U.S. patent application number 13/420025 was filed with the patent office on 2012-09-13 for combination therapy for bipolar disorder.
This patent application is currently assigned to ComGenRx, Inc.. Invention is credited to Bryan T. Oronsky, Neil C. Oronsky.
Application Number | 20120231092 13/420025 |
Document ID | / |
Family ID | 41092217 |
Filed Date | 2012-09-13 |
United States Patent
Application |
20120231092 |
Kind Code |
A1 |
Oronsky; Bryan T. ; et
al. |
September 13, 2012 |
Combination Therapy for Bipolar Disorder
Abstract
Treatment regimens for mood disorders that include
administration of buprenorphine, alone or in combination with
additional pharmacological agents are described. Specifically,
treatment regimens that alleviate racing thoughts associated with
bipolar disorder, and pharmaceutical compositions and kits for use
therein are described. Dosing regimens, compositions, and kits
including buprenorphine for treating mania associated with opioid
withdrawal are also described.
Inventors: |
Oronsky; Bryan T.; (Los
Altos Hills, CA) ; Oronsky; Neil C.; (Los Altos
Hills, CA) |
Assignee: |
ComGenRx, Inc.
Mountain View
CA
|
Family ID: |
41092217 |
Appl. No.: |
13/420025 |
Filed: |
March 14, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12422156 |
Apr 10, 2009 |
8138169 |
|
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13420025 |
|
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61044312 |
Apr 11, 2008 |
|
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61050738 |
May 6, 2008 |
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Current U.S.
Class: |
424/722 ;
514/211.13; 514/220; 514/253.07; 514/254.04; 514/259.41; 514/279;
514/282 |
Current CPC
Class: |
A61K 31/485 20130101;
A61P 25/18 20180101; A61P 25/36 20180101; A61P 25/00 20180101; A61K
45/06 20130101; A61K 31/485 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/722 ;
514/279; 514/253.07; 514/220; 514/259.41; 514/211.13; 514/254.04;
514/282 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 31/496 20060101 A61K031/496; A61P 25/18 20060101
A61P025/18; A61K 31/519 20060101 A61K031/519; A61K 31/554 20060101
A61K031/554; A61K 33/00 20060101 A61K033/00; A61K 31/5513 20060101
A61K031/5513 |
Claims
1-29. (canceled)
30. A composition comprising (i) buprenorphine or a
pharmaceutically acceptable salt thereof and (ii) a second active
agent in a single dosage form, wherein the second active agent
comprises an antipsychotic agent, an atypical antipsychotic agent,
an antiepileptic agent, lithium, a P-450 CYP3A4 inhibitor, a P-450
CYP2D6 inhibitor, salts and acids thereof, and combinations
thereof.
31-35. (canceled)
36. The composition of claim 30, wherein the second active agent
comprises an atypical antipsychotic.
37. The composition of claim 36, wherein the atypical antipsychotic
is selected from the group consisting of aripriprazole,
arisuipride, olanzapine, paliperidone, quetiapine, risperidone,
ziprasidone, and combinations thereof.
38-51. (canceled)
52. A method for treating a bipolar condition and subtypes thereof
in a subject, the subject experiencing at least one episode of
racing thoughts, comprising administering buprenorphine or a
pharmaceutically acceptable salt thereof to the subject to
alleviate the racing thoughts.
53. The method of claim 52, wherein the bipolar condition is
bipolar I disorder.
54. The method of claim 52, wherein the bipolar condition is
bipolar II disorder.
55. The method of claim 52, wherein the bipolar condition is mixed
bipolar disorder.
56-59. (canceled)
60. The method of claim 52, further comprising administering an
opioid antagonist.
61. The method of claim 60, wherein the opioid antagonist comprises
naloxone.
62. The method of claim 61, wherein the buprenorphine and naloxone
are administered together in a unit dose.
63-64. (canceled)
65. The method of claim 52, further comprising administering a
second active agent to the subject.
66. The method of claim 65, wherein the second active agent is
selected from the group consisting of antipsychotic agents,
atypical antipsychotic agents, antiepileptic agents, lithium, and
salts and acids thereof.
67. The method of claim 66, wherein the second active agent
comprises an atypical antipsychotic agent selected from the group
consisting of aripriprazole, olanzapine, paliperidone, quetiapine,
risperidone, ziprasidone, arisulpride, and combinations
thereof.
68-83. (canceled)
84. The method of claim 52, wherein about 2.0 mg of buprenorphine
is administered to the subject.
85. The method of claim 52, wherein about 8.0 mg of buprenorphine
is administered to the subject.
86. A kit for treating a bipolar condition and subtypes thereof
comprising: a plurality of buprenorphine dosage forms; at least one
second dosage form comprising a second active agent; a housing; and
instructions for taking the dosage forms for racing thoughts
associated with the depressed phase of the bipolar condition or
subtype thereof, and according to a predetermined dosing regimen,
wherein the housing is configured to organize the dosage forms
according to the predetermined dosing regimen.
87-94. (canceled)
95. The kit of claim 86, wherein the second active agent is
selected from the group consisting of antipsychotic agents,
atypical antipsychotic agents, antiepileptic agents, lithium, and
salts and acids thereof.
96. The kit of claim 95, wherein the second active agent comprises
an atypical antipsychotic agent selected from the group consisting
of aripriprazole, olanzapine, paliperidone, quetiapine,
risperidone, ziprasidone, arisulpride, and combinations
thereof.
97. (canceled)
98. The kit of claim 86, comprising a plurality of second dosage
forms.
99-123. (canceled)
124. The kit of claim 98, wherein the housing is configured to
organize the buprenorphine dosage forms and second dosage forms
into morning dosage forms and evening dosage forms.
125-129. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application Ser. No. 61/044,312 filed on Apr. 11, 2008 and U.S.
Provisional Patent Application Ser. No. 61/050,738 filed on May 6,
2008, each of which is hereby incorporated by reference in its
entirety.
FIELD
[0002] Treatment regimens for mood disorders that include
administration of buprenorphine, alone or in combination with
additional pharmacological agents are described. Specifically,
treatment regimens that alleviate racing thoughts associated with
bipolar disorder, and pharmaceutical compositions and kits for use
therein are described. The buprenorphine and other pharmacological
agents can be administered at therapeutic or subtherapeutic doses
to treat the racing thoughts. Dosing regimens, compositions, and
kits including buprenorphine for treating mania associated with
opioid withdrawal are also described.
BACKGROUND
[0003] Bipolar disorder, also known as manic-depressive illness, is
a disorder that causes unusual shifts in a individual's mood,
energy, and ability to function. Different from the normal ups and
downs that people experience, the symptoms of bipolar disorder are
generally severe. They can result in damaged relationships, poor
job or school performance, and even suicide.
[0004] Bipolar disorder typically develops in late adolescence or
early adulthood. However, some people have their first symptoms
during childhood, and some develop them late in life. Bipolar
disorder is a long-term illness that usually requires management
throughout an individual's life.
[0005] Bipolar disorder typically causes dramatic mood swings, from
overly elated ("high") and/or irritable to sad and hopeless, and
then back again, often with periods of normal mood in between.
Severe changes in energy and behavior oftentimes are experienced
with these changes in mood. The periods of highs and lows are
referred to as episodes of mania and depression.
[0006] Signs and symptoms of mania (or a manic episode) may include
the following: increased energy, activity, and restlessness;
excessively "high," overly good, euphoric mood; extreme
irritability; racing thoughts and talking very fast, jumping from
one idea to another; distractibility (e.g., difficulty
concentrating); decreased need for sleep; unrealistic belief in
one's abilities and powers; poor judgment; spending sprees; a
lasting period of behavior that is different from usual; increased
sexual drive; abuse of drugs (particularly cocaine, alcohol, and
sleeping medications); and provocative, intrusive, or aggressive
behavior. A manic episode may be diagnosed if elevated mood occurs
with three or more of the other symptoms most of the day, nearly
every day, for one week or longer.
[0007] Signs and symptoms of depression (or a depressive episode)
may include the following: lasting sad, anxious, or empty mood;
feelings of hopelessness or pessimism; feelings of guilt,
worthlessness, or helplessness; loss of interest or pleasure in
activities once enjoyed; decreased energy, a feeling of fatigue or
of being "slowed down"; difficulty concentrating, remembering, or
making decisions; restlessness or irritability; sleeping too much,
or difficulty sleeping; change in appetite and/or unintended weight
loss or gain; chronic pain or other persistent bodily symptoms that
are not caused by physical illness or injury; and thoughts of death
or suicide, or suicide attempts. A depressive episode may be
diagnosed if five or more of these symptoms last most of the day,
nearly every day, for a period of two weeks or longer.
[0008] A mild to moderate level of mania is generally referred to
as hypomania. Hypomania may feel good to the individual who
experiences it and may even be associated with good functioning and
enhanced productivity. Thus, even when family and friends learn to
recognize the mood swings as possible bipolar disorder, the
individual may deny that anything is wrong. Without proper
treatment, however, hypomania can become severe mania or can switch
into depression.
[0009] Sometimes severe episodes of mania or depression include
symptoms of psychosis. Common psychotic symptoms are hallucinations
(hearing, seeing, or otherwise sensing the presence of things not
actually there) and delusions (false, strongly held beliefs not
influenced by logical reasoning or explained by an individual's
usual cultural concepts). Psychotic symptoms in bipolar disorder
tend to reflect the extreme mood state at the time. For example,
delusions of grandiosity, such as believing one is the President or
has special powers or wealth, may occur during mania; delusions of
guilt or worthlessness, such as believing that one is ruined and
penniless or has committed some terrible crime, may appear during
depression.
[0010] It may be helpful to think of the various mood states in
bipolar disorder as a spectrum or continuous range. At one end is
severe depression, above which is moderate depression and then mild
low mood, which many people call "the blues" when it is short-lived
but is termed "dysthymia" when it is chronic. Then there is normal
or balanced mood, above which comes hypomania (mild to moderate
mania), and then severe mania.
[0011] In some people, however, symptoms of mania and depression
may occur together in what is called a mixed bipolar state.
Symptoms of a mixed state often include agitation, trouble
sleeping, a significant change in appetite, psychosis, and suicidal
thinking. An individual may have a very sad, hopeless mood while at
the same time feeling extremely energized.
[0012] Bipolar disorder may also initially present as a problem
other than mental illness. For instance, it may surface as alcohol
or drug abuse, poor school or work performance, or strained
interpersonal relationships. Such problems in fact may be signs of
an underlying bipolar disorder.
[0013] The classic form of the illness, which involves recurrent
episodes of mania and depression, is called bipolar I disorder.
Some individuals, however, never develop severe mania but instead
experience milder episodes of hypomania that alternate with
depression; this form of the illness is called bipolar II disorder.
When four or more episodes of illness occur within a 12-month
period, an individual is said to have rapid-cycling bipolar
disorder. Some individuals experience multiple episodes within a
single week, or even within a single day.
[0014] Bipolar disorder may be treated with medication and
psychosocial therapy. For example, medications known as mood
stabilizers may be prescribed. In general, individuals with bipolar
disorder continue treatment with mood stabilizers for years. Other
medications may be added when necessary, typically for shorter
periods, to treat episodes of mania or depression that break
through despite the mood stabilizer.
[0015] However, despite the use of mood stabilizers, drugs, e.g.,
alcohol, prescription drugs, or other illicit drugs, are often used
as a form of "self-medication" in order to counteract unpleasant
psychological symptoms (such as racing thoughts), which often leads
to abuse of these drugs. Patients with bipolar disorder and other
psychiatric disorders may also demonstrate somatization and
therefore seek out "pain management" doctors, because the
analgesics, hypnotics and stimulants commonly prescribed in this
context can help to temporarily relieve or control dysphoric
symptoms experienced in part as physical pain.
[0016] The high rates of drug abuse amongst patients with
psychiatric disorders has been documented. See, e.g., Cerullo and
Strakowski, Subst Abuse Treat Prey Policy (2007) 2:29. For example,
Cerullo and Strakowski report that the lifetime history of any drug
abuse or dependence is 84% for anti-social personality disorder,
62% for bipolar disorder types I and II, and 47% for schizophrenia,
compared with 27.2% for major depressive disorder and 17% for the
general population.
[0017] However, drug abuse, e.g., opioid abuse, and opioid
withdrawal, can actually worsen mood symptoms and significantly
complicate the course and prognosis of bipolar disorder or any
other psychiatric illness, resulting in increased suffering,
disability, and costs through more frequent and prolonged affective
episodes, decreased compliance with treatment, a lower quality of
life, and increased suicidal behavior.
[0018] Accordingly, new regimens for treating unpleasant and/or
difficult to treat symptoms of psychiatric disorders, especially
bipolar disorder would be useful. Treatment regimens that address
drug abuse and withdrawal, e.g., opioid abuse and withdrawal, would
also be useful. In particular, treatment regimens that are provided
as kits would be desirable.
SUMMARY
[0019] Described here are treatment regimens and compositions and
kits for use therein that may be beneficial in stabilizing mood,
increasing medication compliance, and preventing drug abuse in
subjects with bipolar disorder. The treatment regimens may achieve
mood stabilization by administering a partial opioid agonist, e.g.,
buprenorphine, in a predetermined fashion. For example, when a
plurality of buprenorphine doses are administered per day, the
first dose may be higher than any additional dose given. In one
variation, a morning dose of buprenorphine, e.g., a dose
administered at 6 am, may be higher than a buprenorphine dose given
in the evening, e.g., a dose administered at 6 pm, or in the late
evening, e.g., at 12 am (midnight). The first dose of buprenorphine
may range from about 1.0 mg to about 32 mg. For example, the first
dose may be about 1.0 mg, about 2.0 mg, about 4.0 mg, about 8.0 mg,
about 16 mg, about 24 mg, or about 32 mg of buprenorphine. The
lower dose of administered buprenoprhine may range from about 0 mg
to about 4.0 mg. For example, the first administered dose may be
about 0 mg, about 0.5 mg, about 1.0 mg, about 2.0 mg, or about 4.0
mg. It is understood that any suitable number of doses may be
administered. For example, one dose, two doses, three doses, or
four doses may be administered. In some variations, the treatment
regimens may include rapidly decreasing the buprenorphine dose over
the course of a day. In other variations, a gradual decrease in the
buprenorphine dose is employed (over a day).
