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1. WO2020142644 - METHOD FOR TREATING DRUG OR ALCOHOL DEPENDENCY

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[ EN ]

WHAT IS CLAIMED IS:

1. A method of weaning a drug-dependent subject from a drug dependency, comprising the sequential steps of:

a) blocking a peripheral opioid receptor in said subject by administering to said subject in need thereof a therapeutically effective amount of at least one peripherally-selective opioid receptor antagonist to said subject to block said peripheral opioid receptors;

b) stabilizing the peripheral opioid receptor signaling by maintaining administration of the peripherally selective opioid antagonist at doses sufficient to block peripheral but not central opioid receptors, preventing peripheral opioid adverse effects and resulting in reduction of opioid-induced hyperalgesia and dependence, while reducing the dosage of the opioid agonist; c) blocking a CNS opioid receptor in said subject by adjusting the dosage of said opioid receptor antagonist, and in parallel reducing and ceasing opioid agonist treatment, thereby weaning said subject from said opioid addiction; and

d) administering a maintenance dose with said antagonist at doses sufficient to block central opioid receptors during periods of high relapse risk and at intermediate dose sufficient to block peripheral opioid receptors long-term at doses sufficient to block activation of peripheral opioid receptors.

2. The method according to claim 1, wherein the peripheral opioid receptor is the mu opioid receptor.

3. The method according to claim 1, wherein the drug addiction is alcohol addiction or other drug use disorders such as nicotine and stimulants involving upregulated opioid receptor signaling in a state similar to opioid dependence, further including hyperalgesia and chronic neuropathic pain.

4. The method according to claim 1, wherein said peripherally-selective opioid receptor antagonist is a neutral peripherally-selective opioid receptor antagonist.

5. The method according to claim 4, wherein said neutral peripherally-selective opioid receptor antagonist is 6alpha/beta-naltrexol or 6alpha/beta-naloxol, 6alpha/beta-naltrexamine or 6alpha/beta-naloxamine, or an analog, derivative or metabolite thereof.

6. The method according to claim 1, wherein in step a) blocking of said peripheral opioid receptors is measured by restoration of bowel activity in opioid use disorder without central opioid withdrawal symptoms.

7. The method according to claim 1, wherein in step a) the therapeutically effective amount of 6-beta-naltrexol is 0.5 to 40 mg.

8. The method according to claim 1, wherein in step a) 0.5 to 10 mg of 6beta-naltrexol is administered orally, once or twice daily for 2-4 days, followed by 2 to 20 mg once or twice daily for 4-8 days.

9. The method according to claim 1, wherein in step b) 4-50 mg of 6beta-naltrexol is administered orally, once or twice daily for 1-4 weeks or more, and the opioid agonist dose is reduced until first signs of abstinence symptoms emerge;

10. The method according to claim 1, wherein in step c) the dosage of said opioid receptor antagonist is increased in an amount sufficient to block said CNS opioid receptors, wherein 10-80 mg, preferably 20mg, 6beta-naltrexol is administered orally twice daily for 4-8 days, then 20-120 mg, preferably 40 mg, once or twice daily for 1-4 weeks, and further escalation to range 40-300 mg, preferably 100 mg, once or twice daily for maintenance, while the opioid agonist dose is reduced and discontinued at a rate that elicits only mild, tolerable abstinence symptoms

11. The method according to claim 5, wherein said derivative or metabolite is 6beta-naltrexol.

12. The method according to claim 1, further comprising the step of implementing an opioid antagonist maintenance regimen long-term until the risk of recidivism is considered low.

13. The method according to claim 12, wherein a 6-beta-naltrexol maintenance dose is administered long-term at a dosage range of 40-300mg, preferably lOOmg, per day orally.

14. The method according to claim 12, wherein for long-term maintenance with reduced risk of recidivism, the dosage of 6beta-naltresxol is reduced to 4-50 mg per day.

15. A method for the treatment of conditions other than opioid use disorder involving upregulated basal signaling of the mu opioid receptor (MOR) system in an individual in need thereof, comprising administration to the individual of a therapeutically effective amount of 6beta-naltrexol.

16. The method according to claim 15, wherein the condition involving upregulated basal signaling of the mu opioid receptor (MOR) system is alcohol use disorder, opioid dependence, hyperalgesia, chronic neuropathic pain, alcoholism, nicotine addiction, cocaine and stimulant abuse, anorexia, binge eating, gambling and excessive sexual behaviors, further including hyperalgesia and chronic neuropathic pain.

17. The method according to claim 15, wherein the condition involving upregulated basal signaling of the mu opioid receptor (MOR) system is alcohol use disorder combined with opioid disorder.

18. A method of weaning a subject from a drug use disorder or exhibiting addictive compulsory behaviors, associated with upregulated opioid receptor signaling, comprising the sequential steps of:

a) administering a therapeutically effective amount of at least one peripherally-selective opioid receptor antagonist to said subject to modulate the opioid-receptor dependent state, the selected antagonist being highly potent in reversing or preventing the dependent state while causing minimal withdrawal;

(b) selectively blocking peripheral opioid receptor signaling by maintaining administration of the peripherally selective opioid antagonist at doses sufficient to suppress opioid drug effects at peripheral but not central opioid receptors, to reverse the dependent signaling state of the mu opioid receptor;

c) blocking CNS opioid receptors in said subject by adjusting the dosage of said opioid receptor antagonist, to prevent acute endogenous opioid signaling during addictive behavior episodes, optionally in parallel reducing and ceasing opioid agonist treatment, thereby weaning said subject from said opioid addiction; and

d) long-term administering of said opioid receptor antagonist at doses, first at a sufficiently high dose effective in preventing recidivism of drug use or addictive behaviors by rendering opioid drugs ineffective, and later at a low dose to prevent or reverse dependence.