KR20020063180A - A method of treating substance addiction - Google Patents

Abstract

The present invention includes administering a combination of μ-opioid receptor antagonists and long-lasting or sustained-release calcium channel blockers, wherein the calcium channel blockers are therapeutic methods for substance addiction selected from verapamil, nifedipine, amlodipine and felodipine and these To useful compositions of the invention.

Description

A METHOD OF TREATING SUBSTANCE ADDICTION}

Substance intoxication includes overwhelming and irrepressible physical or mental cravings for certain substances such as alcohol, heroin, morphine, methadone, nicotine, amphetamines, cocaine or marijuana. In many cases, discontinuation of a substance without adjuvant treatment, such as pharmacology or psychotherapy, causes severe physical and mental illness. Psychotherapy, response control, or the treatment of substance addiction by certain drugs has been limited and many addicts have chronic relapses.

It is well known that potent, sustained and competitive specific CNS μ, δ, κ- opiate receptor antagonists naltrexone have been used for acute opiate detoxification. However, this method poses a risk. Chronic toxic effects of ethanol are intrinsically regulated either directly by the CNS opiate receptors or indirectly by the liberation of endogenous opiates. Therefore, the daily long-term treatment with naltrexone has been successfully used to prevent relapse and to detoxify opiate and ethanol poisoning. However, the treatment with naltransson alone is not effective for long-term treatment in this condition, often resulting in chronic opiate or ethanol poisoning within 3 to 12 months.

Combination therapy of μ- opiate receptor antagonists (μORA) and calcium channel blockers (CCB), which are sustained or formulated in sustained release, are effective in treating substance abuse, and include substances such as opium, ethanol and other poisoning drugs. It has been discovered that prolonged alleviation, treatment, or alleviation of the likelihood of chronic or recurrence may occur.

The present invention relates to methods of treatment, compounds and compositions suitable for treatment. More specifically, the present invention relates to methods of treatment for substance abuse, including alcohol and opiate poisoning.

Accordingly, the present invention provides (i) μ- opiate receptor antagonists, and (ii) a sustained or sustained release form in a subject, and includes verapamil, nifedipine, amlodipine and felodipine ( Provided is a method for treating substance addiction, including a method of administering to a subject a combination of calcium channel blockers selected from the group consisting of felodipine).

While not limiting the present invention theoretically, the combination of μORA such as naltrexone and CCB selected from verapamil, nifedipine, amlodipine or felodipine has the following advantages.

The mesolimbic system seems to be the brain's reward zone within the main forms of drug addiction, abused by humans.

For example,

1. Opium such as heroin, codeine and morphine and derivatives such as pethidine and methadone. Because of their very long half-life, methadone is often legally prescribed as a useful modulator to reduce or inhibit the use of prohibited opiates such as heroin.

2. Sedative-hypnotics ethanol, barbiturates pentobarbitons and quinalbarbitone, and benzodiazepines temazepam, diazepam and flunitrazepam ).

3. psychostimulant amphetamine and cocaine, and

4. Chemically distinct agents, nicotine, marijuana and phenyclidene.

Each of these drugs acts on mesolimbic nucleus accumbens (NAC) to stimulate the CNS neurotransmitter dopamine (DA) in the midbrain abdominal tegmental region ( VTA) seems to produce a reward for human addiction by promoting release. The mesolimbic stimulating dopaminergic Neutrotransmitter system originates in VTA that protrudes the efferent dopamine-secreting nerve endings into functional-associated NAC.

Toxic effects due to abuse of drugs in the above list mainly begin with the following consequences that occur in VTA and NAC.

If you use morphine as an example, these results are the four primary CNS neuro-transmitter system (fresh naptik (presynaptic) inhibit GABA _A ergic, fresh naptik suppressed cucumber De tissue (opioidergic), calcium-dependent stimulation guided US neojik (dopaminergic) And calcium-dependent glutamatergic), each resident in the VTA as follows.

