WO1996014071A1 - Combination of chemical compounds used as a medicament intended to suppress the dependence of individuals to opioids - Google Patents

Abstract

Combination of chemical compounds used as a medicament intended to suppress the dependence of individuals to opioids, the combination comprising a laxative or enema of irrigation, repeated doses of alpha-adrenergic agents, antiemetic agents, gastric protectors, optionally inhibitors of the proton pump, an anxiolytic compound, anaesthetic sleep inducing agent and determined doses of an opioid antagonist compound, such as naxalone or naltrexone.

Description

COMBINATION OF PHARMACOS AS A MEDICINAL INTENDED SUPPRESSION OF DEPENDENCY OF INDIVIDUALS TO OPIACEANS

The present description deals with an invention based on the combination of certain chemical compounds or drugs through which the detoxification of drug addicts is carried out to opioid substances in a period of less than 24 hours.

One of the main objectives in opioid addiction treatment is abstinence, which is treated in various documents such as the article "Substance abuse disorders: a psychiatric priority" in Am. J. Psychiatry 148, concentrated on pages 1291 to 1300 written by the Group for the advancement of the Psychiatry Committee for Alcoholism and Addictions in 1991.

There are certain rapid-type procedures in which detoxification needs more than 10 days to complete, as indicated in various publications, such as "Dependence clinical research and treatment unit, the Maυdsley and Bethlem Royal Hospital" (The treatment unit and clinical investigation of drug dependence of the royal hospitals of Maudsley and Bethlem) in Br. J. Addict 83, collected on pages 1387 to 1394 by J.5. Strang, M. Gossop and B. Bradley in 1988.

A publication in the same line was written by TR Kosten, JH Kristal, D.5. Charney, LH Price, CH Morgan and HD Kleber in 1989 with the title "Rapid detoxification from opioid dependence", in the American Journal Psychiatry 146, as well as in another article by the aforementioned authors Kosten et al in 1991 as "Treatment of heroin addicts using buprenorphine" in Am.J. Drυg Alcohol Abuse 17.

Such procedures described in the aforementioned articles are often expensive, in addition to being frustrating due to the high percentage of dropouts. For a hospital detoxification the range of dropouts ranges from 20% to 30% as indicated in the article "Dropping out of substance abuse treatment: A clinically oriented review." (Abandonment during substance abuse treatment: a clinically oriented review) of the clin. Psychol. Rev. 12 on pages 93 to 116, reaching up to 80% in the case of outpatient detoxification, as also cited in the article by M. Gossop, A. Johns and L. Green of 1986 with the title "Opiate withdrawal: impatient versus outpatient programs and preferred versus random assignment to treatment "in Br. Me. J. 293. Detoxification methods may include drug substitution, using an opioid agonist such as methadone as indicated in the article by M. Gossop et al 1989 "Opiate withdrawal responses to 10-day and 21-day methadone withdrawal programs "(10 and 21 day methadone withdrawal programs) from British Journal Psychiatry 154, or through the use of partial opioid agonists such as Buprenorphine as indicated in" Human pharmacology and abuse potential of the analgesic buprenorphine "(Human Pharmacology and potential abuse of analgesic buprenorphine) by Jasinski et al in Arch. Gen. Psychiatry 35 in 1978. Another pattern involves the use of adrenergic agonists such as clonidine or guanfacine as indicated in the articles "clonidine in opiate withdrawal" ( Clonidine in opioid withdrawal) from Ms Gold and others of 1978 in Lancet i, and in "Preliminary results of guanfacine treatment of acute opiate withdrawal" by Schubert et al in American Journal Psychiatry 141.

Recently there is a growing interest in blocking treatments using opioid antagonists such as naloxone or naltrexone associated with adrenergic agonists, as indicated in the publications "Rapid opiate detoxification with clonidine and naltrexone." by Riordan et al. in 1980 collected in Lancet i, and in "The combined use of clonidine and naltrexone as a safe, rapid and effective treatment of abrupt withdrawal from methadone" as the combined, rapid and rapid treatment of methadone abrupt abstinence insurance) published in Am. J. Psychiatry by charney et al in 1989, achieving therapeutic treatments derived from the use of said compounds, in a short period of time, between 48 hours and 4-5 days as indicated in the articles "opioid withdrawal and naltrexone induction in 48-72 h. with minimal dropout using a modi fication of the naltrexone-clonidine technique "(Opioid withdrawal and induction to naltrexone in a period of 48-72 hours with minimal abandonment using a modification of the naltrexone-clonidine technique) in Br. J. Psychiatry 153 conducted by Brewer et al in 1988 Y "Clinical utility of rapid clonidine-naltrexone detoxification for opioid abusers." (Clinical utility of rapid detoxification of clomdine-naltrexone for opioid dependents) in Br. J. Psychiatry 83 by E.vimng, T. Kosten and H.Kleber in 1988.

