DXM & oxidase inhibitor for weaning patients off opiates. But not DXM alone.

[Ethyl]

[top]Dextromethorphan and oxidase inhibitor for weaning patients from narcotics and anti-depressants

Description

BACKGROUND OF THE INVENTION

This invention is in the field of pharmacology, and relates to drug treatments for reducing the dependence of patients on habit-forming and potentially addictive drugs, including narcotics and anti-depressants.

The term "narcotic" as used herein has the same meaning used in standard medical reference works, such as the "more recent" definitions used in Stedman's Medical Dictionary, 26th edition (Williams & Wilkins Publ., Baltimore, 1995) and in the "Analgesics" chapter in the "Drug Evaluations" subscription service published by the American Medical Association (Chicago). Briefly, "narcotics" as used in any definition (either classical or recent) includes: (1) opiate drugs, defined as any preparation or derivative of opium, a natural mixture derived from poppy plants that includes a number of medically important and/or habit-forming or addictive drugs, including morphine, codeine, noscapine, papaverine, thebaine, and heroin; and, (2) opioid drugs, which includes opiates as well as various synthetic narcotic drugs having similar or related chemical structures and effects. Such synthetic narcotics include meperidine (sold under trademarks such as DEMEROL™), hydrocodone (sold under trademarks such as VICODIN™), hydromorphone (sold under trademarks such as DILAUDID™), propoxyphene (sold under trademarks such as DARVON™), oxycodone (sold under trademarks such as PERCODAN™ when mixed with aspirin, or PERCOCET™ when mixed with acetaminophen), levorphanol, fentanyl, and methadone.

Under a more recent definition that has come to be accepted within the medical profession, the term "narcotics" has been broadened somewhat, to include other synthetic drugs which have "effects that are similar to opium and its derivatives". In order for a drug to be to classified as a "narcotic", its effects must include: (1) the ability to induce "significant alteration of mood and behavior"; (2) the ability to induce a condition of "stuporous analgesia"; and (3) a substantial risk of dependence, tolerance, and/or addiction.

As used herein, the term "narcotic" specifically excludes: (1) barbiturate drugs (which are a separate category of drugs, derived from barbituric acid), even though some barbiturate drugs have many of the same types of effects as narcotics; (2) cocaine and its derivatives, such as crack; and (3) drugs with purely anesthetic or analgesic activity, which do not alter mood or pose a serious risk of addiction and abuse. None of those three categories are relevant to the current invention.

This current invention is limited to methods and compounds for "weaning" a dependent or addicted person from the grip of a habit-forming narcotic drug as defined above (or an anti-depressant drug, as discussed below). This invention involves a drug treatment which can help patients (including patients who have suffered for years from chronic and intractable pain) entirely terminate any subsequent use of a habit-forming narcotic drug.

It is recognized by the Applicant that these same or similar methods and compounds may also be highly useful for helping patients break an addiction to or dependence on barbiturates, cocaine, and certain other addictive or habit-forming drugs which have effects similar to narcotics. Accordingly, the combined drug treatment disclosed herein can and should be evaluated on patients addicted to barbiturates, cocaine, and other addictive drugs. However, the teachings and claims herein do not involve any method of terminating the use of cocaine (or crack, or other cocaine derivatives) or barbiturates, since those two classes of drugs are specifically excluded from the teachings herein.

As is well-known to physicians and other health-care providers, dependence on and addiction to narcotic drugs is a serious and widespread medical and sociological problem. It is also a tragic problem, since most such addictions are triggered not by reckless users who want to get "high" or "stoned". Instead, most people who are addicted to narcotic pain-killers first began using them to help them cope with a serious medical problem that required the use of powerful pain-killing drugs.

As is well-known to physicians and other health-care providers, there is a major need for better methods of helping patients who are "hooked" on narcotics. Currently available methods work some of the times, for some people; however, the struggle to break free of an addiction to, or any long-term use of, a narcotic is a terrible ordeal, even under the best conditions (such as in a professionally-staffed rehabilitation center with full-time living quarters). Although some people manage to break free, usually with the help of on-going support from groups similar to Alcoholics Anonymous, the sad fact is that a majority of all patients who try to break free of a narcotic addiction never fully succeed.

