Title:  Triple drug therapy for the treatment of narcotic and alcohol withdrawal symptoms

United States Patent:  6,503,950

Issued:  January 7, 2003

Inventors:  Ockert; David M. (145 E. 32nd St., Sixth Floor, New York, NY 10016)

Appl. No.:  634555

Filed:  August 8, 2000

A triple drug, pharmaceutical kit, composition, and method of treatment containing a combination of effective amounts of at least one anxiolytic agent, at least one centrally acting alpha antiadrenergic agent, and at least one central nervous system stimulant for the reduction or prevention of alcohol and narcotic withdrawal side effects of dizziness, drowsiness, depression, lethargy, orthostatic hypotension, weakness in the extremities, and difficulty in being mobile, caused by therapeutic agents utilized for the treatment of alcohol or narcotic withdrawal symptoms in patients overcoming alcohol or narcotic addiction.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The preferred embodiment is comprised of a pharmaceutical kit, composition, and method of treatment regimen containing a combination of effective amounts of an anxiolytic agent, centrally acting alpha antiadrenergic agent, and central nervous system (CNS) stimulant agent for the reduction or prevention of the withdrawal side effects of drowsiness, dizziness, depression, weakness in the extremities, lethargy, orthostatic hypotension, and difficulty in being mobile associated with therapeutic agents utilized to treat alcohol and narcotic withdrawal symptoms of alcohol and narcotic addiction.

The anxiolytic agent utilized in the preferred embodiment consists essentially of an effective amount of a benzodiazepine, azaspirodecanedione, or piperazine derivative. Suitable benzodiazepine agents include, but are not limited to, diazepam, alprazolam, chlordiazepoxide, clonazepam, clorazepate, halazepam, lorpam, oxazepam, derivatives thereof, and pharmaceutically acceptable salts thereof. Suitable azaspirodecanedione agents include, but are not limited to, buspirone, derivatives thereof, and pharmaceutically acceptable salts thereof. Suitable piperazine derivatives include, but are not limited to, hydroxyzine pamoate and hydroxyzine hydrochloride, derivatives thereof, and pharmaceutically acceptable salts thereof.

The preferred anxiolytic agent for the management of alcohol withdrawal symptoms is about 50 to 60 mg of chlordiazepoxide given to a human being about every 6-8 hours around the clock initially, and gradually tapered by about 10 mg per day for a period of about 5-14 days to reduce or prevent the withdrawal symptom of anxiety and seizure and to prevent patient addiction to chlordiazepoxide, as a substitute for alcohol.

Those skilled in the art will appreciate and will be able to adjust the dose, dosing interval, and dosing length/treatment period of the anxiolytic agent of the preferred embodiment in the treatment of alcohol withdrawal symptoms, based upon the clinical response and therapeutic value required to reduce or prevent withdrawal anxiety and seizure for a particular patient undergoing alcohol abuse treatment. One skilled in the art will appreciate and be able to adjust the dose, dosing interval, and length of treatment with the anxiolytic agent of the preferred embodiment based upon the liver and kidney function of the patient and the amount of CNS stimulant used within the preferred embodiment.

The preferred anxiolytic agent for the management of narcotic withdrawal symptoms is about 0.25 to 10 mg of lorazepam given to a human being about every 4-10 hours, preferably about every 6-10 hours, and most preferably about every 6-8 hours during the day and about every 3-4 hours at night, up to a typical maximum dose of about 10 mg per day or greater, most preferably a maximum of about 7 mg per day. Total daily dosing will occur over about 5-14 days, with initial doses maximizing at about 7-10 mg per day and tapering thereafter by about 1 mg or greater each day of treatment until dosing is completed within a period of about 5-14 days.

Those skilled in the art will appreciate and be able to adjust the dose, dosing interval, and dosing length/treatment period of the anxiolytic agent of the preferred embodiment in the treatment of narcotic withdrawal symptoms based upon the clinical response and therapeutic value required to reduce or prevent withdrawal anxiety for a patient, liver and kidney function of the patient, and the amount of CNS stimulant used within the preferred embodiment.

As the dose of the CNS stimulant is increased or the interval of dosing is decreased, the anxiolytic agent dose can be decreased and dosing interval increased. In addition, it should be understood by those skilled in the art that the dose of the CNS stimulant can be increased to achieve therapeutic efficacy in managing side effect outcomes of the anxiolytic agent of the preferred embodiment as the dose of the anxiolytic agent is increased to treat the withdrawal symptomology of a particular patient undergoing alcohol or narcotic abuse treatment.