(i) Under normal conditions, opioidic and dopaminergic systems show only physiological activity. The former is under the control of endogenous opioid neurotransmitter β-endopin that acts on the opiate receptor, and the latter is under a tonic inhibition control system. _A GABA ergic hits increase Cygnus star (antagonista) pikro toxin (picrotoxin) and bikuk tuberculin (bicucculine) when implanted in the VTA waveguide US neojik (dopaminergic) neurons in the activity.

(ii) VTA dopamine neurons do not contain opiate receptors and do not respond directly to opiates.

(iii) Morphine activates an inhibitory opioidic system that inhibits tonic inhibitory GABA _A ergic regulatory actions. As a result, _morphine-A reproduction GABA ergic inhibition is prevented by increasing the release activates the stimulation waveguide US neojik system and activate the DA in the NAC, and to have a sense of compensation. This increased DA release and action is prevented by filling opiate receptor antagonist naloxone with VTA / NAC, indicating the major importance of the opioidic system.

(iv) The other major poisoning drugs mentioned above are in similar manner by their main action to these, in some cases related neurotransmitter systems (eg, glutamatergic, cholinergic, serotonergic, neuropeptidergic) that are relayed to VTA in other parts of the brain. It seems to produce a compensating effect.

On the one hand non-specific μ, δ, κ- opiate receptor antagonists, naltranssons, and on the other hand, CCBs, verapamil, napedipine, amlodipine and felodipine are the main functional-integrated VTA neurotransmitter systems. Different mechanisms act on different neurotransmitter components. Naltrexone blocks the VTA μ opioid receptor and thus prevents the morphine action of the inhibitory opioidic system. Thus, naltrexone restores GABA _A ergic inhibition of action in DA release and NAC, disrupting the maintenance of a morphine-representation compensatory sense. In addition, naltrexone inhibits action in DA release and NAC, and with dysphoria and cravings similar to the severe aversive effect produced by κ opiate ligands that inhibit action in DA release and NAC in rodents. Promotes opium withdrawal symptoms that accompany humans. Since naltrexone is also a potent inhibitor of the associated CNS δ and κ opiate receptors, it similarly inhibits δ and κ opiate receptor-regulated outputs that may affect opiates, alcohols and related toxic processes.

Verapamil, nifedipine, amlodipine and felodipine, on the other hand, inhibit opiates, ethanol and other poisoning drugs by inhibiting VTA- and NAC-responsive voltage-acting presynaptic and postsynaptic L-type calcium channels. It seems to prevent the compensatory action. Such inhibition inhibits the morphine-representing calcium-dependent freshabetic release of DA from the postsynaptic compensation action of DA released in VTA and NAC.

The desire for drug-induced compensation or fortification is reproduced by the chronic detoxification of opiates, ethanol or related poisoning drugs. Aspiration may mean the action and temporary sub-best release of DA in the NAC until or during the next drug withdrawal and at least partially recover to physiological levels.

Therefore, craving may involve the following symptoms.

1. depression induced by addictive drug withdrawal symptoms of DA release and action in NAC induced by opiates, ethanol and related addictive drugs,

2. Activation induced by addictive drug withdrawal symptoms of local dynorphine-modulated inhibitory κ opioid receptors in NAC, which also reduces DA release and action in NAC and results in associated dysphoria and aversion, which also cracks Tends to promote.

3. VTA / NAC dopamine of irritation that is controlled by the functional delivery systems (controlling excitatory dopaminergic transmitter system) with a functional glutamate acts deemed to be incorporated into the last name (glutamatergic), GABA _A functional (GABA ergic _A), acting serotonin ( serotonergic, auto-dopaminergic inhibition, and related addictive drug implications of opioidergic and non-opioidergic neuropeptide neurotransmitter systems.

4. Addictive drug-responsive calcium-dependent mechanisms in functionally relevant components of the brain's reward system, such as VTA, NAC, and medial pre-frontal cortex in the amygdala, hippocampus, and central frontal lobe. This is likely due to the results of a recent clinical patient pilot study involving selected CCB-induced detoxification of chronic addicts dependent on opiates, ethanol, amphetamines, temazepan or marijuana.