[0020] The treatment regimens may be useful in treating mania
associated with opioid withdrawal. Here it is the belief of the
inventors that when a higher dose of buprenorphine is taken in the
evening or late evening (e.g., to treat opioid withrawal), it acts
as a mood destabilizer and thus, kindles mania or mania-like
symptoms in this patient population. In another variation, the
treatment regimens may be beneficial in alleviating racing thoughts
during the depressive phase of bipolar disorder. The treatment
regimens may further include one or more active agents
(supplemental agents), for treating comorbid conditions associated
with bipolar disorder.
[0021] As used herein, a "manic episode" is defined by criteria set
forth in the DSM-IV (Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition, 2000, American Psychiatric Association,
Washington, D.C), which is hereby incorporated herein by reference
for all purposes, as a distinct period of abnormally and
persistently elevated, expansive, or irritable mood, lasting at
least one week wherein three (or more) of the following symptoms
have persisted and have been present to a significant degree:
[0022] (1) inflated self-esteem or grandiosity [0023] (2) decreased
need for sleep (e-g., feels rested after only 3 hours of sleep)
[0024] (3) more talkative than usual or pressure to keep talking
[0025] (4) flight of ideas or subjective experience that thoughts
are racing [0026] (5) distractibility (i.e., attention too easily
drawn to unimportant or irrelevant external stimuli) [0027] (6)
increase in goal-directed activity (either socially, at work or
school, or sexually) or psychomotor agitation [0028] (7) excessive
involvement in pleasurable activities that have a high potential
for painful consequences (e.g., engaging in unrestrained buying
sprees, sexual indiscretions, or foolish business investments)
[0029] The mood disturbance is sufficiently severe to cause marked
impairment in occupational functioning or in usual social
activities or relationships with others, or to necessitate
hospitalization to prevent harm to self or others, or there are
psychotic features. The symptoms are not due to the direct
physiological effects of a substance (e.g., a drug of abuse, a
medication, or other treatment) or a general medical condition
(e.g., hyperthyroidism).
[0030] A "mixed episode" is observed when criteria are met both for
a manic episode (see above) and for a major depressive episode, as
defined in the DSM-IV, nearly every day during at least a one week
period and the mood disturbance is sufficiently severe to cause
marked impairment in occupational functioning or in usual social
activities or relationships with others, or to necessitate
hospitalization to prevent harm to self or others, or there are
psychotic features. As with a manic episode, the symptoms are not
due to the direct physiological effects of a substance (e.g., a
drug of abuse, a medication, or other treatment) or a general
medical condition (e.g., hyperthyroidism).
[0031] A "hypomanic episode" is defined by the DSM-IV as a distinct
period of persistently elevated, expansive, or irritable mood,
lasting throughout at least four days, that is clearly different
from the usual nondepressed mood. During the period of mood
disturbance, three (or more) of the symptoms listed above for
"manic episode" above, have persisted and have been present to a
significant degree. The episode is associated with an unequivocal
change in functioning that is uncharacteristic of the individual
when not symptomatic. The disturbance in mood and the change in
functioning are observable by others. The episode is not severe
enough to cause marked impairment in social or occupational
functioning, or to necessitate hospitalization, and there are no
psychotic features. The symptoms are not due to the direct
physiological effects of a substance (e.g., a drug of abuse, a
medication, or other treatment) or a general medical condition
(e.g., hyperthyroidism).
[0032] As used herein, the phrase "opioid withdrawal" refers to a
variety of signs and complaints appearing with the abrupt removal
of, or a rapid decrease in the regular dosage of opioids. The
symptoms stop when an opioid agonist is taken again. Physical
manifestations may include sweating, nausea, yawning, chills,
diarrhea, papillary dilation, piloerection, tachycardia, increased
blood pressure, hypersensitivity to pain, stomach cramps, and
muscle cramps. Psychological manifestations of opioid withdrawal
observed may include dysphoria, restlessness, irritability,
anxiety, and depression. Onset often begins within 6-24 hours from
last opioid use.
[0033] The terms "treating" or "alleviating" interchangeably refer
to delaying the onset of, retarding or reversing the progress of,
or preventing either the disease or condition to which the term
applies, or one or more symptoms of such disease or condition.
[0034] The term "patient," "subject," or "individual"
interchangeably refer to a mammal, for example, a domesticated
mammal (canine or feline), a laboratory mammal (murine, rattus,
lagomorpha), or a human.
[0035] A variation of the methods described here includes treating
mania associated with opioid withdrawal in a subject by
administering a first dose of a kappa opioid and at least one
additional dose of the kappa opioid to the subject according to a
predetermined dosage regimen, where the at least one additional
dose is less than the first dose. The first dose may be
administered in the morning, e.g., at 6 am or between about 6 am
and 9 am, and the at least one additional dose may be administered
in the afternoon, e.g., at 12 pm (noon) or between about 12 pm and
3 pm, evening, e.g., at 6 pm or between about 6 pm and 9 pm, or
late evening, e.g., at 12 am (midnight). The kappa opioid may be a
kappa receptor antagonist including, but not limited to,
5'-guanidinonaltrindole, buprenorphine, norbinaltorphimine, JDTic,
and combinations thereof. In one variation, the kappa receptor
antagonist is buprenorphine. The buprenorphine may be administered
in doses of about 0.5 mg, about 1.0 mg, about 2.0 mg, about 8.0 mg,
about 16 mg, about 24 mg, about 32 mg, or combinations thereof. In
some variations, a subtherapeutic dose of buprenorphine is
administered.
[0036] By "subtherapeutic dose" it is meant a dose of a kappa
opioid, e.g., buprenorphine, either as an administered dose of the
kappa opioid, or actual level of the kappa opioid in a subject that
functionally is insufficient to elicit the intended pharmacological
effect in itself (e.g., analgesia, pain relief, reversal of opioid
withdrawal symptoms, reduction of psychotic symptoms, prevention of
epileptic seizure, etc.), or that quantitatively is less than the
established therapeutic dose for that particular kappa opioid
(e.g., as published in a reference consulted by a individual of
skill, for example, doses for a pharmacological agent published in
the Physicians' Desk Reference, 62.sup.nd Ed., 2008, Thomson
Healthcare or Brunton, et al., Goodman & Gilman's The
Pharmacological Basis of Therapeutics, 11.sup.th edition, 2006,
McGraw-Hill Professional). A "subtherapeutic dose" can be defined
in relative terms (i.e., as a percentage amount (less than 100%) of
the amount of the kappa opioid conventionally administered). For
example, a subtherapeutic dose amount can be about 1% to about 75%
of the amount of kappa opioid conventionally administered. In some
variations, a subtherapeutic dose can be about 10%, 20%, 25%, 30%,
50% or 75% of the amount of kappa opioid conventionally
administered.
[0037] In another variation, the kappa opioid may be a kappa
receptor agonist including, but not limited to, butorphanol,
BRL-52537, cyclazocine, enadoline, GR-89696, HZ-2, ICI-204,448,
ketazocine, LPK-26
(2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-(2-isopropyl)-2-(1-(3-pyrrolin-
yl))ethyl]acetamide), nalbuphine, pentazocine, salvinorin A,
spiradoline, tifluadom, U-50488, U-62066, U-69593, and combinations
thereof.
[0038] The predetermined dosing regimens may administer the first
dose of the kappa opioid in the morning and at least one additional
dose of the kappa opioid in the evening. In one variation, two or
more additional doses of the kappa opioid are administered in a
gradually decreasing fashion.
[0039] In other variations, a second active agent may be
administered to help with mood stabilization. Exemplary second
active agents include without limitation, antipsychotic agents,
atypical antipsychotic agents, antiepileptic agents, lithium, P-450
CYP3A4 inhibitors, P-450 CYP2D6 inhibitors, CB1 agonists, CB2
agonists or antagonists, salts, and acids thereof, and combinations
thereof. When atypical antipsychotics are employed, they may
include without limitation, aripriprazole, arisulpride
(amisulpride), olanzapine, paliperidone, quetiapine, risperidone,
ziprasidone, and combinations thereof. The predetermined dosing
regimens may be designed so that the second active agent is
administered in the morning or the evening. In some variations, the
second acitve agent is administered multiple times a day. The
second active agent may also be administered in a rapidly or
gradually increasing or decreasing manner throughout the day. In
some variations, the second active agent is administered in an
increasing manner, i.e., the morning dose is lower than the evening
or late evening dose. In other variations, the dosing of the second
active agent and partial opioid agonist is inverse to one another.
In yet further variations, the second active agent may be
administered so that the highest dose is in the evening and the
lowest dose is in the morning.
[0040] Further active agents (supplemental agents) may be
administered to treat comorbid conditions associated with bipolar
disorder, a side-effect of the second active agent, or another
symptom associated with bipolar disorder. The comorbid condition
may be a sleep disorder. Exemplary sleep disorders include without
limitation, hypoventilation-obesity syndrome (Picwickian syndrome),
idiopathic hypersomnia, narcolepsy, night terrors, parasomnias,
primary snoring, sleep apnea, nocturnal sleep-related eating
disorder, spousal arousal syndrome, upper airway resistance
syndrome, and combinations thereof. In some variations, the sleep
disorder may be due to alcoholism, allergic rhinitis, altered
light-dark cycles, amphetamine use, antidepressant use, anxiety,
asthma, benzodiazepine withdrawal, chronic fatigue syndrome,
chronic obstructive pulmonary disease (COPD), chronic pain, cocaine
use, compulsive hyperphagia, anorexia, bulimia, anorexia-bulimia,
starvation, restricted caloric intake, dementia, disturbances in
circadian rhythm, dyspnea, edema, eneuresis, fibromyalgia, food
intolerance, gastroesophageal reflux, hyperammonemia,
hypersensitivity to stimulants, incontinence, infection,
inflammatory bowel syndrome, irritable bowel syndrome, modafinil
(Provigil.RTM. tablet) use, neuromuscular disorders, nocturia ,
nocturnal myoclonus, orthopnea, paroxysmal nocturnal dyspnea, pica,
Prinzmetal's angina, pruritis, racing thoughts, restless leg
syndrome, seizure disorder, sinusitis, sleepwalking, or
combinations thereof.
[0041] Other comorbid conditions include diabetes mellitus,
obesity, and fibromyalgia. An exemplary side-effect of the second
active agent may be an extrapyrimidal symptom such as
akisthesia.
[0042] The kappa opioids, second active agents, and supplemental
agents may be provided in any suitable dosage form. For example,
the dosage forms may be liquid, solid, or semi-solid. They may also
be formulated for any suitable mode of administration, such as, but
not limited to, oral, sublingual, buccal, parenteral, intravenous,
intramuscular, subcutaneous, topical, inhalation, and needle-free
administration. In some variations, the first dose and the at least
one additional dose of the kappa opioid are provided in the same
dosage form. In other variations, the first dose and the at least
one additional dose of the kappa opioid are provided in different
dosage forms. Exemplary dosage forms include without limitation,
powders, granules, capsules, films, transdermal patches, buccal
patches, sublingual formulations, gums, chewables, oral strips,
rapid dissolve tablets, coated tablets, solutions, ointments,
creams, and gels. In some instances, the composition comprises a
sublingual formulation within a rapid dissolve tablet. In other
instances, the composition comprises a sublingual formulation
surrounded by a buccal patch. In yet further instances, the
composition comprises a sublingual formulation surrounded by a
mouth strip. It is understood that other composition forms are also
contemplated.
[0043] In some variations, the kappa opioids, e.g., buprenorphine,
second active agents, and supplemental agents are provided in
separate dosage forms and co-administered (administered in
combination) with each other, e.g., taken at the same time or
sequentially. In other variations, the kappa opioids, e.g.,
buprenorphine, second active agents, and supplemental agents are co
formulated together, i.e., they are included in a single dosage
form.
[0044] The compositions for use with the methods described herein
may include a partial opioid agonist, e.g., a kappa-receptor
antagonist such as buprenorphine, and a second active agent in a
single dosage form, where the second active agent comprises an
antipsychotic agent, an atypical antipsychotic agent, an
antiepileptic agent, lithium, naloxone, a P-450 CYP3A4 inhibitor, a
P-450 CYP2D6 inhibitor, salts and acids thereof, and combinations
thereof. The single dosage form may be a powder, granules,
capsules, films, transdermal patches, buccal patches, sublingual
formulations, gums, chewables, oral strips, rapid dissolve tablets,
coated tablets, solutions, ointments, creams, and gels. In one
variation, the single dosage form comprises a sublingual
formulation within a rapid dissolve tablet. In some variations, the
second active agent includes an atypical antipsychotic. For
example, the atypical antipsychotic may include aripriprazole,
arisulpride, olanzapine, paliperidone, quetiapine, risperidone,
ziprasidone, or combinations thereof.
[0045] Kits for treating mania associated with opioid withdrawal
that include a plurality of buprenorphine dosage forms and
instructions for administering the dosage forms according to a
predetermined dosage regimen are also described. Here the
predetermined dosing regimen may include administering a first
buprenorphine dose and at least one additional buprenorphine dose
that is less than the first dose. The predetermined dosing regimen
may provide that the first dose be administered in the morning,
e.g., at 6 am or between about 6 am and 9 am, and the at least one
additional dose administered in the afternoon, e.g., at 12 pm
(noon) or between about 12 pm and 3 pm, evening, e.g., at 6 pm or
between about 6 pm and 9 pm, or late evening, e.g., at 12 am
(midnight).