The centrally acting alpha antiadrenergic agent of the preferred embodiment consists essentially of an effective amount of methyldopa, clonidine, guanfacine, guanabenz, lofexidine, derivatives thereof, or pharmaceutically acceptable salts thereof. It is recognized that lofexidine is not currently approved for use in the U.S. by the FDA, but is approved for use in Europe. The preferred centrally acting alpha antiadrenergic agent for treatment of alcohol and narcotic withdrawal side effects is about 0.05-0.7 mg of clonidine given to a human being about every 6-8 hours for a period of about 5-14 days. Use of such agents reduces or prevents central and peripheral nerve agitation associated with alcohol and narcotic withdrawal. Typical maximal dosages of clonidine can be about 2 mg per day or higher depending upon the particular patient response required for the particular detoxification setting, liver and kidney function of the patient, and the dose and dosing interval of the central nervous system stimulant agent of the preferred embodiment during that patient's alcohol or narcotic abuse treatment course.

As the dose of the CNS stimulant is increased or the dosing interval is decreased, the centrally acting alpha antiadrenergic agent dose can be decreased and dosing interval increased. In addition, it should be understood by those skilled in the art that the dose of the CNS stimulant can be increased to achieve therapeutic efficacy in managing side effect outcomes of the centrally acting alpha antiadrenergic agent of the preferred embodiment as the dose of the centrally acting alpha antiadrenergic agent is increased to treat the withdrawal symptomology of a particular patient undergoing abuse treatment. Those skilled in the art will appreciate and will be able to adjust the dose, dosing interval, and dosing length treatment period of the centrally acting alpha antiadrenergic agent of the preferred embodiment based upon the factors listed above, to reduce or prevent central and peripheral nerve agitation for a particular patient undergoing alcohol or narcotic detoxification treatment.

The central nervous system stimulant agent of the preferred embodiment consists essentially of an effective amount of an amphetamine, such as amphetamine sulfate, dextroamphetamine sulfate, methamphetamine hydrochloride, combinations of amphetamines, derivatives and pharmaceutically salts thereof; pemoline, derivatives and pharmaceutically acceptable salts thereof; methylphenidate, derivatives and pharmaceutically acceptable salts thereof; caffeine, derivatives and pharmaceutically acceptable salts thereof; and centrally acting alpha-1 agonists such as modafinil, epinephrine, norepinephrine, phenylephrine, derivatives thereof and pharmaceutically acceptable salts thereof to reduce or prevent dizziness, depression, difficulty in being mobile, drowsiness, lethargy, weakness in the extremities, and orthostatic hypotension associated with anxiolytic and centrally acting alpha antiadrenergic agents utilized to treat alcohol and narcotic withdrawal symptomology.

The preferred central nervous system stimulant agent for the treatment of side effects associated with therapeutic agents used to treat alcohol and narcotic withdrawal symptoms is about 1-20 mg dextroamphetamine sulfate in an immediate release dosage form given to a human being about every 4-8 hours, preferably about every 4-6 hours at regular spaced intervals during the day and up to about 5 mg as a rescue dose during the night if needed for a period of about 5-14 days. In a controlled release dosage form, the central nervous system stimulant, dextroamphetamine sulfate, is dosed as 1-20 mg given to a human being about every 12 hours or once daily without a rescue dose given during the night, for a total treatment period of about 5-14 days.

In an alternative embodiment, for those patients requiring a non-amphetamine based central nervous system stimulant agent or those who cannot receive additional or increased amphetamine doses due to cardiovascular risk concerns, a centrally acting alpha-1 agonist, such as modafinil, can be used as a substitute or adjunct for an amphetamine(s), as the central nervous system stimulant agent of the preferred embodiment.

Centrally acting alpha-1 agonists such as modafinil (Provigil.RTM.) act postsynaptically at alpha-1 adrenergic receptors and may also bind to dopamine carriers to increase stimulation and mental alertness within the human body usually without altering the body's blood pressure and heart rate excessively like that of amphetamines. Further, centrally acting alpha-1 agonists do not decrease stage 2 and REM sleep like amphetamines, and thus offer a treatment alternative for the practitioner when choosing a central nervous stimulant agent of the preferred embodiment.

In the alternative embodiment, the preferred central nervous system stimulant agent for the treatment of side effects associated with therapeutic agents used to treat alcohol and narcotic withdrawal symptomology is about 50-400 mg, preferably about 100-300 mg, and most preferably about 200 mg or higher per day of modafinil administered to a human being every 12 hours, more preferably once daily in the morning, for a period of 5-14 days.

It should be understood by those skilled in the art that the preferred embodiment of the present invention can utilize any of the central nervous system stimulant agents alone or in combination with one another as the central nervous system stimulant agent component of the preferred embodiment. For example, a practitioner administering the preferred embodiment containing an amphetamine initially as the central nervous system stimulant agent could add modafinil as an adjunct central nervous system stimulant to a particular patient's drug treatment therapy where use of an additional amphetamine would not be desirable and dosing of the current amphetamine could not be increased due to blood pressure and heart rate considerations.