Even among people who are merely "dependent" on narcotics, and who use narcotics to help them cope with chronic severe pain (such as pain caused by cancer or chemotherapy, diabetes, an autoimmune disease, repeated back or neck surgeries, neuropathic or phantom pain, lingering effects of a severe injury or infection, etc.), the side effects caused by narcotics can render life miserable. Such people often must struggle through each day feeling dazed, groggy, and semi-stuporous, as well as frequently nauseous and frequently constipated. They would be extremely relieved and grateful for any treatment that would help them return to a more normal life, where the pain is kept at a tolerably low level while the feelings of dazed grogginess, frequent nausea, constipation, and other side effects of the narcotic are gone.

As used herein, "long-term" use of a narcotic or anti-depressant drug refers to use of such drug by the patient for a sufficiently prolonged period of time to allow the patient to develop a substantial level of dependence on, or addiction to, the narcotic or anti-depressant drug. The method of treatment disclosed herein is designed to help patients break free from such drugs, after they have reached a point where they are unable to stop taking them without substantial medical intervention and assistance.

It is also recognized by the Inventor herein that this same general method (i.e., use of dextromethorphan in conjunction with an oxidase inhibitor) may also be able to help patients avoid the gradual development of dependence on, or addiction to, such habit-forming drugs, when DM plus an oxidase inhibitor are administered in conjunction with an opiate or other narcotic and/or with an anti-depressant, to treat a patient suffering from chronic and intractable pain or another long-term medical problem. Based on various results obtained to date, it is further believed by the Inventor herein that such treatment (i.e., DM plus an oxidase inhibitor in conjunction with a narcotic and/or anti-depressant) is likely to perform better than any and all prior efforts to use dextromethorphan (or other mild NMDA antagonist drugs) in conjunction with narcotics, to reduce the development of dependence on such narcotics. However, that promising form of treatment has not yet been specifically tested and evaluated, and is not addressed or covered by the claims herein.

Prior Use of Dextromethorphan to Potentiate Opiate Drugs

A substantial number of published reports and patents have stated that dextromethorphan, dextrorphan, and other NMDA antagonist drugs can "potentiate" and increase the potency of opiate drugs such as morphine. Accordingly, these reports indicate that using DM in combination with an opiate drug can reduce the dosage of an opiate drug that is required to achieve a desired level of pain-killing efficacy. Some of these reports also suggest that administering DM or another NMDA antagonist drug along with an opiate drug can also help reduce the likelihood that a patient will develop tolerance, dependence, or addiction to the opiate drug. US patents include U.S. Pat. No. 5,321,012 (Mayer et al 1994), U.S. Pat. No. 5,556,838 (Mayer et al 1996), and U.S. Pat. No. 5,654,281 (Mayer et al 1997). Published articles include Koyuncuoglu et al 1992, Trujillo et al 1994, Elliott et al 1994, Advokat et al 1995, Elliott et al 1995, Grass et al 1996, Mao et al 1996, Manning et al 1996, Hoffmann et al 1996, Kauppila et al 1998, and Plesan et al 1998.

However, it appears that all of the above-cited articles involved efforts to merely reduce the dosages of opiates that were required to obtain a satisfactory level of pain-reducing efficacy. Apparently, none of these articles seriously contemplated or proposed that DM, in combination with an entirely different drug that none of those researchers used or tested, might be able to completely and totally break and terminate a dependent or addicted person's need for opiates.

Based on two small-scale studies on heroin addicts in Turkey, it was reported that DM in combination with other drugs such as tizanidine or diazepam might be useful in treating addicts who were suffering withdrawal symptoms (Koyuncuoglu et al 1990 and 1995). However, those articles and a subsequent published letter (Bisaga et al 1997, which reported essentially the same results) apparently did not generate serious attention among other researchers trying to treat heroin addicts.