[0046] The kits may include a housing configured to organize the
dosage forms according to the predetermined dosing regimen. For
example, the housing may be configured to organize the plurality of
dosage forms into morning dosage forms and evening dosage forms. In
some variations, the housing may be configured to organize the
plurality of buprenorphine dosage forms according to a rapidly or a
gradually decreasing dosing regimen. In yet further variations, the
housing may be configured to organize the buprenorphine dosage
forms according to the day of the week to be taken.
[0047] The kits may also include a second dosage form having one or
more second active agents. The second active agent may also help to
stabilize the mood of the patient. Exemplary second active agents
include without limitation, aripriprazole, arisulpride, olanzapine,
paliperidone, quetiapine, risperidone, ziprasidone, and
combinations thereof. The kit may further include additional dosage
forms that include one or more additional agents for treating a
comorbid condition. For example, an antihistamine may be useful to
include when the comorbid condition is a sleep disorder. Dosage
forms that include other active agents (e.g., to treat
comorbidities) or second active agents (e.g., for mood
stabilization) may be organized in the housing similar to the
organization provided for the buprenophine dosage forms, as
described above.
[0048] Also described here are methods for treating a bipolar
condition/disorder and subtypes thereof in a subject experiencing
racing thoughts by administering buprenorphine to the subject to
alleviate the racing thoughts. Subtypes of a bipolar condition may
include without limitation, bipolar I disorder, bipolar II
disorder, mixed bipolar disorder, rapid-cycling bipolar disorder,
hypomania, cyclothymia, acute mania, drug-induced mania, or
drug-induced hypomania. The methods may be applicable to racing
thoughts experienced during a depressive episode (instead of during
the manic phase). In some variations, an opioid antagonist is also
administered. In other variations, a second active agent is
administered to the subject to help stabilize their mood. Such
agents may include antipsychotic agents, atypical antipsychotic
agents, antiepileptic agents, lithium, and salts and acids thereof,
and combinations thereof. Supplemental or additional agents may
also be administered to treat a comorbid condition, a side-effect
of the second active agent, a symptom associated with the bipolar
condition, or combinations thereof. In other instances, light
therapy may be used to treat the racing thoughts, other symptoms
associated with the bipolar disorder, a comorbid condition, or a
side-effect of the second active agent.
[0049] The kits for treating the symptom of racing thoughts in
bipolar disorder may include a plurality of buprenorphine dosage
forms, at least one second dosage form comprising a second active
agent that helps to stabilize mood, e.g., an atypical antipsychotic
agent, and instructions for taking the dosage forms according to a
predetermined dosing regimen. Dosage forms including an opioid
antagonist such as naloxone may also be included. In some
variations, dosage forms having a supplemental or additional agent
for treating a comorbid condition, side-effect of second agent,
and/or other symptoms of bipolar disorder may be provided in the
kits.
[0050] The kits may further include a housing configured to
organize the dosage forms according to the predetermined dosing
regimen. For example, the housing may be configured to organize the
plurality of dosage forms into morning dosage forms and evening
dosage forms. In some variations, the housing may be configured to
organize the plurality of dosage forms according to a rapidly or a
gradually decreasing dosing regimen. In yet further variations, the
housing may be configured to organize the dosage forms according to
the day of the week to be taken. The kits may also be tailored to
treat particular bipolar conditions or subtypes. For example, the
kits may be tailored to treat bipolar I disorder, bipolar II
disorder, mixed bipolar disorders, rapidly-cycling bipolar
disorder, acute mania, drug-induced mania, hypomania, cyclothymia,
or combinations thereof.
DETAILED DESCRIPTION
[0051] Described herein are treatment regimens and compositions and
kits for use therein that may be beneficial in stabilizing mood,
increasing medication compliance, and preventing drug abuse in
subjects with bipolar disorder. As previously stated, the treatment
regimens may achieve mood stabilization by administering a partial
opioid agonist, e.g., a kappa-receptor antagonist such as
buprenorphine, in a predetermined fashion. The amount and frequency
of administration of the partial opioid agonist will vary depending
on such factors as the particular type of bipolar disorder
diagnosed, associated symptoms and/or comorbidities, other
medications being taken by the patient, and previous history of
opioid abuse. For example, when a plurality of buprenorphine doses
are administered per day, the first dose may be higher than any
additional dose given. In some variations, a morning dose of
buprenophine may be higher than a buprenorphine dose given in the
evening or late evening. For example, a buprenophine dose
administered at 6 am may be higher than a buprenorphine dose given
in the evening, e.g., at 6 pm, or late evening., e.g., at 12 am
(midnight). In some variations, the treatment regimens may include
rapidly decreasing the buprenorphine dose over the course of a day.
In other variations, a gradual decrease in the buprenorphine dose
is employed (over a day).
[0052] The treatment regimens may be useful in treating mania
associated with opioid withdrawal. This may be due to the
destabilizing effect of buprenophine when taken in the evening by
patients undergoing opioid withdrawal treatment. As previously
stated, it is the belief of the inventors that when higher doses of
buprenorphine are taken in the evening, it acts as a mood
destabilizer and thus, kindles mania or mania-like symptoms in this
patient population. In another variation, the treatment regimens
may be beneficial in alleviating racing thoughts during the
depressive phase of bipolar disorder.
[0053] A variety of studies have implicated buprenorphine in the
induction of mania or manic episodes. See, e.g., Jagadheesan and
Muirhead, Aust NZ J Psychiatry (2004) 38(7):560; Leza, et al., Gen
Pharmacol (1991) 22(2):293-6; and Robertson and Taylor, J Feline
Med Surg. (2004) 6(5):321-33. However, contrary to the published
literature, the inventors have found that kappa opioids such as
buprenorphine, either administered alone or in combination with
other active agents, is efficacious in mood stabilization when a
lower dose is administered in the evening, and also efficacious in
alleviating racing thoughts associated with the depressed phase(s)
of bipolar disorder. Accordingly, buprenorphine may be useful in
treating mania associated with opioid withdrawal. The inventors
have also found that buprenorphine administration may improve
patient compliance with prescribed medication regimes by better
stabilizing their bipolar symptoms, and in some instances, may
improve compliance by reducing the number of medications needed to
effectively treat bipolar disorder symptoms.
[0054] For example, bipolar disorder patients are prone to narcotic
abuse because when initially taken, the narcotics elevate their
mood. However, when the narcotic wears off, the patients become
even more depressed, resulting in a desire to take more narcotics,
which then wear off, etc., resulting in an oscillating behavioral
pattern that negatively effects the course of their bipolar
disorder. For instance, patients with co-occurring substance use
may have more prolonged affective episodes and may generally be
less compliant with treatment. In some cases, more mood stabilizer
needs to be prescribed to help control symptoms. Contrastingly, the
inventors have found that bipolar disorder patients being
administered buprenorphine according to the dosing regimens
described herein may be less likely to take other narcotic
substances. Given that buprenorphine administration has been found
to alleviate symptoms such as anxiety, irritability, and racing
thoughts, patients on buprenorphine therapy may be less predisposed
to self-medicate with benzodiazepines. They may also be less likely
to take antidepressants to alleviate depressive symptoms. This is
also beneficial because antidepressants have been associated with
triggering mania.
[0055] Compliance may also be reduced due to the detrimental
side-effects that may be experienced with conventional bipolar
disorder treatments. Currently, mania is treated with mood
stabilizers and antipsychotic medications. Both classes of
medications are accompanied with potentially harmful side effects.
Lithium, used as a mood stabilizer, can produce sometimes
significant weight gain, acne with scarring, thinning of hair, and
pronounced tremor. Administration of antipsychotic medications can
result in the development of extrapyramidal symptoms (EPS)
consisting of extreme motor restlessness (akathisia), prolonged
muscle contraction (dystonia), parkinsonism and repetitive,
involuntary purposeless movements such as grimacing, blinking, lip
smacking, puckering and pursing (tardive dyskinesia) which have a
significant impact on tolerability and adherence in addition to
impacting function. The use of antipsychotics has also been
associated with neuroleptic malignant syndrome, a life threatening
neurological disorder. These side effects render compliance
difficult. This may be especially true for individuals with
co-occurring substance abuse; a significant proportion of
individuals suffering from mania and/or bipolar disorder.
[0056] Compliance may also be affected by sleep disturbance. Sleep
problems in bipolar disorder are universal and persistent; they
represent both a symptom of the condition and a cause. Bipolars
tend to exhibit impaired sleep efficiency, higher levels of anxiety
and fear about poor sleep, and a tendency to misperceive that the
sleep they are getting is inadequate. See, e.g., Harvey et al., Am
J Psychiatry 162:50-57, January 2005. The underlying cause of their
anxiety is often awareness that sleep loss can herald or intensify
periods of manic or hypomanic activity. This anxiety may then serve
to perpetuate the insomnia which in turn exacerbates the disease.
The prevalence of opioid and benzodiazepine abuse is partially
explainable in terms of the effectiveness of these drugs on
promoting sleep. Medicines other than full opioid agonists and
benzodiazepines which promote sleep may therefore have a
particularly palliative effect in this population both as abortive
therapy during a manic or hypomanic episode and as prophylactic
therapy to prevent an episode.
I. Compositions
[0057] The compositions described here for mood stabilization may
include any suitable active agent in any pharmaceutically
acceptable form. For example, the compositions may include any
pharmaceutically acceptable salts, prodrugs, racemic mixtures,
conformational and/or optical isomers, crystalline polymorphs and
isotopic variants of the active agents. The compositions may also
be configured to have any suitable form, e.g., solid, semi-solid,
or liquid. The compositions may also be provided in unit dose form.
In general, the compositions may include a partial opioid receptor
agonist, e.g., a kappa-receptor agonist or a kappa-receptor
antagonist, and one or more additional active agents. The
compositions may also be configured to include any suitable type of
release kinetics. For instance, the compositions may be configured
to release the partial opioid agonist, or one or more active agents
in a controlled release, delayed release, sustained release,
immediate release, pulsatile, or continuous manner.
Partial Opioid Agonists
[0058] The compositions described here may include any suitable
partial opioid agonist. The partial opioid agonists will generally
be compounds having some agonist activity at opioid receptors.
However, because they are weak agonists, they may also function as
opioid receptor antagonists. Partial opioid agonists that may be
useful here include buprenorphine, thienorphine, pentazocine,
propiram, lofexidine, nalorphine, butorphanol and oxilorphan.
Partial opioid agonists are also generally reviewed in Chapter 21,
section III of Goodman and Gilman's The Pharmacological Basis of
Therapeutics, supra, which is incorporated herein by reference. The
partial opioid agonist may be a kappa opioid, i.e., a compound
having activity at the kappa (.kappa.) opioid receptor. In one
variation, the kappa opioid is a kappa receptor agonist. In another
variation, the kappa opioid is a kappa receptor antagonist, e.g.,
buprenorphine.
[0059] Buprenorphine is
17-(cyclopropylmethyl)-.alpha.-(1,1-dimethylethyl)-4, 5-epoxy-18,
19-dihydro-3-hydroxy-6-methoxy-.alpha.-methyl-6,
14-ethenomorphinan-7-methanol. Buprenorphine is manufactured and
sold as buprenorphine HCl by Reckitt Benckiser Pharmaceuticals
(Richmond, Va., sold as Buprenex (injectable; analgesic); Subutex
(sublingual tablets; opioid addiction)). Buprenorphine is also
manufactured and sold as Suboxone, a combination of buprenorphine
HCl and naloxone HCl dehydrate in a ratio of 4:1. Suboxone, like
Subutex, is generally used in treating opioid addiction and as an
analgesic.
[0060] Buprenorphine is usually administered intravenously and
sublingually. As an analgesic, buprenorphine may be administered
intravenously in relatively low doses, e.g., 0.3-0.6 mg/injection.
In treating opioid addiction, buprenorphine (e.g., alone or in
combination with naloxone) may be administered sublingually in
doses upwards of from about 0.5 mg-32 mg/day, for example, about
0.5, 1.0 2.0, 4.0, 8.0, 24, or 32 mg/day. An effectiveness plateau
may be reached at about 32 mg/day. Higher doses for treating opioid
addiction may be required as a result of opioid experience and
therefore tolerance of addicted individuals. Here administration of
buprenorphine by other modes are also contemplated.
[0061] In another variation, kappa opioids other than buprenorphine
are employed. For example, kappa receptor agonists and antagonists
may be used. Suitable kappa receptor agonists include without
limitation, butorphanol, BRL-52537, cyclazocine, enadoline,
GR-89696, HZ-2, ICI-204,448, ketazocine, LPK-26
(2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-(2-isopropyl)-2-(1-(3-pyrrolin-
yl))ethyl]acetamide), nalbuphine, pentazocine, salvinorin A,
spiradoline, tifluadom, U-50488, U-62066, U-69593, and combinations
thereof. Exemplary kappa receptor antagonists for use in the
compositions include without limitation, 5'-guanidinonaltrindole,
norbinaltorphimine, JDTic, and combinations thereof.
Other Active Agents
[0062] In some variations, buprenorphine is administered in
combination with an opioid antagonist. Suitable opioid antagonists
that may be used without limitation include natrexone and naloxone.
Naltrexone can be administered intravenously in doses of 0.2 mg-0.6
mg; subcutaneously 0.8 mg; and intramuscularly 380 mg/week.
