Methods of treating drug or alcohol dependence

Abstract

Provided herein is a method of abstinging subjects suffering from drug addiction or addiction behavior involving opioid signaling by sequentially blocking peripheral and CNS opioid receptors and modulating opioid dependency.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is a divisional application of the Chinese invention patent application with application number 202080018736.5, application date January 3, 2020, and invention name “Method for treating drug or alcohol dependence”. The original application is the Chinese national phase application of the international application with international application number PCT / US2020 / 012107, which claims priority to U.S. provisional application No. 62 / 788167 filed on January 4, 2019. The contents of the U.S. provisional application are expressly incorporated herein by reference in their entirety. Field of the Invention

[0003] The present invention is directed to a drug addiction withdrawal program, such as an opioid withdrawal program and an alcohol withdrawal program, or withdrawal of addictive behaviors involving opioid signaling.

[0004] All publications, patents, patent applications, and other references cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein should not be construed as an admission that the reference is prior art to the present invention. Background Art

[0005] Drug addiction and other addictive behaviors present a serious social problem. The recent epidemic of fatal opioid-induced overdoses highlights the urgency of addressing addiction. Other drug use disorders and addictive behaviors also appear to involve indirectly activated opioid signaling and are thus treated with opioid antagonists such as naltrexone. (See Br J Pharmacol. 2015 Aug;172(16):3964-79. DOI: 10.1111 / bph.13190. Epub 2015 Jun 26. The opioid receptors as targets for drug abuse medication. NobleF 1,2,3 , Lenoir M 1,2,3 , Marie NPredictors of Naltrexone Response in a Randomized Trial: Reward-Related Brain Activation, OPRM1 Genotype, and Smoking Status. Schacht JP 1 , RandallPK 1 , LathamPK 1 , VoroninKE 1 , Book SW 1 , Myrick H 1,2 , Anton RF 1 J Med Toxicol. 2016 Mar;12(l):71-5. DOI: 10.1007 / sl3181-015-0512-x. Naltrexone: Not Just for Opioids Anymore. Sudakin D 1 ).

[0006] It has been demonstrated that opioid-addicted subjects (subjects with opioid use disorders) are difficult to withdraw from, hindered by strong withdrawal abstentions and high recidivism rates. Typical opioid antagonists can cause severe withdrawal induction even when administered in gradually increasing doses. Studies have shown that opioid withdrawal induced at very low doses of clinically used antagonists is caused by inhibition of spontaneous opioid receptor activity (inverse agonism), where the antagonists act in a non-competitive manner (as inverse agonists) (1, 6, 7, 8). At higher doses of opioid agonists designed to competitively block receptors, the antagonists cause additional withdrawal symptoms. After withdrawal, these typical antagonists (such as naloxone, naltrexone, and nalmefene) can be maintained with a stable opioid antagonist dosing regimen to prevent further opioid abuse. However, these typical opioid antagonists (those that act as inverse agonists) induce aversion even in a subset of non-opioid addicted people; for example, the use of naltrexone to improve alcohol addiction is limited in part by aversion effects in a subset of subjects, resulting in noncompliance. Equally important, these typical antagonists are able to enter the brain immediately and cause opioid withdrawal by acting on both central and peripheral opioid receptors, producing severe overall antagonist-induced opioid withdrawal symptoms. It was determined in mice that naltrexone is equally effective in blocking both peripheral and central opioid analgesic effects even when administered orally because it readily crosses the blood-brain barrier into the central nervous system (7), and naltrexone has extraordinary potency in blocking central opioid effects in mice, guinea pigs, rhesus monkeys, and humans (2, 6, 7, 9, 10).