Although naltrexone on the one hand and CCB verapamil, nifedipine, amlodipine and ferodipine on the other do so by different mechanisms involving different components of this same system, verapamil, nifedipine, amlodipine and amlodipine and In addition to felodipine, naltrexone acts primarily on the same key functionally integrated VTA / NAC multiple neurotransmitter system involved in achieving rewarding, and has a general effect on the major addictive drugs abused. Will seem to give.

The combinations of the present invention may exhibit beneficial additive or synergistic effects in the preventive management of crabbing and / or decline in detoxified addicts who are chronically dependent on opiates, ethanol, or other addictive drugs discussed herein. Each of them appears to require similar calcium-related CNS processes.

Compounds capable of long-term blocking of μ-opioid receptors in the brain may be usefully used in the present invention. Suitable μORAs include naltrexone and nalmefine. Although μORA must be able to bind to and block μ-opioid receptors in the brain, it will also be understood that it must also be able to combine and block other opioid receptors such as δ- and κ- opioid receptors. Preferred μORA for use in the present invention is naltrexone, which does not specifically block the μ, δ, and κ- opioid receptors in the CNS.

CCBs, selected from verapamil, nifedipine, amlodipine or ferodipine, can act long (amlodipine) or be administered in dosages formulated as sustained release preparations. "Long action" refers to amlodipine, which has a half-life of 30-50 hours and takes about 5-10 days to reach dish plasma concentrations. A "sustained release" preparation is a preparation that is slowly released from the body when the active ingredient is administered and maintains the desired drug concentration over a minimum period of time. Sustained release preparations of verapamil, nifedipine or ferodipine preferably release the active ingredient over a period of about 24 hours and maintain a dish concentration that avoids or minimizes acute reflex heart rate acceleration manifested in tremor, dizziness and flushing. Such dish concentration may depend on the patient's overall health, age, and weight and can be readily determined by one skilled in the art or by the attending physician. Preferably the sustained release preparation of verapamil, nifedipine or ferodipine is active over a minimum of 18 hours and preferably 24 hours in maintaining a given dish concentration for at least this period of time, so it needs to be administered to the patient daily.

The active ingredients may be administered in combined dosages or in separate dosages. The active ingredient may be administered alone, but is preferably provided to the subject in a pharmaceutical composition. CCBs are administered to sustained release formulations if they do not inherently act long (eg verapamil, nifedipine and ferodipine). Preparations of sustained release formulations are well known to those skilled in the art and are described in references such as Remington's Pharmaceutical Sciences , Chapter 91, pages 1976-93, 18 ^th Edition, MACK Publishing Company. Dosage forms may also include oral, parenteral, dermal or graft forms. It will be appreciated that even if the active ingredient is released at a rate that avoids or minimizes adverse effects, sustained release dosage forms will release the active ingredient at a rate that provides a useful clinical effect of the present invention.

Oral sustained release dosage forms can include suspensions or dispersions of the active agent in a polymeric matrix that slowly releases the appropriate coating or active agent around the particles, tablets, capsules, and the like.

Parenteral sustained release dosage forms may include emulsions, solutions, and suspensions.

Sustained release forms through the skin may include ointments, lotions, gels, and the like suspended in particles or liposomes that release the active ingredient late. Alternatively, cellulose nitrate / acetate. Patches may also be used which may comprise microporous membranes of suitable materials such as propylene and polycarbonate. The bandage may also include suitable skin adhesive and lining material.

Grafts, eg, subcutaneous grafts, may include a drug resistant polymer device, wherein the polymer is biologically suitable and nontoxic. Suitable polymers may include hydrogels, silicones, polyethylenes and biodegradable polymers.

Compositions comprising the active ingredient may comprise a suitable carrier, diluent or excipient. These include all conventional solvents, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, surfactants, isotonic and absorbents and the like. The composition of the present invention may also include other physiologically active agents as appropriate.