Naltrexone can also be administered orally or sublingually in doses
of about 0.25 mg to about 8.0 mg, for example, about 1.0 mg, 2.0
mg, 4.0 mg or 8.0 mg. Naloxone is available for intravenous,
intramuscular or subcutaneous administration, in concentrations
from about 0.4 mg/mL to 1.0 mg/mL. In some variations, the opioid
antagonist is provided with the partial opioid agonist, e.g.,
buprenorphine, in a single dosage form.
[0063] In some variations, the kappa receptor antagonist, e.g.,
buprenorphine, is administered in combination with a mood
stabilizer. Mood stabilizers for use here include without
limitation, lithium, aripiprazole (Abilify), olanzapine (Zyprexa),
risperidone (Risperidal), quietiapine (Seroquel), and ziprasidone
(Geodon). Therapeutic doses of lithium may be about 300-1800
mg/day, for example, about 900-1200 mg/day. Specifically, lithium
doses of about 300 mg, about 600 mg, or about 900 mg per day may be
useful. Therapeutic doses of ziprasidone may be about 20-160
mg/day, for example, about 80-160 mg/day. Specifially, ziprasidone
doses of about 40 mg, about 80 mg, or about 120 mg per day may be
useful. The therapeutic doses of aripiprazole may be about 1-30
mg/day, for example, about 5-20 mg/day or about 10-15 mg/day.
Specifically, aripriprazole doses may be about 2.0 mg, about 10 mg,
or about 15 mg per day.
[0064] In some variations, the partial opioid agonist, e.g.,
buprenorphine, may be administered in combination with an
antipsychotic agent. The antipsychotic agents may be any class of
antipsychotic, e.g., it may be a typical or atypical antipsychotic.
Some antipsychotic agents may have sedative effects on the patient,
and facilitate sleep. For instance, phenothiazines, thioxanthenes,
and other heterocyclic compounds can all be administered in
combination with buprenorphine.
[0065] Phenothiazines that may be used include without limitation:
chloropromazine hydrochloride, mesoridazine hydrochloride,
thioridazine hydrochloride (Mellaril), fluphenazine hydrochloride
(Prolixin), fluphenazine enanthate, fluphenazine decanoate,
perphenazine, trifluoperazine hydrochloride (Stelazine), and
combinations thereof. Other unlisted phenothiazine antipsychotics
and analogs thereof can also be used.
[0066] Phenothiazines possessing relatively high sedative effect
include without limitation: chlorpromazine hydrochloride
(Largactil, Thorazine), mesoridazine hydrochloride, and
thioridazine hydrochloride. In relation to these, perphenazine
possesses a somewhat lower sedative effect.
[0067] Therapeutic doses for chlorpromazine hydrochloride may be
about 30-2000 mg/day, for example, about 200-800 mg/day.
Therapeutic doses for mesoridazine hydrochloride are about 30-400
mg/day, for example, about 75-300 mg/day. Therapeutic doses for
thioridazine hydrochloride are about 20-800 mg/day, for example,
about 15-600 mg/day. Perphenazine is administered in a therapeutic
dose range of about 4-64 mg/day, for example, about 8-32
mg/day.
[0068] Thioxanthenes for use in the present invention include
chloroprothixene, thiothixene hydrochloride (Navane), clopenthixol,
cis-flupentixol, and pitflutixol. Other unlisted thioxanthene
antipsychotics and analogs thereof can also be used.
[0069] Chloroprothixene is administered in a therapeutic dose range
of about 30-600 mg/day, for example, about 50-400 mg/day.
Chloroprothixene possesses moderately high sedative effects.
[0070] Other antipsychotic compounds, including other heterocyclic
antipsychotic compounds for use herein may include without
limitation: abripiprazole, arisulpride, clozapine, quetiapine
fumarate, haloperidol, loxapine succinate (Loxapac, Loxitane),
clothiapine, metiapine, zotepine, molindone hydrochloride,
olanzapine, paliperidone, pimozide, prochlorperazine (Compazine,
Buccastem, Stemetil or Phenotil) risperidone, trifluoroperazine,
zuclopenthixol (Clopixol), and combinations thereof. Other unlisted
antipsychotics and analogs thereof can also be used.
[0071] When olanzapine is used, it may be provided in a dose of
about 5.0 mg, about 10 mg, or about 15 mg, or combinations thereof.
When paliperidone is provided, it may be provided in a dose of
about 1.5 mg, about 3.0 mg, about 6.0 mg, or about 12 mg, or
combinations thereof. With respect to quietiapine, it may be
provided in a dose of about 50 mg, 100 mg, 300 mg, or combinations
thereof. When risperidone is used, it may be provided in a dose of
about 0.25 mg, about 0.5 mg, about 1.0 mg, about 2.0 mg, about 3.0
mg, about 4.0 mg, or combinations thereof. When arisulpride is
used, it may be provided in a dose of about 50 mg, about 200 mg, or
combinations thereof (between about 400-800 mg/day). When
trifluoroperazine is used, it may be provided in doses of about 1.0
mg, 2.0 mg, 5.0 mg, 10 mg, or combinations thereof.
[0072] In some variations, buprenorphine is administered in
combination with ziprasidone (Geodon). Ziprasidone can be
administered in a therapeutic dose range of about 20-160 mg/day,
for example, about 80-160 mg/day. Ziprasidone may be a favorable
antipsychotic because it is hepatically metabolized by aldehyde
oxidase. Only minor metabolism occurs via CYP3A4 so there is a
decreased likelihood of interactions from medications that induce
or inhibit this enzyme (e.g., buprenorphine). Also, compared to
other atypical antipsychotics, namely olanzapine, ziprasidone has a
benign metabolic side effect profile with less likelihood of
medication-induced weight gain, dyslipidemia, and insulin
resistance leading to diabetes. Because the prevalence of the
metabolic syndrome and obesity in patients with bipolar disorder is
even higher than the already very high prevalence that has been
estimated for the U.S. general population, the use of drugs which
are metabolically neutral may therefore be beneficial.
[0073] In some variations, buprenorphine is administered in
combination with aripiprazole (Abilify). Aripiprazole can be
administered in a therapeutic dose range of about 1-30 mg/day, for
example, about 5-20 mg/day or about 10-15 mg/day. Aripiprazole is
another favorable antipsychotic because, similar to ziprasidone, it
has a benign metabolic side effect profile.
[0074] In some variations, buprenorphine is administered in
combination with quetiapine fumurate (Seroquel). Quetiapine
fumurate can be administered in a therapeutic dose range of about
50-750 mg/day, for example, about 300-500 mg/day.
[0075] Clozapine can be administered in a therapeutic dose range of
about 12.5-900 mg/day, for example, about 150-450 mg/day.
Aripiprazole can be administered in a therapeutic dose range of
1-30 mg/day, for example, about 5-20 mg/day or about 10-15 mg/day.
Clozapine and quetiapine fumarate exert moderately high sedative
effects. Aripriprazole and ziprasidone possess relatively low
sedative effects.
[0076] In other variations, the partial opioid agonist, e.g.,
buprenorphine, is administered in combination with an antiepileptic
or an anticonvulsant. Exemplified antiepileptic agents include
topiramate, zonisamide and the like. Anticonvulsant agents may have
sedative effects on the patient, and facilitate sleep.
Anticonvulsants or antiepileptics for use herein along with their
therapeutic doses include without limitation the following classes
of compounds: barbiturates (e.g., phenobarbitol (150-300 mg/day)
and mephobarbitol), hydantoins (e.g., phenytoin (300-1000 mg/day)),
iminostilbenes (e.g., carbamazepine (400-1600 mg/day) and
oxcarbazepine (450-2400mg/day)), and succinimides (e.g.,
ethosuximide (250-2000 mg/day)). Other useful
anti-convulsants/epileptic compounds include: gabapentin (300-3600
mg/day), topiramate (50-1600 mg/day), tiagabine (4-56 mg/day),
levetiracetam (1000-3600 mg/day), felbamate (1200-3600 mg/day),
zonisamide (100-600 mg/day), and valproic acid (10-100 mg/kg/day).
Divalproex, lamotrigine, and oxacarbazine may also be used.
Divalproex may be provided in doses of about 1000 mg, about 1500
mg, or about 2000 mg, or combinations thereof. Lamotrigine may be
provided in doses or about 50 mg, about 100 mg, about 200mg, or
combinations thereof.
[0077] Drowsiness is a side effect of the barbiturates, as a class,
and gabapentin, topiramate, ethosuximide, zonisamide, tiagabine. A
side effect of carbamazepine, after long term treatment, may be
drowsiness.
[0078] In some variations, the partial opioid agonist, e.g.,
buprenorphine, is administered in combination with muscle relaxant.
Muscle relaxants for use in the present invention include:
carisoprodol (1000-1400 mg/day), meprobamate (200-2400 mg./day),
baclofen (15-80 mg/day), and tizanidine (4-36 mg/day).
[0079] In some variations, the partial opioid agonist, e.g.,
buprenorphine, is administered in combination with ziprasidone
(Geodon) and carisoprodol.
[0080] In some variations, the partial opioid agonist is
administered in combination with an agent that potentiates its
pharmacological effect, for example, an agent that competes with
the P-450 enzymes that metabolizes the partial opioid agonist.
P-450 CYP3A4 or CYP2D6 Inhibitors (Buprenorphine Potentiators)
[0081] Buprenorphine is primarily metabolized by the cytochrome
P450 enzymes CYP3A4 and CYP2D6. Therefore, administering
buprenorphine in combination with an inhibitor of CYP3A4 and or
CYP2D6 may potentiate the pharmacological effect of buprenorphine
(e.g., by enhancing bioavailability). Combined administration of an
inhibitor of CYP3A4 and/or CYP2D6 with buprenorphine (either as
separate dosage forms or in a single dosage form) may allow for
administration of fewer therapeutically effective doses of
buprenorphine and/or for administration of subtherapeutic doses of
buprenorphine.
[0082] In some variations, buprenorphine is administered in
combination with or co-formulated with a CYP3A4 inhibitor as a
second active agent. Exemplary CYP3A4 inhibitors include, without
limitation, amiodarone, cannabinoids (e.g., dronabinol, nabilone,
and Sativex), cimetidine, clarithromycin, delavirdine,
erythromycin, fluconazole, indinavir, itraconazole, ketoconazole,
metronidazole, miconazole, nefazadone, nelfinavir, nicardipine,
norfloxacin, omeprozol, quinine, ritonavir, saquinavir, verapamil,
zafirlukast and zileuton.
[0083] In some variations, buprenorphine is administered with a 2D6
inhibitor, e.g., cimetidine (Zantac). In some variations, the
cimetidine is administered at doses above 200 mg, for example,
about 300 mg, 400 mg, 600 mg or 800 mg. In other variations,
buprenorphine is administered with a CB1 and CB2 agonist (e.g.,
Cannabinor and KN38-7271) or a CB1 antagonist (e.g., Taranabant,
Otenabant, Ibibipinabant, Surinabant, and Drinabant).
[0084] In other variations, buprenorphine is administered in
combination with or co-formulated with a CYP2D6 inhibitor as a
second active agent. Exemplary CYP2D6 inhibitors include, without
limitation, quinidine, terbinafine, celecoxib, chloipheniramine,
chlorpromazine, clemastine, clomipramine, cocaine, amiodarone,
diphenhydramine, doxorubicin, goldenseal, halofantrine, histamine
H1 receptor antagonists, hydroxyzine, levomepromazine,
metoclopramide, mibefradil, midodrine, moclobemide, perphenazine,
ranitidine, red-haloperidol, ritonavir, ticlopidine, and
tripelennamine.
[0085] The CYP3A4 and/or CYP2D6 inhibitors are administered at
their recommended or smaller doses for their approved uses. See,
e.g., Goodman and Gilman's, supra, Physician's Desk Reference,
supra, and the FDA Orange Book.
Sugar
[0086] It has been reported that glucose and sucrose ingestion
induces production of endogenous opioids, which may alleviate
opioid withdrawal symptoms. See, e.g., Kracke, et al., Anesth Analg
(2005) 101:64-8; Gharavi, et al., Pediatr Int (2007) 49:652; Jain,
et al., Brain Res Bull. (2004) 64:319-22; and Calantuoni, et al.,
Obesity Res (2002) 10:478. Glucose administration can also
alleviate opioid-induced memory loss. See, e.g., Ragozzino, et al.,
Brain Res (1994) 655:77-82; Ragozzino, et al., J Neurosci (1998)
18:1595-1601; and Talley, et al., Neurobiol Learn Mem (1999)
71:62-79. Sugars are also useful for the transdermal delivery of
opioids. See, e.g., U.S. Pat. No. 4,956,171 and PCT Publ. No.
WO98/54196.
[0087] Accordingly, in some variations, the partial opioid agonist,
e.g., buprenorphine, is administered in combination with glucose or
sucrose. The sugar can be in a solid or liquid form, as desired.
For example, the partial opioid agonist, e.g., buprenorphine, is
co-administered with a concentrated glucose or sucrose solution, or
formulated with glucose or sucrose in sufficient amounts to induce
induction of endogenous opioids and/or to delay or alleviate
withdrawal symptoms. In some variations, glucose is co-administered
at a concentration of about 100 mg/kg. In some variations, sucrose
is co-administered in a solution containing at least about 20%
sucrose, for example, about 25%, 30%, 35% sucrose solution.
Supplements/Additional Agents
[0088] In some variations, the partial opioid agonist, e.g.,
buprenorphine, is administered in combination with one or more
supplements. The supplements may, for example, be used to treat a
comorbid condition, counteract any undesirable side effects of the
partial opioid agonist or any other co-administered pharmacological
agent, or counter nutritional deficiencies in the subject being
treated.
[0089] In some variations, the supplement counteracts the side
effect of constipation. For example, the partial opioid agonist can
be co-administered or formulated with fiber or a bulking agent
(e.g., psyllium, inulin), a stool softener or a laxative.