Given the information published so far, which we have cited above, it is observed that there is a problem in detoxification, especially in substitution with methadone, this being the most prolonged withdrawal syndrome. The use of antagonists allows a significant reduction in the duration of the detoxification process. In this line, a treatment experience with seven individuals in methadone maintenance, included the incorporation of an opioid antagonist, naloxone, a sedative, midazolam, at doses much higher than recommended as well as the use of a sedative antagonist, flυmazeml , to reverse sedation. During the treatment, heart rate and blood pressure were monitored according to the instructions commented in the Loimer et al. Article of 1991, which appeared in Am. J. Psychiatry 148 as "Techniqυe for greatly shortening the transition from methadone to naltrexone maintenance of patients addicts to opiates" (Technique to minimize the transition in the maintenance of methadone to naltrexone in patients with opioid addiction). More recently, a new treatment route has been used with twenty individuals addicted to heroin. The procedure was non-invasive, that is, all medication was given orally and began twelve hours after the last heroin use as extracted from the article by N. Loimer and others of 1993 "ultrashort non invasive opiate detoxification" (Detoxification ultra short opioid non-invasive) published in Am. J. Psychiatry 150. This procedure consisted of using the same sedative as in the previous experience, midazolam, but at even higher doses than in the previous case. This procedure also included an alpha-adrenergic agonist, a clonidine that enhances sedation and decreases the symptoms of opioid withdrawal syndrome and an antiemetic, ondansetron. To accelerate detoxification, two opioid antagonists, naloxone and naltrexone, were used in very high doses, 4 and 50 milligrams respectively in a single dose.

These last two forms of detoxifying represent, in the experience that has led to the use of the set of compounds object of the invention, a serious risk to the life of the individual and are impracticable with the doses of antagonists and sedatives used, as well as with the type of sedatives used, without, in addition, adequate monitoring. As the latest publication on this field of therapeutic medicine, we comment on the article "A 24-h impatient treatment for heroin addicts: a preliminary investigation" (A 24-hour hospital treatment for heroin addicts: preliminary investigation) of the head of the This application, published in Drug and Alcohol Dependence in 1994. This article indicates certain guidelines and products in line with what has been commented so far, there being certain differences with the products and the use of said products that will be developed in this description. These differences are based on the use of certain sedatives and antagonists at lower doses than before, so the recommended doses of product use are provided to the body, which in the case of Antagonists use focus on a range between 6 and 40, preferably between 10 and 30 milligrams and even more preferably between 12 '5 and 18.5 milligrams, in the case of using naltrexone dose, and can also be used as an antagonist, dose of naloxone in a range of 0.4 to 1.5 milligrams per hour, by venous route, another difference, until now maintained by vain authors such as Loymer etc ... will be based on the use of monitoring and sedation in a period greater than 2 hours.

The present invention represents a combination of drugs that allows an ultra-rapid pattern for the detoxification of drug illuminators addicted to heroin and / or methadone or other opiates. The use of certain compounds will be carried out according to guidelines that, in the first place, can begin, unlike other guidelines, immediately after the patient has made his last opioid consumption, therefore, it is not necessary to wait as he puts in practice according to other treaties, just as it is not necessary to substitute an opioid for another before starting the application of the detoxification products provided for in the present invention, an additional novelty is the incorporation of one of the anesthetic sleep inductors used, the Propofol, a product that has never been used by other specialists in this field and both this and any other, for example midazolam, can be supplied in the recommended therapeutic doses without the need to dangerously increase its dosage.

On the other hand, patient monitoring must necessarily include blood pressure, cardiac activity and oxygen saturation in arterial blood. This last parameter has not been previously used by Other specialists in this field. Additionally, it should be mentioned that the products of the invention are used by invasive procedures. Likewise, sedation and / or anesthesia is maintained with monitoring for a minimum period of three hours. In addition, there are minimum requirements necessary to perform this type of intervention, a secretion aspirator and an apparatus for assisted breathing. The application of the drugs, therefore, must be carried out in the vicinity of an intensive care unit or in it, or in a hospital cabin that meets the necessary requirements.