Just as importantly, none of the patents or articles cited above taught or suggested, in any way, a combination of dextromethorphan with a cytochrome oxidase inhibitor for weaning people from opiates.

Despite all the ongoing efforts to try to help addicts and others who are dependent on or addicted to opiates and other narcotics, there are no adequate and satisfactory ways under the prior art to help opiate users completely terminate their use of opiates and other habit-forming narcotics. A major and important need still exists for improved methods to help people break completely free of dependence on, or addiction to, habit-forming opiates and other narcotics.

It should also be noted that the Applicant/Inventor herein, Richard Smith, is also the inventor or co-inventor on a number of prior US patents involving a combination of dextromethorphan with an oxidase enzyme inhibitor. Those prior US patents include U.S. Pat. No. 5,166,207 (on treating neurological disorders), U.S. Pat. No. 5,206,248 (on treating emotional lability), U.S. Pat. No. 5,350,756 (on treating intractable coughing), U.S. Pat. No. 5,366,980 (on treating dermatitis), and U.S. Pat. No. 5,863,927 (on treating chronic and intractable pain). Smith's research in this field in conjunction with other collaborators is also described in Zhang et al 1992. However, none of those items relate to or suggest the newly discovered use and treatment disclosed herein.

Accordingly, one object of this invention is to disclose a medical treatment involving a certain type of drug combination which can help people break free of dependence on, or addiction to, habit-forming narcotic drugs, so that affected people (including patients who suffer from chronic pain) can completely terminate their use of narcotic drugs.

During the research which led to this invention, it was also discovered that patients who suffered from chronic intractable pain, and who were able to completely terminate their dependence on pain-killing narcotics using a DM/oxidase inhibitor combination, can also, in at least some cases, break free of anti-depressant drugs as well. Accordingly, another object of this invention is to disclose a medical treatment which can help people terminate long-term use of anti-depressant drugs.

These and other objects of the invention will become more apparent through the following summary and description of the preferred embodiments.

SUMMARY OF THE INVENTION

Patients can be helped to break free of addictive or habit-forming narcotics and anti-depressants, by treatment using two drugs. One drug is dextromethorphan (DM), which has been used for decades as an anti-tussive (cough-suppressing) drug in cough syrups. The other drug is an oxidase inhibitor which suppresses activity of a liver enzyme called cytochrome P450-2D6 (also called debrisoquin hydroxylase, sparteine monooxygenase, cytochrome P450-DB, and CYP2D6). In most patients, this oxidase enzyme rapidly degrades DM and converts it into a metabolite called dextrorphan. An oxidase inhibitor (such as quinidine) which suppresses cytochrome P450-2D6 activity increases the half-life and concentration of DM in the circulating blood. When this combined treatment was administered orally to patients who had become dependent on morphine and anti-depressant drugs because of chronic intractable pain, it initially helped the patients reduce their dosages of morphine and other drugs, including anti-depressants. When additional testing was done, the combined treatment allowed patients to entirely terminate all use of morphine and anti-depressants, with minimal withdrawal or other adverse effects. Importantly, these same patients received no substantial benefit from taking dm by itself, without an oxidase inhibitor. Accordingly, the combination of dextromethorphan plus an anti-oxidase drug can allow at least some patients to break entirely free of narcotics and/or anti-depressants, even after years of use for chronic pain and other medical problems, even when they are not substantially helped by dextromethorphan alone.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The treatment disclosed herein involves administration (such as by oral ingestion) of a balanced regimen of two drugs. One drug is dextromethorphan (DM), which has been used for decades as an anti-tussive (cough-suppressing) drug, mainly in cough syrups. DM is available from numerous suppliers. University Compounding Pharmacy (San Diego, Calif.) supplied all DM used in the trials below, in powdered form which was loaded into capsules.