[0090] In other variations, the supplement is used to counteract
extrapyrimidal side-effects. Here the supplement may include an
antihistamine, an anticholinergic, or combinations thereof.
Exemplary antihistamines include without limitation, certrizine,
diphenydramine, fenofexadine, loratidine, and combinations
thereof.
[0091] In some variations, the supplement counteracts a nutritional
deficiency. For example, the partial opioid agonist can be
co-administered or formulated with one or more B vitamins, e.g.,
thiamin (B-1), riboflavin (B-2), niacin, pyridoxine (B-6), folic
acid, cobalamin (B-12), biotin, and/or pantothenic acid. In some
variations, one or more of vitamins A, C, D, E or K is
co-administered with the partial opioid agonist. In some
variations, the partial opioid agonist is co-administered or
co-formulated with one or more of calcium, iron, zinc, selenium,
magnesium, manganese, copper and/or chromium. In some variations,
the partial opioid agonist is co-administered or co-formulated with
an antioxidant, e.g., lycopene, acetylcysteine.
[0092] In other variations, the supplement or additional agent is
used to treat a comorbid condition. For example, the comorbid
condition may be diabetes, obesity, or fibromyalgia. When diabetes
is the comorbid condition, the additional agent may be metformin.
When the comorbid condition is obesity, the additional agent may be
metformin, topiramate, or combinations thereof. When the comorbid
condition is fibromyalgia, the additional agent may be
carisoprodol, colchicine, cyclobenzaprine, duloxetine, gabapentin,
guafenisin, interferon, methocarbamol, pregabalin, probenecid,
sulfinpyrazone, vitamin B 12, or combinations thereof.
[0093] In some variations, the partial opioid agonist is
administered in combination with or co-formulated with an opioid
abuse deterrent agent, for example, an opioid antagonist.
[0094] Abuse deterrent agents find use that are healthful or benign
when co-administered at low concentrations, but produce undesirable
or unpleasant side effects when co-administered at higher
concentrations, for example, when a patient attempts to administer
more than the prescribed dose of the partial opioid agonist. For
example, niacin at low doses (e.g., 10-50 mg) serves as a B vitamin
supplement, but at higher doses will cause flushing. Acetylcysteine
at low doses serves as an antioxidant, but at higher doses, the
sulfur content has a noticeable and unpleasant smell. Glucose or
sucrose administered at lower doses will potentiate the effects of
the partial opioid agonist, as discussed above, but at higher doses
will cause unpleasant side effects, for example, due to high levels
of insulin release.
[0095] Other sulfur-containing compounds find use as abuse
deterrent agents. Nociceptive agents also find use as abuse
deterrent agents, for example, capsaicin, chili pepper and other
hot pepper extracts.
[0096] It may be important here to mention that in the methods,
compositions, and kits described here, some agents may not
contemplated for combination with the opioid agonists. In some
variations, the partial opioid agonist, e.g., buprenorphine, may be
administered to a subject without administering in combination an
antidepressant. It is unfavorable to administer antidepressants to
patients who are subject to manic or hypomanic episodes, including
individuals with bipolar disorder, because all antidepressants can
precipitate or exacerbate mania or hypomania.
[0097] Antidepressant compounds excluded include, for example,
atypical antidepressants (e.g., atomoxetine, bupropion, duloxetine,
mirtazapine, nefazodone and trazodone), tricyclic antidepressants
(e.g., amineptine, amitriptyline, clomipramine, desipramine,
doxepin, dothiepin, imipramine, nortriptyline, protriptyline,
trimipramine, lofepramine, amoxapine and the muscle relaxant
cyclobenzaprine), monoamine oxidase inhibitors (e.g., phenelzine,
tranylcypromine, and selegiline), norepinephrine reuptake
inhibitors (e.g, amitriptyline, clomipramine, doxepin, imipramine,
trimipramine, amoxapine, desipramine, maprotiline, nortriptyline
and protri.sub.pt.sub.yline), serotonin-norepinephrine reuptake
inhibitors (e.g., milnacipran, mirtazapine, duloxetine, venlafaxine
and sibutramine), norepinephrine-dopamine reuptake inhibitors
(e.g., amineptine, modafinil and bupropion), and selective
serotonin reuptake inhibitors (e.g, citalopram, escitalopram,
fluoxetine, fluvoxamine, paroxetine, and sertraline).
[0098] In other variations, the partial opioid agonist may be
administered to a subject without administering in combination a
benzodiazepine. Benzodiazepines excluded include, for example,
alprazolam (Xanax), valium, diazepam, temazepam (Restoril),
lorazepam, chlordiazepoxide (Librium) and clonazepam
(Klonopin).
Dosage Forms
[0099] Also described here are pharmaceutical compositions
comprising a partial opioid agonist, a second active agent, and/or
an additional/supplemental agent. The compositions may include a
mixture of an effective amount of a partial opioid agonist (e.g.,
buprenorphine) and one or more opioid antagonist(s) and/or one or
more antipsychotic(s) and/or one or more anticonvulsant(s) and/or
one or more antiepileptic(s) and/or one or more muscle relaxant(s)
agents and/or one or more mood stabilizer(s). The partial opioid
agonist and/or the combined pharmacological agents, i.e., opioid
antagonist(s), antipsychotic(s), anticonvulsant(s),
antiepileptic(s), muscle relaxant(s), may be included in
therapeutic or subtherapeutic doses. In some variations, the
compositions comprise one or both pharmacological agents in
subtherapeutic doses. The compositions can be co-formulated with
one or more opioid potentiators, supplements and/or opioid
deterrent agents, as discussed above.
[0100] In some variations, the pharmaceutical compositions comprise
one or more opioid antagonists. In one variation, the
pharmaceutical composition comprises naltrexone. In another
variation, the pharmaceutical composition comprises naloxone.
[0101] In some variations, the pharmaceutical compositions comprise
one or more antipsychotics. The antipsychotic may include without
limitation, a phenothiazine, a thioxanthene, or other heterocyclic
compounds and prodrugs thereof. In one variation, the
pharmaceutical composition comprises one or more antipsychotics
selected from the group of quetiapine, aripiprazole, clozapine and
ziprasidone. Additional antipsychotics can find use, for example,
those described herein. In one variation, the pharmaceutical
composition comprises subtherapeutic amounts of
antipsychotic(s).
[0102] In some variations, the pharmaceutical compositions comprise
one or more anticonvulsants(s)/antiepileptic(s). The
anticonvulsant/antiepileptic can be selected from barbiturates,
hydantoins, iminostilbenes, succinimides, valproic acid and
prodrugs thereof. Additional anticonvulsants can find use, for
example, those described herein. In one variation, the
pharmaceutical composition comprises one or more
anticonvulsive(s)/antiepileptic(s) in subtherapeutic amounts.
[0103] In some variations, the pharmaceutical compositions comprise
one or more mood stabilizer(s) and the prodrugs thereof. In one
variation, the pharmaceutical composition comprises one or more
mood stabilizer selected from the group of lithium and ziprasidone.
Additional mood stabilizer can find use, for example, those
described herein. In one variation, the pharmaceutical composition
comprises one or more mood stabilizers in a subtherapeutic
amount.
[0104] In some variations, the pharmaceutical compositions comprise
one or more muscle relaxant(s) and the prodrugs thereof. In one
variation, the pharmaceutical composition comprises the muscle
relaxant carisoprodol. Additional muscle relaxants can find use,
for example, those described herein. In one variation, the
pharmaceutical composition comprises one or more muscle relaxant(s)
in a subtherapeutic amount.
[0105] A combination of partial opioid agonist (e.g.,
buprenorphine) and/or one or more opioid antagonist(s) and/or one
or more antipsychotic(s) and/or one or more anticonvulsant(s)
and/or one or more antiepileptic(s) and/or one or more muscle
relaxant(s) and/or one or more mood stabilizer(s) agents can be
administered to a subject, e.g., a human patient, a domestic animal
such as a dog or a cat, independently or together in the form of a
pharmaceutically acceptable salts, or in the form of a
pharmaceutical composition where the compounds are mixed with
suitable carriers or excipient(s) in an effective amount.
[0106] A combination of partial opioid agonist (e.g.,
buprenorphine) and/or one or more opioid antagonists and/or one or
more antipsychotic(s) and/or one or more anticonvulsant(s) and/or
one or more antiepileptic(s) and/or one or more muscle relaxant(s)
and/or one or more mood stabilizer(s) agents of this invention can
be incorporated into a variety of formulations for therapeutic
administration. More particularly, a combination of the present
invention can be formulated into pharmaceutical compositions,
together or separately, by formulation with appropriate
pharmaceutically acceptable carriers or diluents, and can be
formulated into preparations in solid, semi-solid, liquid or
gaseous forms such as tablets, capsules, pills, powders, granules,
dragees, gels, slurries, ointments, solutions, suppositories,
patches, films, injections, inhalants, and aerosols.
[0107] Suitable formulations for use in the present invention are
found in, for example, in Remington: The Science and Practice of
Pharmacy, 21.sup.st Ed., 2005; Martindale: The Complete Drug
Reference, Sweetman, 2005, London: Pharmaceutical Press; Niazi,
Handbook of Pharmaceutical Manufacturing Formulations, 2004, CRC
Press; and Gibson, Pharmaceutical Preformulation and Formulation: A
Practical Guide from Candidate Drug Selection to Commercial Dosage
Form, 2001, Interpharm Press, which are hereby incorporated by
reference herein. The pharmaceutical compositions described herein
can be manufactured in a manner that is known to those of skill in
the art, i.e., by means of conventional mixing, dissolving,
granulating, dragee-making, levigating, emulsifying, encapsulating,
entrapping or lyophilizing processes. The following methods and
excipients are merely exemplary and are in no way limiting.
[0108] The pharmaceutical preparations of the present invention can
be prepared for delivery in a sustained-release, controlled
release, extended-release, timed-release or delayed-release
formulation, for example, in semi-permeable matrices of solid
hydrophobic polymers containing the effective agent(s). Various
types of sustained-release materials have been established and are
well known by those of skill in the art. Current extended-release
formulations include film-coated tablets, multiparticulate or
pellet systems, matrix technologies using hydrophilic or lipophilic
materials and wax-based tablets with pore-forming excipients (see,
for example, Huang, et. al., Drug Dev. Ind Pharm. 29:79 (2003);
Pearnchob, et. al., Drug Dev. Ind Pharm. 29:925 (2003); Maggi, et.
al., Eur. J. Pharm. Biopharm. 55:99 (2003); Khanvilker, et. al.,
Drug Dev. Ind. Pharm. 228:601 (2002); and Schmidt, et. al., Int. J.
Pharm. 216:9 (2001). Sustained-release delivery systems can,
depending on their design, release the compounds over the course of
hours or days, for instance, over 4, 6, 8, 10, 12, 16, 20, 24 hours
or more Sustained release formulations can be prepared using
naturally-occurring or synthetic polymers, for instance, polymeric
vinyl pyrrolidones, such as polyvinyl pyrrolidine (PVP);
carboxyvinyl hydrophilic polymers; hydrophobic and/or hydrophilic
hydrocolloids, such as methylcellose, ethylcellulaose,
hydroxypropylcellulose, and hydroxypropylmethylcellulose; and
carboxypolmethylene.
[0109] The sustained or extended-release formulations can also be
prepared using natural ingredients, such as minerals, including
titanium dioxide, silicon dioxide, zinc oxide, and clay (see, U.S.
Pat. No. 6,638,521, herein incorporated by reference). Exemplified
extended release formulations that can be used in delivering a
combination of partial opioid agonist (e.g., buprenorphine) and/or
one or more opioid antagonist(s) and/or one or more
antipsychotic(s) and/or one or more anticonvulsant(s) and/or one or
more antiepileptic(s) and/or one or more muscle relaxant(s) and/or
one or more mood stabilizer(s) agents of the present invention
include those described in U.S. Pat. Nos. 6,635,680; 6,624,200;
6,613,361; 6,613,358, 6,596,308; 6,589,563; 6,562,375; 6,548,084;
6,541,020; 6,537,579; 6,528,080 and 6,524,621, each of which is
hereby incorporated herein by reference. Controlled release
formulations of particular interest include those described in U.S.
Pat. Nos. 6,607,751; 6,599,529; 6,569,463; 6,565,883; 6,482,440;
6,403,597; 6,319,919; 6,150,354; 6,080,736; 5,672,356; 5,472,704;
5,445,829; 5,312,817 and 5,296,483, each of which is hereby
incorporated herein by reference. Those skilled in the art will
readily recognize other applicable sustained release
formulations.
[0110] For oral administration, a combination of partial opioid
agonist (e.g., buprenorphine) and/or one or more opioid
antagonist(s) and/or one or more antipsychotic(s) and/or one or
more antipsychotic(s) and/or one or more anticonvulsant(s) and/or
one or more antiepileptic(s) and/or one or more muscle relaxant(s)
and/or one or more mood stabilizer(s) agents can be formulated
readily by combining with pharmaceutically acceptable carriers that
are well known in the art. Such carriers enable the compounds to be
formulated as tablets, pills, dragees, capsules, emulsions,
lipophilic and hydrophilic suspensions, liquids, gels, syrups,
slurries, suspensions and the like, for oral ingestion by a patient
to be treated. Pharmaceutical preparations for oral use can be
obtained by mixing the compounds with a solid excipient, optionally
grinding a resulting mixture, and processing the mixture of
granules, after adding suitable auxiliaries, if desired, to obtain
tablets or dragee cores. Suitable excipients are, in particular,
fillers such as sugars, including lactose, sucrose, mannitol, or
sorbitol; cellulose preparations such as, for example, maize
starch, wheat starch, rice starch, potato starch, gelatin, gum
tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If
desired, disintegrating agents can be added, such as a cross-linked
polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such
as sodium alginate.