Carriers, diluents or excipients must be pharmaceutically "acceptable" with the other ingredients of the composition and not harmful to the patient. Preferably the compositions are suitable for oral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by methods known in the art of pharmacy. Such methods include the step of combining the active ingredient with a carrier consisting of one or more accessory ingredients. In general, the compositions are prepared by uniformly and smoothly combining the active ingredient with a liquid carrier or a finely divided solid carrier or both and then give the product a form if necessary.

Compositions of the invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets containing a predetermined amount of the active ingredient; Powder or granules; Suspension in solvent or aqueous or non-aqueous solution; Or as an oil liquid emulsion in water or a water liquid emulsion in oil. The active ingredient may also be provided as a round lump or as a paste.

Tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may optionally contain active ingredients such as powders or granules in combination with a non-flowable active ingredient (e.g. inactive diluent, preservative, disintegrant (e.g. starch glycol sodium, cross-linked polyvinyl pyrrolidone, cross-linked carboxymethyl). Sodium cellulose, surfactant or dispersant) and then compressed in a suitable machine. Molded tablets are made by molding in a suitable machine a mixture of the wetted powder compound with an inert liquid diluent. Tablets may be selectively coated or marked and formulated to slow or control the release of the active ingredient, for example using hydroxypropylmethyl cellulose, with varying proportions to provide the desired release profile. Tablets optionally provide an enteric coating to be released in other intestines other than the stomach.

Suitably the active ingredient is administered as its salt or prodrug.

The term "salt" or "prodrug" includes pharmacologically acceptable salts, esters, solvates, hydrates or other compounds that can provide (directly or indirectly) μORA or CCB depending upon administration to the receptor. . The term "prodrug" is used in its broadest sense and includes derivatives thereof which are converted in vivo to the active ingredient used in the present invention. Such derivatives are readily predicted by those skilled in the art.

Suitable pharmaceutically acceptable salts include, but are, for example, salts of pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid, or for example acetic acid, Propionic acid, butyric acid, tartaric acid, hydroxylmaleric acid, fumaric acid, maleic acid, lactic acid, munic acid, gluconic acid, benzic acid, succinic acid, oxalic acid, phenylacetic acid, methansulphonic acid, toluenesulfonic acid, Benzenisulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, stearic acid, palmitic acid, oleic acid, lauric acid, phantothenic acid, tannic acid, ascorbic acid, valeric acid It is not limited to salts of the same pharmaceutically acceptable organic acids.

Basic salts include, but are not limited to, salts formed with pharmaceutically acceptable cations such as, for example, sodium, potassium, lithium, calcium, magnesium, ammonium and alkylmmonium.

Basic nitric acid containing groups include low alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; Dialkyl sulfates such as dimethyl and diethyl sulfate; And quadrant with the same reagents as the rest.

In a preferred form of the invention the combination of μORA and CCB is administered to the subject for about 12 to 24 weeks. In another preferred form, following a combination administration of about 12 to 24 weeks, if the beneficial effects of naltrexone can no longer be maintained, the treatment may be followed by administration of the CCB alone as long as it is safe. Activity continues.

Said subject to addiction may be a properly detoxified subject, preferably detoxified subject for at least 5-7 days. Long term alcohol or opioid dependent subjects are generally detoxified before receiving the new combination treatment of the present invention. Detoxification processes are well known to those skilled in the art.

Opium dependent subjects treated with the combinations of the present invention were detoxified. Detoxification methods are known in the art. For opioids, detoxification may include short-term naltrexone medication and subsequent symptomatic treatment. About 6-7 days after detoxification, withdrawal can be measured by the Narcan test administered naloxone. Then symptoms of morphine poisoning are observed.

Alcohol addicts can be selectively detoxified. Again, detoxification methods are known in the art. For alcoholics, acamprosate can be administered and the subject is then treated with symptoms for 5-6 days. If the preceding symptoms of alcoholism (eg, impaired awareness and motor skills) are no longer or minimal, the subject is considered detoxified.