The second drug in the combined treatment disclosed herein must inhibit the activity of an enzyme which exists mainly in the liver. This enzyme was initially referred to as debrisoquin hydroxylase, based on the early discovery that it degrades a drug called debrisoquin, which is used to control high blood pressure.

The debrisoquin hydroxylase enzyme belongs to a family of enzymes known as "cytochrome P-450" enzymes (since they absorb light in the 450 nanometer range), or as "cytochrome oxidase" enzymes (since they oxidize a wide range of compounds that do not naturally occur in circulating blood). These enzymes are found at high concentrations in liver cells, and at lower concentrations in other organs and tissues such as the lungs (e.g., Fonne-Pfister et al 1988). By oxidizing lipophilic compounds, which makes them more water-soluble, cytochrome oxidase enzymes help the body eliminate (via urine, or in aerosols exhaled out of the lungs) compounds that might otherwise act as toxins or accumulate to undesired levels. Since the debrisoquin hydroxylase enzyme fell within the cytochrome P-450 class of enzymes, it was referred as "cytochrome P450-DB", where "DB" referred to debrisoquin.

Some years later, other researchers discovered that a certain oxygenase enzyme in liver tissues degrades an entirely different drug called sparteine. They called that enzyme sparteine monooxygenase. It wasn't until later that researchers realized that debrisoquin hydroxylase and sparteine monooxygenase apparently are the same enzyme.

Still later, as other researchers began trying to organize the complex and overlapping set of cytochrome oxidase enzymes into a logical system of names, they began referring to the debrisoquin hydroxylase/sparteine monooxygenase enzyme as the cytochrome P450-2D6 enzyme. In addition, in some recent articles, the cytochrome P450-2D6 name is abbreviated as "CYP2D6".

Accordingly, this same enzyme has been referred to by at least five different names: debrisoquin hydroxylase, cytochrome P450-DB, sparteine monooxygenase, cytochrome P450-2D6, and CYP2D6.

Since the cytochrome P450-2D6 name appears to have become the predominant and systematized name in recent published reports, that enzyme is referred to herein as cytochrome P450-2D6 (or simply as P450-2D6, for convenience).

In a "normal" and healthy person who has not been treated with an oxidase inhibitor drug, the P450-2D6 enzyme rapidly degrades dextromethorphan, converting it into a similar but altered compound called dextrorphan. However, certain drugs are known which can inhibit the activity of the P450-2D6 enzyme. If a patient is treated with one of these oxidase inhibitor drugs, it will substantially increase the half-life, and the concentration, of DM in the circulating blood of the patient.

One potent oxygenase inhibitor drug is called quinidine, which is a dextrorotatory stereoisomer of quinine. Quinidine normally is used to treat cardiac arrhythmias. Inaba et al 1986 and Nielsen et al 1990 discuss the ability of quinidine to inhibit the oxidation of sparteine in in vivo animal tests. Brinn et al 1986, Brosen et al 1987, and Broly et al 1989 discuss the ability of quinidine to inhibit the degradation of DM by the P450-2D6 enzyme, in liver cell preparations.

Various other drugs are also known to be inhibitors of the P450-2D6 enzyme; a fairly extensive list is provided in Inaba et al 1985. Since quinidine is not tolerated well by everyone, and since quinidine should never be given to anyone who has a heart condition known as a "prolonged QT interval", these other drugs may be of interest to some doctors and their patients. The more potent inhibitors include yohimbine, haloperidol, ajmaline, lobeline, pipamperone, and fluoxetine. Still other drugs that have less potent yet still significant oxidase inhibiting activity include labetalol, chlorpromazine, domperidone, nortriptyline, quinine, oxprenolol, propranolol, timolol, metaprolol, diphenhydramine, papaverine, and mexiletine.