To understand the combination of the products gathered in the invention and their purpose in achieving detoxification, the procedure in which they are immersed will be developed.

In the first instance, the optional intake, one day before admission, of a laxative is required in order to perform as well as possible intestinal cleansing, the patient fasting at least eight hours before the intervention. Likewise, a complete medical and psychological examination will be carried out, discarding any type of pathology that contraindicates the treatment and the necessary analytical determinations such as blood count, biochemistry, pregnancy test will be performed in the case in which the patient is a woman in fertile age, and other complementary examinations directed according to the semiology found in the physical examination, such as chest x-ray, computerized axial tomography, electrocardiogram and electroencephalogram. Repeated doses of alpha adrenergic agents, such as guanfacine or clomdine, will be administered at the time of admission, ensuring tension Blood pressure is not less than 90-60 mmHg or the heart rate is less than 55 systoles per minute, once the patient's examination is finished, the intervention can begin. In this case, a peripheral venous route will be taken and, in the absence thereof, a central route, antiemetics such as ondansetron, and gastric protectors such as H2 antihistamines are administered, among which ranitidine and / or pump inhibitors can be found. protons such as omeprazole and the patient is sedated or anesthetized with anesthetic agents such as propofol or propofol and a benzodiazepine such as midazolan and which will be kept in constant infusion at a dose adjusted to the patient's response and not higher than recommended by the pharmaceutical laboratory. The opioid antagonist, naloxone and / or naltrexone is then given. During the period of sedation or anesthesia the administration of opioid antagonist will be repeated as appropriate and at doses that depend on the amount of heroin to which the patient is accustomed. Each dose of naltrexone should never exceed 40 milligrams, nor will the total dose exceed 50 milligrams. when the individual to be treated ceases to show signs of opioid withdrawal such as piloerction, rhinorrhea and motor agitation, usually four hours after the induction of sleep. a naloxone test consisting of the intravenous administration of 0.8 milligrams of said substance is performed. If this test is negative, that is, no signs of withdrawal appear, the anesthetic administration is suspended, the patient is awakened, and the administration of an analgesic such as ketorolac, an H2 antihistamine such as ranitidine, a benzodiazepine such as ketazolam and an adrenergic agonist such as guanfacine. Ending drug administration, 24 hours after admission Initially, the patient can be discharged by re-administering a long-lived opioid antagonist such as naltrexone. Once the nature of the present invention has been sufficiently described, as well as a way or arrangement to put it into practice, it remains only to be added that the system of the invention may undergo a series of variations in parts of its content, given that said Alterations do not substantially vary the characteristics claimed below.

Claims

1.- Combination of drugs as a medicine for the suppression of dependence of individuals to opiates, characterized by consisting of: - A laxative or irrigation enema.

 - Repeated doses of alpha-adrenergic. - At least one dose of antiemetics.

 - Gastric protectors.

 - Optionally proton pump inhibitors,

 At least one dose of anxiolytic.

 At least one dose of anesthetic sleep inducers,

 At least one dose of an opioid antagonist drug.

2.- Combination of drugs, according to the first claim, characterized in that the alpha-adrenergic agents are guanfacine or clonidine.

3.- combination of drugs, according to the first claim, characterized in that the antiemetic is ondansetron.

4.- Combination of drugs, according to the first claim, characterized in that the gastric protectors are H2 antihistamines, such as ranitidine.

5.- combination of drugs, according to the first claim, characterized in that the inhibitor of Proton pump is omeprazole.

6.- Combination of drugs, according to the first claim, characterized in that the anxiolytic is midazolam.

7.- Combination of drugs, according to the first claim, characterized in that the inducers of anesthetic sleep are propofol or propofol and a benzodiazepine such as midazolam.

8.- Combination of drugs, according to the first claim, characterized in that the opioid antagonist drug is naloxone between 0.4 and 1.5 milligrams per hour; or naltrexone between 6 and 40 milligrams, preferably between 10 and 30 milligrams and even more preferably between 12.5 and 18.5 milligrams.

9.- Combination of drugs, according to the first claim, characterized by using a sene of additional compounds after the drugs, these being an alpha-adrenergic agonist, a gastric protector and a benzodiazepine.