It will be appreciated that the μORA and CCB may be administered simultaneously, or successively, one after the other is administered or separately at appropriate intervals. When the μORA and CCB are administered simultaneously, they may be administered in isolated drug form or in combined form, ie a combination comprising both μORA and CCB.

Thus, in another aspect, the present invention also provides a combination comprising μORA and CCB in a long acting or sustained release form wherein the CCB selected from the group is verapamil, nifedipine, amlodipine and ferodipine. (felodipine).

In another aspect, the invention provides a kit comprising μORA and CCB in long acting or sustained release form, wherein the CCB is selected from verapamil, nifedipine, amlodipine and ferodipine, wherein the kit is a combination of the μORA and CCB and It is a classification form suitable for subsequent administration.

In another embodiment, the present invention contemplates the use of μORA in the preparation of a drug for the treatment of underlying addiction, wherein the drug is suitable for administration to a patient in combination with a CCB, wherein the CCB is in long acting or sustained release form, The CCB is selected from the group of verapamil, nifedipine, amlodipine and ferodipine.

The present invention also contemplates the use of CCBs selected from the group of verapamil, nifedipine, amlodipine and ferodipine in the preparation of drugs for the treatment of underlying abuse, wherein the CCB is in long-acting or sustained release form and the drug is combined with μORA. Suitable for administration.

The present invention contemplates the use of μORA and CCB selected from verapamil, nifedipine, amlodipine and ferodipine in the preparation of a drug for the treatment of the underlying addiction, wherein the CCB is a long-acting or formulated form in the drug and the drug is combined with μORA. It is suitable for administration.

The μORA and CCB are administered in therapeutically effective amounts. A therapeutically effective amount is attenuated, reduced craving (eg, at least 30%, more preferably at least 50%, even more preferably at least 70%, 80%, or 90%) when administered according to the required dosing regimen. , Or provide the necessary therapeutic effect, such as preventing or delaying relapse to chronic dependence on underlying addiction. The active ingredient can be administered in an effective amount of addition or synergy. Preferably the active ingredients may be administered in combination, each of the amounts of the active ingredients being less than the therapeutically effective ingredients when administered alone, ie the active ingredients are administered in an effective amount of synergy. . In a preferred embodiment, each of the above active ingredients is administered at about half the ratio of the conventionally recommended therapeutic dosage. Thus, approximately half of the therapeutic drugs of each component of the combination drug form are formulated so that the therapeutic drug may contain the required amount or alternatively, for example, a larger amount except the form of the tablet drug. It may be, and is formed to be easily nutrient without affecting the sustained release mechanism, for example, the evaluation of the tablet.

Appropriate amounts and therapies of medicine can be determined by the attending physician and depend not only on the particular underlying addiction being treated but also on the overall health, age, and weight of the patient.

For example, the ratio of naltrexone to verfamil or nifedipine may be from 1 part by weight of naltrexone to 1 to 20 parts by weight of verapamil and preferably 3 to 5; And 1 part by weight of naltrexone to 0.1 part by weight of nifedipine (eg 1 to 10 parts by weight) and preferably 0.5 to 4 parts by weight of nifedipine. In a preferred embodiment, the component or combination of the drug form is from 12.5 to 100 mg (eg 25 to 50 mg) of naltrexone to 120 to 480 mg of sustained release verfamil, or 30 to 120 mg (eg 60 mg) of sustained release nifedipine. It includes.

It is preferred to administer orally compatible long-acting or sustained release formulations on a daily basis and most preferably seek patient cooperation once daily. Examples of combinations include: naltrexone as a conventional 50 mg tablet; Verapamil as 180 or 240 mg sustained release tablet; Nifedipine is a sustained release tablet of 30 or 60 mg.