Since people have major variations in their oxidative enzyme activities, screening tests can be undertaken under the supervision of a physician to select a preferred antioxidant for any specific patient. The preferred dosage of any such drug, if it is being used to inhibit the P450-2D6 enzyme in order to boost the levels of DM in a patient who is trying to terminate dependence on a narcotic or anti-depressant, can be determined through trial-and-error tests (more accurately described as "trial-and-adjustment" tests). In this procedure, a patient is prescribed an initial dosage of DM without an oxidase inhibitor, to establish certain baseline values, to ensure that the patient has a properly functioning set of cytochrome enzymes and is not a "poor metabolizer", and to ensure that the patient does not suffer an adverse reaction to the DM. After that baseline test has been completed, the patient is also given a very low "starting" dosage of the oxidase inhibitor or a "best guess" oxidase inhibitor dosage, for a period such as one or two weeks. At the end of that trial period, the patient's sense of well-being is evaluated, along with his/her ability to continue reducing the dosage of the habit-forming narcotic drug to progressively lower levels without suffering from unacceptable levels of pain. In addition, a blood test can be taken to evaluate the concentration of DM in the blood, in the presence of the oxidase inhibitor that is being tested during that time period. Based on the patient's oral report, and the result of any such blood test, the dosage of either or both of the two drugs (DM and the oxidase inhibitor) can be adjusted for the next 1 or 2 week trial period.

Since at least three different drugs will be involved (the habit-forming narcotic drug, the DM, and the oxidase inhibitor), and since the goal of this treatment is to progressively reduce and then completely eliminate the dosage of the habit-forming narcotic drug, this treatment method involves an on-going procedure of weekly, biweekly, or monthly adjustments, wherein a trained physician can adjust the dosage of any or all of the three relevant drugs after each periodic evaluation. Therefore, this process can be regarded as a "weaning" process, since the patient is being weaned (i.e., gradually but entirely removed) from the habit-forming narcotic drug, with the assistance of both (i) dextromethorphan, as an "opiate substitute" drug, and (ii) an oxidase inhibitor, which is administered in order to increase and sustain relatively high concentrations of DM in the circulating blood of the patient.

It should also be recognized that a potent oxidase inhibitor such as quinidine (or even a less potent oxidase inhibitor, at a relatively high dosage) can convert a patient into a "poor metabolizer", as described in articles such as Guttendorf et al 1988, Kupfer et al 1984, and Koppel et al 1987. A small yet significant fraction of the population (roughly 7 to 10 percent of adult Caucasians) has relatively low natural levels of the P450-2D6 enzyme, because of genetic factors. Such people are regarded by the medical profession as somewhat high-risk patients; they must be treated with extra care and attention, since they may be overly sensitive to certain drugs, compared to people with a full set of cytochrome P450 enzymes (usually referred to as "extensive metabolizers" or "good metabolizers"). Dextromethorphan is often used as a test drug, to determine whether a certain patient is an "extensive metabolizer" (with a full set of cytochrome P450 enzymes) or a "poor metabolizer" (with a deficiency in his or her ability to metabolize and eliminate various drugs and potential toxins). Accordingly, if a patient is administered an oxidase inhibitor compound such as quinidine, in a deliberate effort to inactivate that patient's debrisoquin hydroxylase enzyme, the patient should be advised to try to reduce his/her intake of potential toxins, including tobacco products and alcohol.

The combined DM-plus-inhibitor treatment was first tried on a patient who arrived at the offices of the Inventor herein, Dr. Richard Smith, a neurologist who is the founder and Director of the Center for Neurologic Study, in La Jolla, Calif. The patient, who is described in further detail in Example 1, was badly depressed, after having been on narcotic drugs for several years to treat peripheral neuropathy, which caused a burning sensation in her hands and feet, and which had appeared spontaneously with no known cause. She had been to pain management and other medical specialists at the Scripps Institute in La Jolla, but the best treatment they could give her was to place her on a combination of a narcotic pain-killer (morphine sulfate), and two anti-depressants (WELLBUTRIN™ and ELAVIL™). Accordingly, about 5 years after she first began to experience the burning pain in her hands and feet, and after years of taking morphine and anti-depressant drugs, she was referred to the Center for Neurologic Study for a complete neurological evaluation.

Reputation Comments on this post:

good find!