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

• US 6,207,674 B1
• Filed: 12/22/1999
• Issued: 03/27/2001
• Est. Priority Date: 12/22/1999
• Status: Expired due to Term

• Current Assignee: Avanir Pharmaceuticals, Inc. (Otsuka Holdings Company Limited)
• Original Assignee: Center for Neurologic Study
• Inventors: Smith, Richard A.
• Primary Examiner(s): Krass, Frederick
• Assistant Examiner(s): JAGOE, DONNA A
• Application Number:
  US09/471,060
• Time in Patent Office: 461 Days
• Field of Search: 514/289, 514/305, 514/491, 514/649, 514/651, 514/652, 514/654
• US Class Current: 514/289
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/49 Cinchonan derivatives, e.g. quinine
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 Opioid-abuse

Abstract

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.

Claims

1. A method of weaning a patient from long-term use of a habit-forming narcotic drug, comprising administering to the patient a combination of dextromethorphan and a second drug which suppresses oxidation of dextromethorphan by cytochrome oxidase enzyme P450-2D6, wherein:

a. the second drug is administered at an effective concentration which increases measurable levels of dextromethorphan in the patient'"'"'s blood;

b. the dextromethorphan is administered at a therapeutically effective concentration which, when coadministered with the second drug, allows the patient to reduce his or her dosage of a habit-forming narcotic drug, without intolerable adverse effects, during a gradual weaning process; and

,

c. the dextromethorphan and the second drug are co-administered to the patient in a manner which allows the patient to decrease and then stop taking the habit-forming narcotic drug without suffering intolerable adverse effects.

2. The method of claim 1 wherein the second drug is quinidine.

3. The method of claim 1 wherein the second drug is selected from the group consisting of yohimbine, haloperidol, ajmaline, lobeline, pipamperone, and fluoxetine, and salts and isomers thereof.

4. The method of claim 1 wherein the second drug is selected from the group consisting of labetalol, chlorpromazine, domperidone, nortriptyline, quinine, oxprenolol, propranolol, timolol, metaprolol, diphenhydramine, papaverine, and mexiletine, and salts and isomers thereof.

5. A method of helping a patient terminate use of a habit-forming narcotic drug, comprising administering, to a patient suffering from dependence on a habit-forming narcotic drug, a combination of dextromethorphan and a cytochrome oxidase inhibitor drug, wherein:

a. the cytochrome oxidase inhibitor drug is effective in increasing measurable levels of dextromethorphan in the patient'"'"'s blood;

b. the dextromethorphan is administered at a therapeutically effective concentration which, in conjunction with the oxidase inhibitor, allows the patient to reduce and terminate use of the habit-forming narcotic drug, without intolerable adverse effects.

6. The method of claim 5 wherein the second drug is quinidine.

7. The method of claim 5 wherein the second drug is selected from the group consisting of yohimbine, haloperidol, ajmaline, lobeline, pipamperone, and fluoxetine, and salts and isomers thereof.

8. The method of claim 5 wherein the second drug is selected from the group consisting of labetalol, chlorpromazine, domperidone, nortriptyline, quinine, oxprenolol, propranolol, timolol, metaprolol, diphenhydramine, papaverine, and mexiletine, and salts and isomers thereof.

9. A method of weaning a patient from long-term use of a habit-forming narcotic drug, comprising administering to the patient a combination of dextromethorphan and an oxidase inhibitor drug which suppresses oxidation of dextromethorphan by cytochrome oxidase enzyme P450-2D6, wherein:

a. the oxidase inhibitor drug is administered at a concentration which increases dextromethorphan levels in the patient'"'"'s blood;

b. the dextromethorphan is administered at a concentration which, when coadministered with the oxidase inhibitor drug, allows the patient to terminate administration of a habit-forming narcotic drug without suffering intolerable adverse effects; and

,

c. the dextromethorphan and the second drug are co-administered to the patient in a manner which allows the patient to terminate administration of the habit-forming narcotic drug.

10. The method of claim 9 wherein the oxidase inhibitor drug is quinidine.

11. The method of claim 9 wherein the oxidase inhibitor drug is selected from the group consisting of yohimbine, haloperidol, ajmaline, lobeline, pipamperone, and fluoxetine, and salts and isomers thereof.

12. The method of claim 9 wherein the oxidase inhibitor drug is selected from the group consisting of labetalol, chlorpromazine, domperidone, nortriptyline, quinine, oxprenolol, propranolol, timolol, metaprolol, diphenhydramine, papaverine, and mexiletine, and salts and isomers thereof.

13. A method of weaning a patient who suffers from chronic pain from long-term use of at least one anti-depressant drug, comprising administering to such patient a combination of dextromethorphan and a second drug which suppresses oxidation of dextromethorphan by cytochrome oxidase enzyme P450-2D6, wherein:

a. the second drug is administered at an effective concentration which increases measurable levels of dextromethorphan in the patient'"'"'s blood;

b. the dextromethorphan is administered at a therapeutically effective concentration which, when coadministered with the second drug, allows the patient to eliminate use of at least one anti-depressant drug.

14. The method of claim 13 wherein the second drug is quinidine.

15. The method of claim 13 wherein the second drug is selected from the group consisting of yohimbine, haloperidol, ajmaline, lobeline, and pipamperone, and salts and isomers thereof.

16. The method of claim 13 wherein the oxidase inhibitor drug is selected from the group consisting of labetalol, chlorpromazine, domperidone, quinine, oxprenolol, propranolol, timolol, metaprolol, diphenhydramine, papaverine, and mexiletine, and salts and isomers thereof.

17. A method of weaning a patient from long-term use of an anti-depressant drug, comprising administering to such patient a combination of dextromethorphan and a second drug which suppresses oxidation of dextromethorphan by cytochrome oxidase enzyme P450-2D6, wherein:

a. the second drug is administered at an effective concentration which increases measurable levels of dextromethorphan in the patient'"'"'s blood;

b. the dextromethorphan is administered at a therapeutically effective concentration which, when coadministered with the second drug, assists the patient in eliminating subsequent use of the anti-depressant drug.

18. The method of claim 17 wherein the second drug is quinidine.

19. The method of claim 17 wherein the second drug is selected from the group consisting of yohimbine, haloperidol, ajmaline, lobeline, and pipamperone, and salts and isomers thereof.

20. The method of claim 17 wherein the oxidase inhibitor drug is selected from the group consisting of labetalol, chlorpromazine, domperidone, quinine, oxprenolol, propranolol, timolol, metaprolol, diphenhydramine, papaverine, and mexiletine, and salts and isomers thereof.