As another example, the ratio of naltrexone to amlodipine or leodipine is 1 part by weight of naltrexone to 1 to 0.1 part by weight of amlodipine (eg, 0.1-10 or 1-10), and 3 to 5 parts of amlodipine; 1 part by weight of naltrexone to 0.1 to 20 parts by weight of felodipine (eg, 0.1-100), and 0.5 to 4 parts by weight of felodipine. In a preferred embodiment, the combination or component of the drug form comprises 12.5 to 100 mg (eg 25 or 50 mg) to 2.5 to 10 mg (eg 5 or 10 mg) of amlodipine or 2.5 to 20 mg (eg, by weight of naltrexone). 2.5 5, 10 or 20 mg) of sustained release felodipine. Thus, for example, the treatment may be based on naltrexone 50 mg drug once daily and 2.5 or 5 mg of amlodipine for long-acting once daily or 2.5 or 5 mg or 10 mg of sustained release felodipine or 120 or 180 mg of sustained release verapamil. Can be.

It is desirable to administer oral long-term or sustained release drugs to ensure patient cooperation on a daily basis. Examples of combinations include: naltrexone as a conventional 50 mg tablet; Half of 5 mg (2.5 mg), or 5 or 10 mg of long-acting tablet as amlodipine; 2.5 mg or 5 mg, or 10 mg of sustained release tablet is felodipine.

Throughout the description and claims below, the contexts of the words “comprise” and variations thereof “comprises” and “comprising” are mentioned unless otherwise noted. It is to be understood that it includes an integer or integer step or group and does not exclude any other integer or integer step or group.

Those skilled in the art will recognize that the invention described herein may be subject to variations or modifications other than those specifically described. It is to be understood that the present invention includes all such modifications and variations that fall within the spirit and scope of the present invention. The invention also includes any or all combinations of any two or more of the above steps or features with the steps, features, compositions and compounds cited or indicated individually or collectively herein.

The invention will be described with reference to the following examples which are intended for illustrative purposes only and are not to be understood as limiting the scope of the above described generally.

Example 1

Suitable examples of combinations and compositions according to the invention include:

a) 12.5 mg naltrexone and 120, 180, 240, 360, or 480 mg sustained release verapamil as a daily dose.

b) 25 mg naltrexone and 120, 180, 240, 360, or 480 mg sustained release verapamil as a daily dose.

c) 50 mg naltrexone and 120, 180, 240, 360, or 480 mg sustained release verapamil as a daily dose.

d) 100 mg naltrexone and 120, 180, 240, 360, or 480 mg sustained release verapamil as a daily dose or twice daily for naltrexone.

e) 12.5 mg naltrexone and 30, 60, 90 or 120 mg sustained release verapamil as a daily dose.

f) 25 mg naltrexone and 30, 60, 90 or 120 mg sustained release verapamil as a daily dose.

g) 50 mg naltrexone and 30, 60, 90 or 120 mg sustained release verapamil as a daily dose.

h) 100 mg naltrexone and 30, 60, 90 or 120 mg sustained release verapamil as a daily dose or twice daily for naltrexone.

i) 12.5 mg naltrexone and 2.5, 5 or 10 mg long acting amlodipine as a daily dose.

j) 25 mg naltrexone and 2.5, 5 or 10 mg long acting amlodipine as the daily dose.

k) 50 mg naltrexone and 2.5, 5 or 10 mg long acting amlodipine as the daily dose.

l) 100 mg naltrexone and 2.5, 5 or 10 mg of long acting amlodipine as a daily dose or twice daily for naltrexone.

m) 12.5 mg naltrexone and 2.5, 5, 10 or 20 mg sustained release felodipine as a daily dose.

n) 25 mg naltrexone and 2.5, 5, 10 or 20 mg sustained release felodipine as a daily dose.

o) 50 mg naltrexone and 2.5, 5, 10 or 20 mg sustained release felodipine as a daily dose.

p) 100 mg naltrexone and 2.5, 5, 10 or 20 mg sustained release felodipine as a daily dose or twice daily for naltrexone.

Example 2

Double blind placebo-controlled trial involving 3 patients

Three detoxified opiate dependent (18, 19, 32) patients were treated over two weeks under double blind gastric fluid control conditions. Each opioid dependent patient received oral administration of naltrexone (25 mg) and one of the CCBs once daily. All experimental subjects were detoxified and treatment was performed at least one week after detoxification.