[0111] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds can
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers can be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0112] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions can be used, which can
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments can be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0113] The compounds can be formulated for parenteral
administration by injection, e.g., by bolus injection or continuous
infusion. For injection, a combination of partial opioid agonist
(e.g., buprenorphine) and one or more mood stabilizers, one or more
antipsychotics and/or one or more anticonvulsants and/or one or
more antiepileptics and/or one or more muscle relaxant(s) agents
can be formulated into preparations by dissolving, suspending or
emulsifying them in an aqueous or nonaqueous solvent, such as
vegetable or other similar oils, synthetic aliphatic acid
glycerides, esters of higher aliphatic acids or propylene glycol;
and if desired, with conventional additives such as solubilizers,
isotonic agents, suspending agents, emulsifying agents, stabilizers
and preservatives. Preferably, a combination of the invention can
be formulated in aqueous solutions, preferably in physiologically
compatible buffers such as Hanks's solution, Ringer's solution, or
physiological saline buffer. Formulations for injection can be
presented in unit dosage form, e.g., in ampules or in multi-dose
containers, with an added preservative. The compositions can take
such forms as suspensions, solutions or emulsions in oily or
aqueous vehicles, and can contain formulatory agents such as
suspending, stabilizing and/or dispersing agents.
[0114] Pharmaceutical formulations for parenteral administration
include aqueous solutions of the active compounds in water-soluble
form. Additionally, suspensions of the active compounds can be
prepared as appropriate oily injection suspensions. Suitable
lipophilic solvents or vehicles include fatty oils such as sesame
oil, or synthetic fatty acid esters, such as ethyl oleate or
triglycerides, or liposomes. Aqueous injection suspensions can
contain substances which increase the viscosity of the suspension,
such as sodium carboxymethyl cellulose, sorbitol, or dextran.
Optionally, the suspension can also contain suitable stabilizers or
agents which increase the solubility of the compounds to allow for
the preparation of highly concentrated solutions. Alternatively,
the active ingredient can be in powder form for constitution with a
suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0115] Systemic administration can also be by transmucosal or
transdermal means. For transmucosal or transdermal administration,
penetrants appropriate to the barrier to be permeated are used in
the formulation. For topical administration, the agents are
formulated into ointments, creams, salves, powders and gels. In one
variation, the transdermal delivery agent can be DMSO. Transdermal
delivery systems can include, e.g., patches. For transmucosal
administration, penetrants appropriate to the barrier to be
permeated are used in the formulation. Such penetrants are
generally known in the art. Exemplified transdermal delivery
formulations that can find use in the present invention include
those described in U.S. Pat. Nos. 6,589,549; 6,544,548; 6,517,864;
6,512,010; 6,465,006; 6,379,696; 6,312,717 and 6,310,177, each of
which are hereby incorporated herein by reference.
[0116] For buccal administration, the compositions can take the
form of tablets or lozenges formulated in a conventional
manner.
[0117] In addition to the formulations described previously, a
combination of partial opioid agonist (e.g., buprenorphine) and/or
opioid antagonist(s) and/or one or more antipsychotics and/or one
or more anticonvulsants and/or one or more antiepileptics and/or
one or more muscle relaxant(s) and/or one or more mood
stabilizer(s) agents of the present invention can also be
formulated as a depot preparation. Such long acting formulations
can be administered by implantation (for example subcutaneously or
intramuscularly), or by needle-free injection. Thus, for example,
the compounds can be formulated with suitable polymeric or
hydrophobic materials (for example as an emulsion in an acceptable
oil) or ion exchange resins, or as sparingly soluble derivatives,
for example, as a sparingly soluble salt.
[0118] The pharmaceutical compositions also can comprise suitable
solid or gel phase carriers or excipients. Examples of such
carriers or excipients include but are not limited to calcium
carbonate, calcium phosphate, various sugars, starches, cellulose
derivatives, gelatin, and polymers such as polyethylene
glycols.
II. Kits
[0119] The compositions described here may be provided in a kit.
Kits for treating mania associated with opioid withdrawal may
include a plurality of buprenorphine dosage forms and instructions
for administering the dosage forms according to a predetermined
dosage regimen. Here the predetermined dosing regimen may include
administering a first buprenorphine dose and at least one
additional buprenorphine dose that is less than the first dose. The
predetermined dosing regimen may provide that the first dose be
administered in the morning, e.g., at 6 am or between about 6 am
and 9 am, and the at least one additional dose administered in the
afternoon, e.g., at 12 pm (noon) or between about 12 pm and 3 pm,
evening, e.g., at 6 pm or between about 6 pm and 9 pm, or late
evening, e.g., at 12 am (midnight).
[0120] The aforementioned kits may include a housing configured to
organize the dosage forms according to the predetermined dosing
regimen. For example, the housing may be configured to organize the
plurality of dosage forms into morning dosage forms and evening
dosage forms. In some variations, the housing may be configured to
organize the plurality of buprenorphine dosage forms according to a
rapidly or a gradually decreasing dosing regimen. In yet further
variations, the housing may be configured to organize the
buprenorphine dosage forms according to the day of the week to be
taken.
[0121] The kits may also include a second dosage form having one or
more second active agents. The second active agent may also help to
stabilize the mood of the patient. Exemplary second active agents
include without limitation, aripriprazole, arisulpride, olanzapine,
paliperidone, quetiapine, risperidone, ziprasidone, and
combinations thereof. The kit may further include additional dosage
forms that include one or more additional agents for treating a
comorbid condition. For example, an antihistamine may be useful to
include when the comorbid condition is a sleep disorder. Dosage
forms that include other active agents (e.g., to treat
comorbidities) or second active agents (e.g., for mood
stabilization) may be organized in the housing similar to the
organization provided for the buprenophine dosage forms, as
described above.
[0122] Kits for treating the symptom of racing thoughts in bipolar
disorder may include a plurality of buprenorphine dosage forms, at
least one second dosage form comprising a second active agent that
helps to stabilize mood, e.g., an atypical antipsychotic agent, and
instructions for taking the dosage forms according to a
predetermined dosing regimen. Dosage forms including an opioid
antagonist such as naloxone may also be included. In some
variations, dosage forms having a supplemental or additional agent
for treating a comorbid condition, side-effect of second agent,
and/or other symptoms of bipolar disorder may be provided in the
kits.
[0123] These kits may also further include a housing configured to
organize the dosage forms according to the predetermined dosing
regimen. For example, the housing may be configured to organize the
plurality of dosage forms into morning dosage forms and evening
dosage forms. In some variations, the housing may be configured to
organize the plurality of dosage forms according to a rapidly or a
gradually decreasing dosing regimen. In yet further variations, the
housing may be configured to organize the dosage forms according to
the day of the week to be taken. The kits may also be tailored to
treat particular bipolar conditions or subtypes. For example, the
kits may be tailored to treat bipolar I disorder, bipolar II
disorder, mixed bipolar disorders, rapidly-cycling bipolar
disorder, acute mania, drug-induced mania, hypomania, cyclothymia,
or combinations thereof.
[0124] In some variations, the kits comprise a partial opioid
agonist (e.g., buprenorphine) and/or one or more opioid
antagonist(s) and/or one or more antipsychotic(s) and/or one or
more anticonvulsant(s) and/or one or more antiepileptic(s) and/or
one or more muscle relaxant(s) and/or one or more mood
stabilizer(s) agents in separate formulations or dosage forms. In
other variations, the kits comprise a partial opioid agonist (e.g.,
buprenorphine) and/or one or more opioid antagonist(s) and/or one
or more antipsychotic(s) and/or one or more anticonvulsant(s)
and/or one or more antiepileptic(s) and/or one or more muscle
relaxant(s) and/or one or more mood stabilizer(s) agents within the
same formulation or dosage form.
[0125] In further variations, the kits may provid the of partial
opioid agonist (e.g., buprenorphine) and/or one or more opioid
antagonist(s) and/or one or more antipsychotic(s) and/or one or
more anticonvulsant(s) and/or one or more antiepileptic(s) and/or
one or more muscle relaxant(s) and/or one or more mood
stabilizer(s) agents independently in uniform dosage formulations
throughout the course of treatment. In some variations, the kits
provide the of partial opioid agonist (e.g., buprenorphine) and/or
one or more opioid antagonist(s) and/or one or more
antipsychotic(s) and/or one or more anticonvulsant(s) and/or one or
more antiepileptic(s) and/or one or more muscle relaxant(s) and/or
one or more mood stabilizer(s) agents independently in graduated
dosages over the course of treatment, either increasing or
decreasing, according to the requirements of the subject or
according to a predetermined dosing regimen.
[0126] In some variations, the kits comprise a partial opioid
agonist, buprenorphine. In one variation, the kit comprises
compositions comprising a subtherapeutic amount of
buprenorphine.
[0127] In some variations, the kits comprise compositions
comprising one or more opioid antagonist(s). In one variation, the
opioid antagonist is naloxone.
[0128] In other variations, the kits comprise dosage forms
comprising one or more antipsychotic(s). The antipsychotics can be
selected from a phenothiazine, a thioxanthene, or other
heterocyclic compounds. In one variation, the kit comprises one or
more antipsychotics selected from the group of quetiapine,
aripiprazole, clozapine and ziprasidone. In one variation, the kit
comprises compositions comprising antipsychotic(s) in a
subtherapeutic amount.
[0129] In one variation, the kit comprises one or more mood
stabilizers. In one variation, the kit comprises a mood stabilizer
selected from the group consisting of lithium and ziprasidone. In
one variation, the kit comprises compositions comprising mood
stabilizer(s) in a subtherapeutic amount.
[0130] In one variation, the kits comprise of
anticonvulsant/antiepileptic agents. In some variations, the kit
comprises one or more anticonvulsants/antiepileptics that are
barbiturates, hydantoins, imminostilbenes and/or succinimides. In
one variation, the kit comprises subtherapeutically effective
amounts of anticonvulsant/antiepileptic agent(s).
[0131] In some variations, the kits comprise muscle relaxant(s). In
some variations, the kit comprises the muscle relaxant
carisoprodol. In one variation, the kit comprises compositions
comprising muscle relaxant(s) in a subtherapeutic amount.
[0132] The kits may also comprising a housing configured to
organize the dosage forms according to a predetermined dosing
regimen. For example, the housing may be configured to organize the
plurality of dosage forms into morning dosage forms and evening
dosage forms. The housing may also be configured to organize the
plurality of buprenorphine dosage forms according to a rapidly or a
gradually decreasing dosing regimen.
III. Methods
[0133] The methods described here may find use in the treatment and
prevention of mood disorders involving manic episodes. In
particular, the methods may find use in the amelioration,
inhibition, reduction and prevention of symptoms indicative of a
manic episode or hypomanic episode, e.g., racing thoughts, as
described herein. Exemplified general categories of disorders
treatable by the present methods and compositions include, without
limitation, bipolar disorder, mania and manic episodes, hypomania,
cyclothymia, and drug-induced mania, among others. The methods
promote and facilitate regular sleep patterns in individuals
subject to manic or hypomanic epidodes. The methods may also treat
or prevent manic or hypomanic episodes occurring in these disorders
in subjects afflicted with concurrent substance addiction and/or
withdrawal from substances of abuse.
[0134] For example, during opioid withdrawal, many adverse
withdrawal symptoms may occur. Physical manifestations often
include sweating, nausea, chills, diarrhea, papillary dilation,
piloerection, tachycardia, increased blood pressure,
hypersensitivity to pain, stomach cramps, and muscle cramps.
Psychological manifestations of opioid withdrawal include
dysphoria, restlessness, irritability, mania, anxiety, and
depression. Due to the often severe nature of the withdrawal
symptoms, individuals who are addicted to or dependent on opioids
often choose to remain addicted or dependent rather than seek
treatment. This may present significant inhibition to an individual
being able to overcome his/her addiction. The methods here address
this need by providing methods for preventing or inhibiting these
withdrawal symptoms, especially mania triggered experienced during
opioid withdrawal. Therapeutic or subtherapeutic amounts of
buprenorphine may be administered to treat or prevent opioid
withdrawal induced mania.
[0135] As previously stated, the treatment regimens may achieve
mood stabilization by administering a partial opioid agonist, e.g.,
buprenorphine, in a predetermined fashion. The amounts and
frequency of administration of the partial opioid agonist will vary
depending on such factors as the particular type of bipolar
disorder diagnosed, associated symptoms and/or comorbidities, other
medications being taken by the patient, and previous history of
opioid abuse. For example, when a plurality of buprenorphine doses
are administered per day, the first dose may be higher than any
additional dose given. In some variations, a morning dose of
buprenophine may be higher than a buprenorphine dose given in the
evening or late evening. For example, a buprenophine dose
administered at 6 am may be higher than a buprenorphine dose given
in the evening, e.g., at 6 pm, or late evening., e.g., at 12 am
(midnight). In some variations, the treatment regimens may include
rapidly decreasing the buprenorphine dose over the course of a day.
In other variations, a gradual decrease in the buprenorphine dose
is employed (over a day). Exemplary (predetermined) dosing regimens
are shown below in Table 1.
TABLE-US-00001 TABLE 1 Exemplary Dosing of Buprenorphine For
Treatment of Mania Associated With Opioid Withdrawal First Dose
Additional Dose Additional Dose (e.g., morning Additional Dose
(e.g., evening (e.g., late evening dose at 6 am) (e.g., 12 pm) dose
at 6 pm) dose at 12 am) in mg in mg in mg in mg 32 0 0 0 24 0 0 0
24 4 2 1 16 0 0 0 16 8 0 0 16 8 4 0 16 8 4 2 16 4 2 1 8 8 0 0 8 4 4
0 8 4 2 1 4 0 0 0 4 4 4 0 4 2 1 0 4 2 1 0.5 2 0 0 0 2 2 2 0 2 2 1 0
2 2 1 0.5
[0136] In some variations, the treatment regimens may include
rapidly decreasing the buprenorphine dose over the course of a day.
