable of
delivery the
appropriate amount of a benzodiazepine and disulliram in a form in which the
patient
is not able to take one without also ingesting or absorbing the other.
25 Preparation of a disultiram-benzodiazepine combination medicine
Disulfiram Premix
Each gram of the disulfiram premix contains
Disulfiram 1 gram


Fumed silica0.030 gram


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CA 02414500 2002-12-17
Clonazepam Premix
The clonazepam premix of about 160 grams may be prepared as outlined in the
table
below:
Clonazepam ~ 2.0



Lactose Monohydrate USP 64.2



Microcrystalline Cellulose80.


Croscarmellose sodium 9.
NF



Magnesium Stearate NF 4.8


The two ingredients were mixed together in sufficient quantity to yield the
required amount of disulllram and clonazepaan to yield capsules containing the
inseparable combination of clonazepam 1 mg. and disulliram 250 mg or 2 mg and
disulfiram 250.
I o An example of an alternative formula using the following ingredients is
presented below:
Ingredient Amount in
Mg


Disulfiram 250



Clonazepam 2


Cornstarch 40



Magnesium stearate 2


Povidone 4


Veegum 2


Total weight 300


(tablet or capsule contents)


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Many other formulations for capsules, caplets, tablets, wafers, suspensions
and oral
liquids will be evident to those skilled in the art of product formulation.
Given that alochol use is a common co-morbid psychiatric disorder of
depression, a combination of an antidepressant with disultiram would treat a
patient's
depressive state and ensure the abstinence from alcohol. Examples of
antidepressants
with which disulfiram can be combined are presented below:
Class Antidepressant