Those skilled in the art can appreciate and would be able to adjust the dose, dosing interval, and dosing length treatment period of the central nervous system stimulant of the preferred embodiment based upon the clinical and therapeutic response desired for a particular patient undergoing alcohol or narcotic abuse treatment, liver and kidney function of that patient, as well as drug interactions between the central nervous system stimulant agent and other components of the preferred embodiment.

All of the components of the preferred embodiment can be used separately, but administered contemporaneously and can be given via a singular pharmaceutically acceptable dosage form for each component or combination of all the components as an immediate release or controlled release dosage form. Contemporaneously means the three agents are administered separately over time, but have a combined effect together after their individual administrations. Suitable pharmaceutical dosage forms for the preferred embodiment include, but are not limited to, tablets, capsules, caplets, dose-paks, solutions, syrups, suppositories, transdermal applications, creams, lotions, emulsions, powders and the like. Preferred dosage forms for the present invention include tablets, caplets, capsules, dose-paks, solutions, and transdermal applications with a tablet, caplet, or capsule being the most preferred.

The triple drug therapeutic composition, kit, and method of treatment of the preferred embodiment can be administered to the human body via a variety of medically and pharmaceutically acceptable administration routes. Those routes include, but are not limited to, the oral, rectal, intravenous, intradermal, subcutaneous, cutaneous, intramuscular, buccal, transdermal, and other pharmaceutically and medically acceptable routes of administration for the human body. Preferred routes of administration for the preferred embodiment are the oral, rectal, intravenous and intramuscular routes, with the oral route being most preferred.

By combining the pharmaceutical medicaments of the preferred embodiment in a kit, composition, and method of treatment regimen, the preferred embodiment achieves far superior alcohol and narcotic withdrawal side effect management results than can be achieved with current conventional prior art treatment modalities. Current treatment modalities for alcohol and narcotic withdrawal symptoms utilize anxiolytic agents and centrally acting alpha antiadrenergic agents to reduce or prevent anxiety and central and peripheral nerve agitation for patients undergoing alcohol or narcotic abuse treatment. Current treatment modalities do not, however, prevent or reduce the negative withdrawal side effects of drowsiness, dizziness, lethargy, depression, difficulty in being mobile, weakness in the extremities, and orthostatic hypotension caused by anxiolytic agents and centrally acting alpha antiadrenergic agents used to treat alcohol or narcotic withdrawal symptoms.

As a result, most patients become non- or mal-compliant in taking such medications because of these negative side effect outcomes which, in turn, can cause an increase in the incidence of relapse for alcohol or narcotic abuse requiring further treatment. In addition, these negative side effects associated with the use of anxiolytic and centrally acting alpha antiadrenergic agents place patients at a greater risk of injury, and health personnel at a greater risk of liability prompting the increased use of in-patient treatment settings only. Such increased risks and liability further increase healthcare costs.

Although not being bound to any particular theory, it is believed that the preferred embodiment reduces or prevents the negative withdrawal side effects of drowsiness, dizziness, depression, difficulty in being mobile, lethargy, weakness in the extremities, and orthostatic hypotension associated with the use of centrally acting alpha antiadrenergic agents and anxiolytic agents used to treat alcohol and narcotic withdrawal symptoms through the use of a central nervous system stimulant agent or agents to stimulate the release of norepinephine from central nonadrenergic neurons, epinephrine from adrenergic neurons, and the release of dopamine from the mesolimbic system of the human central nervous system to counteract the negative withdrawal side effects of agents used to treat alcohol or narcotic withdrawal symptomology.

Thus, patients become more compliant with their therapy by experiencing fewer of the negative withdrawal side effects caused by anxiolytic and centrally acting alpha antiadrenergic agents, thereby decreasing the incidence of relapse and the need for additional cycles of abuse treatment. Further, by increased central nervous system stimulation, patients are at a reduced risk of syncope allowing for the increased use of out-patient treatment settings for these individuals, thereby decreasing the overall cost of health care.

The above description is considered that of the preferred embodiments only. Modifications of the invention will occur to those skilled in the art and to those who make or use the invention. Therefore, it is. understood that the embodiments shown in the drawings and described above are merely for illustrative purposes and not intended to limit the scope of the invention, which is defined by the following claims as interpreted according to the principles of patent law, including the Doctrine of Equivalents.

Claim 1 of 63 Claims

The invention claimed is:

1. A pharmaceutical kit for treatment of alcohol withdrawal symptoms comprising the following three separate ingredients, combined in a kit:

at least one anxiolytic agent;

at least one centrally acting alpha antiadrenergic agent; and

at least one central nervous system stimulant agent.
 

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