Some patients showed only early, mild, typical metastatic CCB-induced symptoms (eg, palpitations, flushing) that do not require symptomatic treatment or discontinuation of specific test samples. In all patient self-assessments, the frequency and intensity of their drug abuse dependence was reported to be reduced by 30-50% (for size of 0-10). It was reported to be completely out of drug dependence.

Opium addicts self-assessed (0-10 size) the following four questions, frequency and intensity of drug dependence, recurrence potential from specific drug abuse, and consumption or abstinence. These patients also provided answers regarding any treatment-induced or other drug effects they experienced and the progression of such events.

Example 3

Subject Open-Care Clinical Trial of Long-Term Opium-Dependent Trials Decoded by Seven Naltrexones

A co-published clinical trial was conducted with 50 mg of oral prophylactic naltrexone on a daily basis to opioids detoxified with naltrexone that were fully recovered.

Subjects from these seven detoxified trials participated in this trial and received daily adjuvant oral CCB with the same type and dosage from the double-blown clinical trial. Subjects in these experiments (four males and three females between 21-44) have intermittently self-administered (about 0.5-1.5 gm of heroin per day) and three subjects have been intermittently intermittent for about 2-15 years. Methadone maintenance therapy has been undertaken, and most have been moderately taking other common major addiction drugs such as alcohol, benzodiazepines, psychostimulants, or marijuana. These subjects such as public prior to entering the test about 2-8 weeks during an emergency or receiving Trek hands detoxification treatment, long-term with naltrexone 50mg - acting amlodipine (2.5mg), nifedipine _sr (30mg), the Faroe dipin _sr ( 2.5 mg), Verapamil _sr (180 mg), once daily oral administration, was able to determine whether drug dependence improved the duration and quality of subjects' abstinence and recovery, and recurred with dominant drug abuse. These subjects self-assessed such parameters (although less focused) for such parameters (where 0 is no drug dependence and 10 is maximum, a magnitude of 0-10). Three subjects received amlodipine, three with nifedipine sr and one with verapamil sr at the doses mentioned above. the results are as follow.

One or two patients (6 or 8 weeks prior to detoxification and receiving oral doses of 50 mg of naltrexone daily) complained of mild cravings and severe vomiting and abdominal pain. They stopped taking naltrexone, which quickly stopped vomiting and abdominal pain. However, their craving increased significantly, and they experimentally agreed with oral administration of nifedipine (30 mg) or amlodipine (2.5 mg) daily with naltrexone (50 mg). These treatments were performed daily for two weeks, resulting in a 50-70% reduction in cravings in both cases, and vomiting and abdominal pain completely disappeared.

2. Two subjects (previous 2 or 8 weeks of detoxification and 50 mg of naltrexone daily orally) were incidentally administered naltrexone (50 mg) and verapamil (180 mg) or amlodipine (2.5 mg) once daily. In both cases there was a mild, progressive CCB side effect, which did not need to be changed. These two subjects continued to resection, and after two weeks of treatment, subjective symptoms reduced their craving by 50% -70%, and continued the treatment.

3. Two subjects (previous 2 or 3 weeks of detoxification and 50 mg of naltrexone daily orally) were given oral naltrexone (50 mg) and nifedipine (30 mg) once every two weeks. In the first patient, CCB treatment was stopped because of painful peripheral edema in both legs. After 2-3 days of treatment, it became clean. The woman again continued oral administration of 50 mg of naltrexone every day, and she still had a mild craving, sinking into another drug. The second subject reported a rapid, moderate, transient CCB side effect, and reported that the intensity of craving decreased about 30% after two weeks of naltrexone / nifedipine treatment, and the treatment continues.

4. The last patient (3 weeks prior to detoxification and 50 mg of naltrexone daily orally) was given oral naltrexone (50 mg) and amlodipine (2.5 mg) daily. The woman reported that the treatment began to make her craving noticeably in about five days without any confusing side effects. About two weeks after this combination of treatments, she also almost lost her cravings, if she had not been stressed by her husband, regained confidence, almost losing her dependence on drugs, and her aggressive alcoholic husband It reported that the plan of life to escape from the problem caused by

Source of medicine used for the kill.