'Tricyclics Amitriptyline


Clomipramine


Doxepin


Imipramine


Secondary Amine Tricyclics Amoxapine
~


Desipramine


Maprotiline


Nortriptyline


Serotonin-Reuptake Inhibitors Fluoxetine


hluvoxamine


Paroxetine


Sertral ine


Venlafaxine


Atypical Antidepressants l3upropion


Nefazodone


Trazodone


Monoamine Oxidase Inhibitors Phenelzine


Tranylcypromine


Selegiline i


This list in not meant to be exhaustive but merely to show examples of
antidepressants that could be combined with disulliram. Treatment with an
antidepressant helps the patient overcome feelings of worthlessness and
hopelessness.
To achieve this benefit from the antidepressant the patient is also required
to take the
disulfiram as part of the combination disulfiram-antideprssant medicine. The
disulfiram in turn discourages the patient from consuming alcohol. Abstinence
from
alcohol is important in the overall management of depression.
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While alcohol can help someone to fall asleep, it also "fragments" the sleep
pattern. Alcohol dependent insomnia is a state in which even the consumption
of
moderate amounts of alcohol increases awakenings in the second half of the
night.2'
Patients will seek sedatives or hypnotics to treat this type of insomnia. It
is often
difficult for patients to break the habit of an evening alcoholic or drink or
two. For
the clinician, prescribing sedatives or hypnotics to such a patient is
problematic
because the patient may become dependent on the sedative or hypnotic. The real
problem is evening time alcohol consumption. Once a pattern of alcohol and
sedative
hypnotic consumption is established it is very difficult to get a patient off
the
sedative or hypnotic. It is also very difficult for a patient to break a long
established
habit of consuming alcoholic beverages in the evening. Short term treatment
with a
combination of a suitable sedative or hypnotic with an appropriate amount of
dislufiram will give the patient the. sleep they desire and help them break
their
ritualized automatic evening alcohol consumption behaviors. 'The sedative or
t 5 hypnotic in this case may be but need not be a member of the
benzodiazepine class.
Non-benzodiazepine examples include zopiclone a cyclopyrrolone derivative,
zaleplon a member of the pyrazolopyrimidine class and secobarbital of the
barbiturate
class.
Substance abuse often involves multiple substances. For example some
2o patients abuse opioids and alcohol or opioids, cocaine and alcohol.
Rehabilitation of
opioid dependent persons may involve a methadone maintenance program or
maintenance with an anolgue of methadone. Methadone has almost all of the
properties of heroin but to blocks the euphoria associated with heroin use.'-
g. Heroin
use may be associated with alcohol abuse and can complicate rehabilitation. A
25 combination of methadone and disulfiram would be usefull in the treatment
of
patients with both opioid and alcohol abuse. The patient is incented to
consume
methadone in order to manage their opioid addiction. The concommitant
consumption of disultiram would help the patient avoid alcohol consumption.
Chronic pain management with opioids may be associated with excessive
a0 alcohol consumption. Alcohol acts as a relaxant and also has some analgesic
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CA 02414500 2002-12-17
properties. Alcohol abuse can however be a block to rehabilitation. A
combination
opioid analgesic with disulfiram would be helpful in managing the alcohol use
and
abuse component of the patients clinical situation. The patient would be
incented to
take the combination medicine inorder to get pain relief and would be
discouraged
from consuming alcohol because of the disulfiram content of the pain medicine.
Some examples of opioids to which disultiram could be added include methadone,
codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone,
pentazocine, meperidine, and propoxyphene..
Many physical conditions are exacerbated if the the patient consumes
alcohol. Alcohol intake can result in inflammation of the stomach resulting
from an
increase in gastric acid production and damage to the gastric mucosal barrier.
This
may exacerbate pain associate with gastric and duodenal ulcers.. Treatment
with
agents such as histamine H~ receptor antagonist and proton pump inhibitors (or
H+,
K+ ATPase inhibitor) provide the patients with relief of symptoms such as
pain.
l s Examples of histamine H, receptor antagonist are cimetidine, famotidine,
ranitidine
and nizatidine and examples of a proton pump inhibitor are omeprazole,
lansoprazole,
rabeprazole, pantoprazole and esomeprazole. Combining these agents with
disulfiram
can result in improved healing of the gasric or duodenal ulcer. The patient
would be
incented to take the combination medicine inorder to get pain relief and would
be
2o discouraged from consuming alcohol because of the disulfiram content of the
medicine containing a histamine H, receptor antagonist or a proton pump
inhibitor.
Disulfiram is of course only one of many aversive medicines available on
the market. Other medicines that could be substituted for disulfiram in the
combination medicines outlined above, to achieve the same fundamental purpose
i.e.
25 the reduction of alcohol consumption in a clinical situation in which
alcohol
complicates the treatment of an undelying illness, are calcium carbimide,
naltrexone,
and acamprosate. Calcium carbimide, like disulfiram is an aldehyde
dehydrogenase
inhibitor. Naltrexone is an opioid antagonist and acamprosate interferes with
central
neurotransmitter effects of ale.ohol, both of which block the effects of
alcohol
3o although the exact mechanism of action is not yet fully understood.
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A benzodiazepine naltrexone combination medicine could contain 1 mg
clonazepam and 50 mg of naltrexone. Other strengths of clonazepam may be used.
Naltrexone is usually administered at a dose of 50 mg per day. Acamprosate
clonazepam combination medicine could contain 0.5 mg clonaepam and 666 mg of
acamprosate. Such a combination given three time per day would give an
effective
amount of clonazepam and acamprosate. In other circumstances I mg clonazepam
and 666 mg of acamprosate given twice daily would also provide an effective
amount
of both medicines. Calcium carbimide clonazepam combination medicine could
contain 0.5 mg clonaepam and 100 mg of calcium carbimide. Such a combination
given twice a day would give an effective amount of clonazepam and calcium
carbimide.
The above examples relate to treatment of a variety of disease states,
addictions and ailments for which alcohol consumption has deleterous effects.
The
invention also relates to the combination of disultiram, calcium carbimide,
naltrexone
~ s or acamprosate with another pharmaceutical when that pharmaceutical has
deleterious
effects or reduced benefits when alcohol is consumed.
The combination medicine can be comprised of disulfiram, calcium carbimide,
naltrexone or acamprosate with a pharmaceutical for the treatment of a disease
or
condition that is negatively affected by alcohol consumption such as anxiety,
2o depression, pain, insomnia, alcohol abuse, drug abuse, gastric or duodenal
ulcer,
epilepsy. The combination medicine can be comprised of disultiram, calcium
carbimide, naltrexone or acamprosate with a pharmaceutical from the group of
anxiolytics, anti-depressants, sedatives, hypnotics, opioids, histamine H2
receptor
antagonists, proton pump inhibitors.
2s Example No. One
A 43-year-old female suffers from chronic depression, panic disorder with
agoraphobia and post-traumatic stress disorder. l:Ier alcohol abuse resulted
in
ineffective psychiatric rehabilitation because it led to drinking and
isolation.
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CA 02414500 2002-12-17
The patient is taking fluoxetine 40 mg, olanzapine 10 mg, clonazepam 0.5 mg
during
the day and clonazepam 1.5 mg at bed time. In order to control her drinking
her
clonazepam was replaced with the combination medicine consisting of clonazepam
2
mg and disulfiram 250 mg . This combination prevented her from drinking. Her
anxiety and insomnia improved and she was able to function much better.
Example No. Two
This 42-year-old mother of two has a struggle controlling her drinking and
marijuana
use. She numbs herself with alcohol and this has resulted in poor self=care.
Two
months prior to treatment she was admitted to hospital with pneumonia. She is
taking
citalopram 40 mg and lorazepam 1 mg to manage her chronic dysfhymia and
generalized anxiety. Two week prior to treatment she entered a pharmacy in an
intoxicated state for a renewal of her benzodiazepine prescription. She was
hospitalized for two weeks to detoxify from her bout of alcohol abuse.
While in hospital the patient was started on a clonazepam I mg and disuli-iram
250 mg
~ 5 combination medicine. At discharge she was given a clonazepam 0.5 mg and
disulfiram 125 mg combination medicine. On this medicine she has been able to
control her urges to drink. As a result she has been able to improve her
relationship
with her husband and to re-enter the work force. After 2 months of use, her
complete
blood count was normal as were her liver and renal function tests. Her urine
tested
2o negative for drugs of abuse. Five months after initiation of the
combination
clonazepam disulfiram combination medicine the patient remains on drug and is
doing
well.
Here we see this combination disulfiram-benzodiazepine medicine acts in
an agonist-aversive manner that parallels but differs from the agonist-
antagonist
25 properties of methadone. If the alcohol itself is the cause of the
patient's anxiety
symptoms an alcohol induced anxiety disorder is diagnosed. 'this diagnosis is
given
whether the anxiety comes on during the intoxication or withdrawal phase of
the
alcohol. Removal of the alcohol is always the initial intervention. Even if
the
patient's anxiety were directly caused by alcohol a disulfiram-benzodiazepine
pill
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CA 02414500 2002-12-17
would be useful for treatment. The disulfiram-benzodiazepine medicine would
treat
this anxiety at the same time as it prevented the patient from being able to
drink
comfortably. There are not only short term benefits oi~this combined medicine
but
also long term effects of using a benzodiazepine to treat anxiety in an
alcohol
dependent patient.
Various embodiments of the present invention having been thus described in
detail by way of example, it will be apparent to those skilled in the art that
variations
and modifications may be made without departing from the invention. The
invention
includes all such variations and modifications as fall within the scope of the
appended
claims.
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CA 02414500 2002-12-17
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