In other variations, a gradual decrease in the buprenorphine dose
is employed (over a day). The treatment regimens may be useful in
treating mania associated with opioid withdrawal. As previously
stated, the inventors believe that when higher doses of
buprenorphine are taken in the evening, it acts as a mood
destabilizer and thus, kindles mania or mania-like symptoms in this
patient population. In another variation, the treatment regimens
may be beneficial in alleviating racing thoughts during the
depressive phase of bipolar disorder.
[0137] In Table 1, certain doses of buprenorphine are shown as 0
mg. In these instances, a dosage form may be administered that
includes a carrier, filler, second active agent,
supplemental/additional agent, etc., but it will lack
buprenorphine. In other instances, no dosage form may be
administered.
[0138] When a second active agent is administered with
buprenorphine (or another partial opioid agonist), it may also be
administered in a rapidly or gradually increasing or decreasing
manner throughout the day. In some variations, the second active
agent is administered in an increasing manner, i.e., the morning
dose is lower than the evening or late evening dose. In other
variations, the dosing of the second active agent and partial
opioid agonist is inverse to one another.
[0139] Administered dosages for partial opioid agonists, e.g.,
buprenorphine, opioid antagonist(s), antipsychotic(s), mood
stabilizer(s), anticonvulsant(s), antiepileptic(s), and muscle
relaxant(s) are in accordance with dosages and scheduling regimens
practiced by those of skill in the art. For example, buprenorphine
may be administered daily in doses of about 2 mg, about 4 mg, about
6 mg, about 8 mg, about 10 mg, about 12 mg, about14 mg, about 16
mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg, about 26
mg, about 28 mg, about 30 mg, or about 32 mg. In some variations,
when a higher dose of buprenorphine is administered, a high dose of
mood stabilizer is also administered. General guidance for
appropriate dosages of all pharmacological agents used in the
present methods is provided in Goodman and Gilman's The
Pharmacological Basis of Therapeutics, 11.sup.th Edition, 2006,
supra, in a Physicians' Desk Reference (PDR), for example, in the
62n.sup.d (2008) Ed., Thomson PDR, and in the FDA Orange Book,
which are hereby entirely incorporated by reference herein. In the
compositions and methods of the present invention, efficacious
dosages of opioid partial agonist(s), opioid antagonist(s),
antipsychotic(s), mood stabilizer(s), anticonvulsant(s),
antiepileptic(s), and muscle relaxant(s) for practicing the present
invention can be equal to or less than (e.g., about 25, 50, 75, or
100%) the dosages published for other indications. Combining an
opioid partial agonist with a mood stabilizer, an antipsychotic, a
mood stabilizer, an anticonvulsant, an antiepileptic or a muscle
relaxant allows for both pharmacological agents to be administered
at subtherapeutic doses and elicit an efficacious effect in
reducing or preventing the symptoms of a manic episode.
[0140] The appropriate dosage of partial opioid agonists
(buprenorphine), opioid antagonist(s), antipsychotic(s), mood
stabilizer(s), anticonvulsant(s), antiepileptic(s), and muscle
relaxant agent(s) will vary according to several factors, including
the chosen route of administration, the formulation of the
composition, patient response, the severity of the condition, the
subject's weight, and the judgment of the prescribing physician.
The dosage can be increased or decreased over time, as required by
an individual patient. Usually, a patient initially is given a low
dose, which is then increased to an efficacious dosage tolerable to
the patient. Patients who have not before been exposed to opioids
will require lower doses. Patients who have been exposed to
opioids, or who have opioid dependence or addiction, will require
higher doses.
[0141] For the methods of the present invention, subtherapeutic
dosages of buprenorphine are administered at doses that are about
25% or less of a full dose for the indicated purposes of
buprenorphine. For example, in the present methods buprenorphine is
administered in amounts that are about 25%, 20%, 15%, 10%, 5%, 2%,
1% or less than a full dose. Dosing of buprenorphine is known in
the art and published in standard reference texts commonly
consulted by trained clinicians, including for example, Goodman and
Gilman's The Pharmacological Basis of Therapeutics, 11th Edition,
2006, supra, in a Physicians' Desk Reference (PDR), for example, in
the 62nd (2008) Ed., Thomson PDR, and in the FDA Orange Book. In
treating opioid addiction, buprenorphine (e.g., alone or in
combination with naloxone) typically is administered sublingually
in full doses of from about 2-32 mg/day, for example, about 2, 4,
8, 16 or 32 mg/day. In some embodiments, the subtherapeutic amounts
of buprenorphine are administered sublingually, for example, in
amounts that are about 25% of a full dose or less, for example,
about 20%, 15%, 10%, 5%, 2% of a full dose. In some embodiments,
the subtherapeutic amounts of buprenorphine are administered
sublingually in doses of from about 0.4-8 mg/day, for example,
about 0.4, 1, 2, 4 or 8 mg/day. In some embodiments, standard or
full doses of sublingually formulated buprenorphine are
administered orally (based on a 20% or 1/5 bioavailability of the
sublingual formulation when orally administered).
[0142] Generally, in practicing the present methods, effective
amounts of one or more partial opioid agonists are administered
alone or in combination with and/or one or more opioid
antagonist(s), and/or one or more antipsychotic(s) and/or one or
more anticonvulsant(s) and/or one or more antiepileptic(s) and/or
one or more muscle relaxant(s) and/or one or more mood stabilizers.
Co-administered pharmacological agents can be administered together
or separately, simultaneously or at different times. When
administered, the partial opioid agonist(s), alone or in
combination with opioid antagonist(s), antipsychotic(s), mood
stabilizer(s), muscle relaxant(s), and/or anticonvulsant(s)/
antiepileptic(s) agents independently can be administered once,
twice, three, four times daily or more or less often, as needed. In
some variations, the administered pharmacological agents are
administered once daily. In some variations, the partial opioid
agonist is administered at a high dose, alone or in combination
with another aforementioned pharmacological agent, in the morning,
and then at a lower dose in the evening, for example, before
bedtime. This regimen may be less likely to kindle mania and
promote drowsiness and sleep. When a mood stabilizer is also
employed in the dosing regimen, it may be monodosed, e.g., given
before bedtime, or at a multiple times throughout the day.
[0143] For certain patients, the methods are carried out
concurrently administering the one or more partial opioid agonist
and/or then one or more opioid antagonist(s) and/or one or more
antipsychotic(s) and/or one or more anticonvulsant(s) and/or one or
more antiepileptic(s) and/or one or more muscle relaxant(s) and/or
one or more mood stabilizer(s) from the initiation of treatment.
For certain patients, the methods are carried out by first
administering the one or more partial opioid agonist(s), and then
subsequently co-administering the and/or one or more opioid
antagonist and/or one or more antipsychotics and/or one or more
anticonvulsants and/or one or more antiepileptics and/or one or
more muscle relaxant(s) and/or one or more mood stabilizer.
[0144] Administration of the partial opioid agonist, for example,
buprenorphine, alone or in combination with and/or one or more
opioid antagonist and/or one or more antipsychotic(s) and/or one or
more anticonvulsant(s) and/or one or more antiepileptic(s) and/or
one or more muscle relaxant(s) and/or one or more mood
stabilizer(s), can be achieved in various ways, including oral,
buccal, parenteral, intravenous, intradermal, subcutaneous,
intramuscular, transdermal, transmucosal, intranasal, etc.,
administration. Buprenorphine, or other partial opioid agonist, can
be administered by the same or different route of administration
when co-administered with one or more opioid antagonist(s) and/or
one or more antipsychotic(s) and/or one or more anticonvulsant(s)
and/or one or more antiepileptic(s) and/or one or more muscle
relaxant(s) and/or one or more mood stabilizer(s).
[0145] In some variations, a partial opioid agonist, for example,
buprenorphine, alone or in combination, can be administered in a
local rather than systemic manner, for example, transdermally or
via another route in a depot or sustained release formulation. In
some variations, the partial opioid agonist is administered orally.
In some variations, the partial opioid agonist is administered
sublingually.
EXAMPLES
[0146] The following examples are offered to illustrate the
treatment regimens, compositions, and kits described herein.
Example 1
[0147] A 35 year old man presented with an addiction to Methadone.
Patient was tearful, admitting to feeling depressed and was prone
to paroxysms of grandiose and irritable behavior. He had been
diagnosed with bipolar disease type I several months ago and was
started on Seroquel. Even though he liked the effects of Seroquel
on sleep promotion, he only remembered to take it intermittently
and instead predominantly used opioid drugs to self-treat
prepsychotic and psychotic symptoms. With 8 mg of Suboxone tid, his
psychiatric symptoms largely resolved and he began taking the
Seroquel regularly, resulting in maximum stabilization of mood
fluctuation 1 month later.
Example 2
[0148] A 35 year old female with a history of bipolar disease and
oxycontin use presented with hypomania as characterized by an
expansive, elevated mood, and rapid speech. She had been started on
Lithium 300 mg tid but stopped it because she missed her "highs."
She was, however, complaining of severe "back pain" for which she
wanted a narcotic. She was started on 8 mg of Suboxone bid along
with Geodon 40 mg bid and the patient has remained compliant on her
medications for over 3 months. On her follow-up visits she
demonstrates no manic or hypomanic symptoms.
Example 3
[0149] A 45 year old opioid addicted female with schizoaffective
disorder and completely noncompliant with her oral psychiatric meds
presented in florid psychosis. 2 mg of Suboxone was administered
sublingually and the psychosis immediately resolved. Geodon and
Lithium were restarted and in combination with psychotherapy, the
patient has remained on her medications (including Suboxone) and
otherwise drug-free for over 6 months.
Example 4
[0150] A 39 year old bipolar female presented with a history of
regular crack cocaine use and high doses of intermittent opioids.
Previous attempts at initiating an atypical antipsychotic had
failed. After starting on Seroquel and Suboxone, she has achieved
full remission of symptoms and full return to functioning.
Example 5
[0151] A 23 year old male presented with bipolar disorder and
prescription drug addiction. He had been unable to tolerate any
mood stabilizers or psychotropics. Shortly after starting on
Suboxone, Lamictal was begun and the patient remained on therapy
with considerable normalization of his mood.
Example 6
[0152] A 27 year old male presented with an opioid addiction and
bipolar disorder. Although he formerly did not adhere regularly to
his medication regimen which included Seroquel and thorazine, once
he started Suboxone he became very compliant and his psychiatric
symptoms have abated considerably.
Example 7
[0153] A 47 year old female with a history of opioid addiction and
bipolar disease presented with a mania and was started on lithium
300 mg tid, but stopped it due to intolerable side effects. She was
started on Suboxone 8 mg bid and, although she states she does not
notice a change from the Suboxone, her mood has normalized. Three
months later she continues to do well.
Example 8
[0154] A woman presented with a manic episode immediately after her
husband's death due to a subdural hematoma after a car accident.
The outburst of manic episode that emerges after the death of a
close family member is termed bereavement mania in the literature.
There was a history of bipolar disorder in the patient which had
been previously very well-controlled by 1200mg of Lithium tid. The
DSM IV criteria for manic episode were met even though blood tests
showed her lithium levels to be in therapeutic range. She was
asking for narcotics to take away her nearly constant headache. She
was started on Suboxone 8 mg tid and her mania subsided. A month
later the Suboxone was stopped. There has been no recurrence of
mania for almost 4 months
Example 9
[0155] Patient swallowed two Norcos (1 Norco=10 mg hydrocodone+325
mg acetaminophen) 30 minutes prior to taking 1/4 of an 8 mg tablet
of Suboxone sublingually. He took the 1/4 of an 8mg tablet of
Suboxone sublingually 3 times in day without experiencing any
precipitated withdrawal. Norco is a short-acting narcotic; he was
taking around 40-50 mg of Norco/day.
Example 10
[0156] This patient was taking 100 mg of long-acting morphine
(Kadian) twice a day and 30 mg of short-acting oxycodone
(Roxicodone) 5 times a day. He had just taken 1 Kadian and 2
Roxicodones 45 minutes prior to taking 1/4 of an 8 mg tablet of
Suboxone sublingually but experienced no withdrawal symptoms. He
took 1/4 of an 8 mg tablet of Suboxone tablet sublingually 6 more
times that day without experiencing any withdrawal symptoms.
Example 11
[0157] This patient who had been previously placed on Suboxone had
relapsed and was receiving about 40 mg of Methadone from "the
street." She was restarted on 1/4 of an 8 mg tablet of Suboxone
taken twice a day and did not experience any withdrawal symptoms in
spite of having taken her last dose of Methadone about 6 hours
earlier.
Example 12
[0158] Seven patients diagnosed with bipolar II disorder and
cyclothymia were determined to have initial GAF (global assessment
of functioning) scores ranging from 31 to 60. Upon administration
of Suboxone 8.0 mg twice a day and Geodon 40 mg once daily all
seven patients experienced mood stabilization for three months or
longer and an increase in GAF scores over 80. Specifically,
administration of this medication regimen has resulted in mood
stabilization for 12 months and an increase in GAF score from 31-40
to 81-90 (patient 1), mood stabilization for 7 months and an
increase in GAF score from 51-60 to 81-90 (patient 2), mood
stabilization for six months and an increase in GAF score from
51-60 to 81-90 (patient 3), an increase in GAF score from 31-40 to
81-90 (patients 4 and 5), mood stabilization for 17 months and an
increase in GAF score from 11-20 to 81-90 (patient 6), and mood
stabilization for four months and an increase in GAF score from
11-20 to 81-90.