Naltrexone (Levi, Opan Australia Co., Ltd.) This drug is manufactured by Oppon, USA for Dupan.

Amlodipine (Novak, Paiza Australia Inc.)

Nifedipine (Adrat Orros, Bayer Australia)

Pelodipine (Flendil, Ostrazeneca Co., Ltd.)

Verapamil (Ah Tin Aesop ^®, play Australia Ltd).

Claims (21)

administering to a subject a combination of (i) a μ-opioid receptor antagonist and (ii) a long-acting or sustained release and calcium channel blocker selected from the group consisting of verapamil, nifedipine, amlodipine and felodipine. A method of treating substance addiction in a subject. The method of claim 1, wherein the μ-opioid receptor antagonist is naltrexone. The method of claim 1, wherein the calcium channel blocker is sustained release verapamil. 3. The method of claim 1 or 2, wherein the calcium channel blocker is sustained release nifedipine. The method of claim 1 or 2, wherein the calcium channel blocker is sustained release felodipine. The method of claim 1 or 2, wherein the calcium channel blocker is amlodipine. The method of claim 1 or 2, wherein the calcium channel blocker and / or μ-opioid receptor antagonist is orally administered. 8. The method of claim 7, wherein naltrexone is administered orally once daily at a dose of 25 or 50 mg. 4. The method of claim 3 wherein verapamil is administered orally once daily at a dosage of 180 mg. The method of claim 4, wherein nifedipine is administered orally once daily at a dosage of 30 mg. The method of claim 5, wherein the felodipine is administered orally once daily at a dose of 2.5 mg. The method of claim 6, wherein the amlodipine is administered orally once daily at a dose of 2.5 or 5 mg. 3. The μ-opioid receptor according to claim 1, wherein the μ-opioid receptor antagonist and calcium channel blocker are 1 to 20 parts of verapamil, 0.1 to 10 parts of nifedipine, 1 to 20 parts of amlodipine or 0.1 to 10 parts of felodipine. A method of administering at a rate of 1 part antagonist. The method of claim 1 wherein the addiction agent is an opiate or an alcohol. A composition that is long-acting or sustained release and comprises a calcium channel blocker and μ-opioid receptor antagonist selected from the group consisting of verapamil, nifedipine, amlodipine and felodipine. μ- opioid receptor antagonists and long-acting or sustained release calcium channel blockers, wherein the calcium channel blockers are kits selected from the group consisting of verapamil, nifedipine, amlodipine and felodipine, the kit A kit in a compartment that is partitioned to be subjected to simultaneous or continuous administration of opioid receptor antagonists and calcium channel blockers. Use of μ-opioid receptor antagonists in the manufacture of a medicament for the treatment of substance addiction, wherein the medicament is long-acting or sustained release and is selected from the group consisting of verapamil, nifedipine, amlodipine and felodipine. Use of μ-opioid receptor antagonists administered in combination with channel blockers. Use in the manufacture of a medicament of a calcium channel blocker selected from the group consisting of verapamil, nifedipine, amlodipine and felodipine, which is long-acting or sustained release, wherein the medicament is administered in combination with μ-opioid receptor antagonists The use of calcium channel blockers. A composition comprising μ-opioid receptor antagonists and calcium channel blockers that are long-acting or sustained release, wherein the calcium channel blockers are selected from the group consisting of verapamil, nifedipine, amlodipine and felodipine. μ- opioid receptor antagonists and long-acting or sustained release calcium channel blockers, wherein the calcium channel blockers are selected from the group consisting of verapamil, nifedipine, amlodipine and felodipine, and Calcium channel blockers are reagents for treating substance addiction administered separately or in combination. The use of μ-opioid receptor antagonists and calcium channel blockers which are formulated in a medicament to be enteric or sustained release in the manufacture of a medicament for the treatment of substance addiction and selected from verapamil, nifedipine, amlodipine and felodipine.