Example 13
[0159] A patient diagnosed with mixed bipolar II disorder
(depression and mania characterized by anxiety, impulsiveness,
grandiosity, and pressured speech) and opioid-induced hypogonadism
was initially determined to have a GAF score between 21-30. The
patient was started on Suboxone 16 mg/day and Seroquel 100 mg/day.
After three months of treatment, the patient remained highly
anxious, and had intermittent manic episodes although he is no
longer depressed.
Example 14
[0160] A patient diagnosed with mixed bipolar I disorder was
determined to have a GAF score between 11-20. The patient was
extremely depressed and manic simultaneously, with irritability,
grandiosity, pressured speech, agitation, and impulsiveness
coexisting with negative thoughts, guilty feelings, distractibility
and suicidal ideation. She was in pain all the time, and barely
able to get out of bed. She was also dependent on multiple
narcotics. After treatment with 32 mg of Suboxone (8 mg four times
a day) and 40 mg of Geodon, her GAF score improved to between
41-50. She also had more energy and less pain and was now able to
get out of bed, but still felt highly anxious and manic for three
months. Two months after increasing her Geodon to 120 mg, she is
still stable and compliant with a GAF score between 71-80.
Example 15
[0161] A patient diagnosed with mixed bipolar I disorder (ultra
rapid cycling) was initially determined to have a GAF score of
between 0-10, and was addicted to multiple narcotics. She was also
suicidal and completely non-functional with rapidly alternating
mood swings multiple times in a day. She always complained of
fibromyalgia pain. Her psychiatrist was giving her Seroquel but
that had elevated her blood sugar. Since starting Suboxone 32
mg/day and Geodon 120 mg/day and stopping Seroquel, her GAF score
improved to 71-80, and has been maintained at this level for one
year. The patient is able to get out of bed, has less pain, and her
diabetes mellitus is better controlled.
Example 16
[0162] A patient diagnosed with bipolar I disorder was initially
determined to have a GAF score of 1-10. He was very depressed, in
pain all the time both from the neuropathy and the fibromyalgia,
and had attempted to overdose on two occasions. His psychiatrist
had placed him on three antidepressants (Prozac, Elavil and
Remeron) and 90 mg/day of Valium. After treatment with Suboxone 32
mg/day, Geodon 120 mg/day, Seroquel 25 mg/day, Remeron 30 mg/day,
and Valium 30 mg/day, his GAF score was consistently in the range
of 71-80 for the past seven months. The Prozac, Elavil, and Remeron
are being stopped, and he has decreased his Valium from 90 mg/day
to 30 mg/day. He is no longer depressed but complains of anxiety
and neuropathic pain. The plan is to discharge the Seroquel if
possible and start an anti-epileptic both for the neuropathic pain
and control of the bipolar disease.
Example 17
[0163] A patient diagnosed with bipolar I disorder was initially
determined to have a GAF score of 11-20. After treatment with
Suboxone 8 mg four times a day (32 mg total), and Seroquel 300
mg/day, the patient's GAF score has been consistently between 81-90
for 18 months.
Example 18
[0164] A patient diagnosed with mixed bipolar I disorder was
initially determined to have a GAF score of 21-30. She went to work
everyday but suffered from extreme depression alternating with
manic periods characterized by financial profligacy, grandiosity
and insomnia with racing thoughts. Her course was worsened by drug
and alcohol addiction. She was started on 24 mg of Suboxone and 400
mg of Seroquel and became manic. The Suboxone was decreased to 16
mg and now she is stable with a GAF between 81-90 for the past two
months. However, she complains of excessive sedation in the AM
because of Seroquel, so the dose will probably have to be lowered
to 200 mg.
Example 19
[0165] This bipolar II patient presented for Suboxone maintenance.
He was already taking Suboxone 8 mg twice a day, and his GAF score
was 61-70. However, he suffered from extreme fatigue secondary to
sleep apnea and opioid-induced low testosterone. Subsequently he
was referred to a sleep clinic, started on CPAP, prescribed
Seroquel 25 mg and testosterone replacement. This patient is now
doing wonderfully well with a GAF greater than 90 over the past
four months.
Example 20
[0166] A patient diagnosed with bipolar I disorder was initially
determined to have a GAF score of 31-40. After administering
Suboxone 8 mg twice a day for four months, his GAF score improved
to 61-70. However, he still complained of depression. After
addition of Seroquel 50 mg/day, his GAF score has improved to 81-90
for four months.
Example 21
[0167] This high functioning patient diagnosed with bipolar II
disorder was initially determined to have a GAF score of greater
than 70. She was taking Suboxone 8 mg twice a day, which was her
maintenance dose. However, she began to show signs of
hypomania--excessive talking, distraction, racing thoughts and
insomnia. Thus, lithium 600 mg/day was added but the patient
complained of side effects including tremulousness and stomach
discomfort along with diarrhea. On her own the patient decreased
the lithium dose to 300 mg and reported improvement in side
effects. It is not clear whether she consistently takes the
lithium, having consistently failed to get her blood levels
checked. Nevertheless, she is stable and calmer with a GAF score of
80 for over a year.
Example 22
[0168] This patient diagnosed with bipolar I disorder was initially
determined to have a GAF score of GAF of 21-30. He was addicted to
hydrocodone, and very depressed. He managed to hold on to a job but
his attendance was sporadic because he did not have the energy to
report to work. After starting Zyprexa 5 mg/day and Suboxone 8 mg
twice a day, his GAF score increased to 71-80, and he has
consistently gone to work for one month. The plan going forward
will also be to treat his sleep apnea and hypogonadism.
Example 23
[0169] This was a patient with mixed bipolar I features in which
symptoms of severe depression and mania existed simultaneously. She
was a poorly functioning patient with a GAF score between 0-10. She
consistently complained of severe fibromyalgia-type pain, was
addicted to high doses of morphine and repeatedly stated without
expressing a specific plan to end her life and that she would be
better off dead. Her GAF score has now been 51-60 for three months
after starting Suboxone 8 mg four times a day, and Seroquel 200
mg/day, and Zyprexa 5 mg/day. She is better able to function and o
longer expresses vague suicidal ideation. Conversations are more
coherent because manic symptoms have abated and she is no longer
hypervoluble. The plan going forward is to treat her sleep apnea
with CPAP.
Example 24
[0170] A patient diagnosed with mixed bipolar I disorder was
initially determined to have a GAF score of 31-40. This patient
managed to hold down a job in spite of an addiction to painkillers
and symptoms which included fatigue, irritability, grandiosity,
impulsivity, distractibility, hopelessness, helpless and feelings
of guilt and worthlessness. At 16 mg of Suboxone he improved to a
GAF score of 41-50 for two months. While his manic symptoms
disappeared, he was still very depressed. The Suboxone was
increased to 32 mg and the patient reported that his depression
diminished but he felt highly anxious. His GAF score was still in
the range of 41-50. Mood stabilizers were then started (Seroquel
400 mg/day), and the Suboxone dose was decreased to 24 mg. He now
has been functioning at a GAF score of 71-80 for four months. His
major complaint is extreme exhaustion which may be attributable to
his sleep apnea and hypogonadism which need to be addressed going
forward.
Example 25
[0171] This bipolar I patient (rapid cycling) was initially
determined to have a GAF score of 1-10 and extreme manic behavior.
With Suboxone alone (2 mg/day), GAF score improved to 61-70. With
Zyprexa 2.5 mg/day, GAF score improved to 71-80. The patient has
been stable and compliant for three months.
Example 26
[0172] This mixed bipolar I patient was compliant and stable with a
GAF score of around 80 for four months. The treatment regimen
included Suboxone 8 mg twice a day and an antiepileptic (Lamictal
200 mg/day), which helped the bipolar symptoms and the pain from
fibromyalgia. Due to financial constraints the patient could no
longer afford Suboxone.
Example 27
[0173] This bipolar II patient's presentation was marked by
excessive fatigue. She was unable to stay awake during the day and
had difficulty sleeping at night. She was ruled out for any other
causes of fatigue including anemia, underlying infection,
narcolepsy, and sleep apnea. Her GAF score was initially 41-50. She
was taking Methadone and Ritalin and was stable and compliant but
exhausted and denied depression. Antidepressants did not seem to
help. After starting on Suboxone 8 mg twice a day her GAF improved
to 51-60. She reported a little more energy but not much. After 2
months on Risperdal 4 mg/day and Suboxone 8 mg twice a day, she has
stopped Adderall, and her fatigue has virtually disappeared and her
demeanor is very bright and animated. Her GAF score had been 81-90
now for two months.
Example 28
[0174] This was an extremely dysfunctional schizoaffective patient,
disheveled, addicted to narcotics and benzodiazepines, unable to
hold down a job, with disorganized schizophrenic symptoms
consisting of bizarre and unpredictable behaviors, and inability to
hold a conversation. GAF score has been 71-80 for two months since
starting on Suboxone 24 mg and Trilafon 8 mg three times a day.
Example 29
[0175] A patient diagnosed with mixed bipolar I disorder was
initially determined to have a GAF score of 11-20. With 16 mg of
Suboxone and 5 mg of Zyprexa, the patient had an improved GAF score
of 51-60, but was still depressed and experienced episodes of
mania. Last month he was increased to Suboxone 24 mg/day. His GAF
score is currently 61-70.
Example 30
[0176] This was a high functioning mixed bipolar II patient who
presented with coexistent dysthymia and insomnia, fatigue with
racing thoughts, and irritability in the context of drug addiction.
The patient is now stable and compliant with a GAF score greater
than 90 for over six months on a regimen of Suboxone 8 mg twice a
day and Neurontin 1800 mg/day.
Example 31
[0177] A patient diagnosed with mixed bipolar II disorder had an
initial GAF score of 61-70 with dysthymia, and extreme fatigue and
insomnia with racing thoughts. After starting Suboxone 8 mg twice a
day and Lyrica 50 mg/day, the patient's GAF score has increased to
81-90, and has remained stable at this level for 9 months.
Example 32
[0178] A patient diagnosed with mixed bipolar I disorder had an
initial GAF score of 11-20. The patient was simultaneously
depressed and manic with an inability to sleep because of racing
thoughts and an inability to cope with any stressful situation. On
4 mg/day of Suboxone for 18 months, her GAF score was 31-40. She
complained of extreme anxiety towards the evening. Now she is
taking Suboxone 4 mg twice a day, and her GAF score has increased
to over 80 for one month.
Example 33
[0179] A patient diagnosed with mixed bipolar I disorder had an
initial GAF score of 0-10, and had two previous suicide attempts.
Since starting Suboxone 32 mg/day and Geodon 160 mg/day, her GAF
has improved to 31-40 for 6 months. She is still depressed but the
depression is no longer catatonic and she no longer has suicidal
thoughts. She was subsequently started on Zyprexa 5 mg/day and her
GAF improved to 75 for three months. The plan going forward is to
treat the sleep apnea.
Example 34
[0180] This mixed bipolar I patient had a GAF score of 21-30 while
taking Suboxone 16 mg/day. The patient suffered from anorexia, and
also displayed both manic and depressive symptoms. After starting
Seroquel 100 mg/day, the patient's GAF score has now been 71-80 for
13 months. The patient has also gained 8 lbs.
Example 35
[0181] This patient with rapidly cycling bipolar disorder initially
presented with a GAF score of 11-20. The GAF score has been 61-70
for two months after starting Suboxone 24 mg/day and Geodon 20
mg/day.
Example 36
[0182] This patient with rapidly cycling bipolar disorder initially
presented with a GAF score of 31-40. The GAF score has been 81-90
for three months after starting Suboxone 24 mg/day and Zyprexa 5
mg/day.
Example 37
[0183] This patient with rapidly cycling bipolar disorder initially
presented with a GAF score of 31-40. The GAF score has been 71-80
for six months after starting Suboxone 24 mg/day and Geodon 40
mg/day.
Example 38
[0184] A patient with bipolar II disorder (depression predominant),
had an initial GAF score of 51-60. The GAF score is now 71-80 with
Suboxone 24 mg/day and Seroquel 200 mg/day.
Example 39
[0185] This patient with bipolar I disorder had a GAF score of
11-21, and was manic appearing. The patient was already on Suboxone
24 mg/day, Lamictal 300 mg/day, Gabapentin, Trazadone, and Geodon
200 mg/day. The Trazadone (antidepressant) was discontinued and in
its place Seroquel 200 mg/day and Zypexa 80 mg/day were started.
Now the patient's mood is stabilized and GAF score is 41-50.
Example 40
[0186] A patient with rapidly cycling bipolar disorder had an
initial GAF score of 11-20. Upon taking Suboxone 16 mg/day for six
months, their GAF score improved to 51-60 but episodes of hypomania
interspersed with depression still occurred. The Suboxone was
increased to 32 mg/day. GAF score has subsequently increased to
81-90 now for 6 months.
Example 41
[0187] This patient with mixed bipolar I disorder had an initial
GAF score of 21-30. For three months on Seroquel 100 mg/day and
Suboxone 16 mg/day, the patient's GAF score improved to 61-70, but
mixed episodes were still occurring. Geodon 40 mg/day was then
started, and the patient's GAF score improved to 71-80, which has
now been stable for 7 months.
Example 42
[0188] This patient with mixed bipolar I disorder had an initial
GAF score of 21-30 and a history of crack cocaine addiction. His
major complaint was difficulty sleeping due to racing thoughts.
Geodon 80 mg/day and Suboxone 8 mg/day were started, but initially
he could not tolerate the Geodon because it made him feel like he
was "crawling out of his skin." He was started on an antihistamine
(Benadryl 1.times./day) for akisthisia and reported significant
improvement. His GAF score is now 81-90, and has been stable for
five months.
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