[0007] Previous studies have pointed to neutral opioid antagonists, which strongly inhibit the activation of opioid receptors by agonists (opioid analgesics) without inhibiting spontaneous receptor signaling, which may be a hallmark of the dependent state and is elevated in the state. Previous results showed that constitutively active MOR receptors can maintain the opioid dependent state by continuously transmitting MOR receptor signals (Corder et al. 2013), and thus contribute to the problem of persistent relapse. As a result, neutral opioid antagonists cause slightly less severe withdrawal, and only at higher doses designed to compete with opioid antagonists at the receptor. For example, in opioid-dependent mice, even high doses of neutral antagonists do not induce any withdrawal 24 hours after the last morphine administration (when all morphine is eliminated), whereas naloxone and naltrexone still induce robust withdrawal by inhibiting spontaneous receptor activity (Raehal KM, Lowery JJ, Bhamidipati CM, Paolino RM, Blair JR, Wang D, Sadée W, Bilsky EJ. (2005) In vivo characterization of 6beta-naltrexol, an opioid ligand with less inverse agonist activity compared with naltrexone and naloxone in opioid-dependent mice. J Pharmacol Exp Therapeutics. Ther. 313, 1150-1162). In addition, the neutral opioid antagonist 6-β-naltrexol (6BN) can actually prevent naloxone (inverse agonist)-induced withdrawal jumping in acute morphine-dependent mice, a key benchmark for neutral opioid antagonists. In addition, studies have shown that naloxone and naltrexone-derived antagonists with reduced C-6-OH or C-6-NH2 function not only act as neutral opioid antagonists, but also appear to be exported from the brain by export transporters in the blood-brain barrier (BBB), thereby acquiring peripheral selectivity.For example, 6BN is 10% as effective in blocking opioid antinociception (centrally mediated) in mice as in blocking opioid effects on the gastrointestinal tract (Yancey Wrona et al. 2009 Yancey-Wrona JE, Raymond, TJ, Mercer, HK, Sadee, W and Bilsky, EJ (2009) "6bnaltrexol preferentially antagonizes sopioid effects on gastrointestinal transit compared to antinociception in mice". Life Sci 85, 413-420.), and in humans, is at most 10% as effective in blocking opioid antinociception (primarily relief) as in blocking opioid effects in the gastrointestinal tract (11). Furthermore, in rhesus monkeys (10) and guinea pigs, 6BN was approximately 1% as effective as naltrexone in blocking opioid antinociception (Porter et al. 2002 Porter SJ, Somogyi AA, White JM (2002) In vivo and in vitro potency studies of 6beta-naltrexol, the major human metabolite of naltrexone. Addict. Biol. 7:219-225).

[0008] These results lead to the conclusion that 6BN, as the major metabolite of naltrexone, does not substantially contribute to its major effects on opioid receptors; however, the molecular properties of this type of neutral opioid antagonist have not been taken into account in this conclusion. For example, 6BN has been shown to be highly effective in preventing the development of opioid dependence in young mice treated with morphine at dose levels that are not expected to block conventional morphine effects, such as antinociception (Oberdick et al. (2016)). In this study, morphine was co-injected subcutaneously with increasing doses of 6β-naltrexol for several days, followed by a naloxone-induced withdrawal jump to test dependence. 0.02 mg / kg of 6β-naltrexol significantly reduced the naloxone withdrawal jump when co-injected with 20 mg / kg morphine. Internal unpublished results show that similarly, 6β-naltrexol at doses as low as 0.01 mg / kg administered with morphine or methadone reduced or prevented subsequent opioid withdrawal in mice and guinea pigs, supporting the idea that low-dose 6β-naltrexol affects dependence at opioid agonist doses below those that block CNS-mediated analgesia. These results suggest that treatment of opioid subjects using opioid medications with low 6BN doses can reverse opioid dependence without causing acute CNS-mediated withdrawal and without blocking opioid analgesia. In addition, Corder et al. (2017) have demonstrated that prevention of opioid-induced hyperalgesia by peripherally selective opioid antagonists is a key element in opioid tolerance that requires increasing doses to maintain analgesia. Taken together, these results indicate that the apparent peripheral selectivity of 6BN results from two mechanisms, the first being a relatively limited ability to enter the brain, and the second being binding with high affinity to different μ opioid receptor conformations that occur at different rates in the CNS and periphery, and having distinct roles in opioid dependence. 6BN and its analogs can therefore be viewed as peripherally selective neutral opioid antagonists that strongly interact with different forms of μ opioid receptors involved in dependence and hyperalgesia, involved in basal μ receptor signaling, thereby modulating the opioid dependence state - it is a dependence modulator. This finding is relevant to the treatment of any addiction condition involving enhanced opioid receptor signaling with 6BN and its analogs acting at high titers.(See Corder G, Doolen S, Donahue RR, Winter M, Jutras B, He Y, Hu X, Wieskopf JS, Mogil JS, Storm DR, Wang ZJ, McCarson KE and Taylor BK. Constitutive μ-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science 2013; 341, 1394-1399; Corder G, Tawfik VL, Wang D, Sypek EI, Low SA, Dickinson JR, Sotoudeh C, Clark JD, Barres BA, Bohlen CJ, Scherrer (2017). Loss of μ-opioid receptor signaling in nociceptors but not microglia abolishes morphine tolerance without disrupting analgesia. ofμopioid receptor signaling in nociceptors, but not microglia, abrogates morphinetolerance without disrupting analgesia). Nat Med. 23:164-173; J.Oberdick, YL, M A Helps, M S Yudovich, K. Schilling, and W. Sadee. Preferential delivery of an opioid antagonist to the fetal brain in pregnant mice. J. Pharmacol. Exp. Ther. 358:22-30 (2016). PMID: 27189967).

[0009] Therefore, there is a need in the art for an effective strategy to wean opioid addicts from opioid abuse without the limiting adverse effects seen in the art, and to inhibit the effects of up-regulating μ opioid receptor signaling on addictive pathologies involving opioid components, such as alcohol abuse. It should be understood that the proposed treatment does not exclude currently accepted interventions designed to aid in opioid withdrawal or abstinence from other addictive drugs and behaviors, but rather may serve as an additional tool to support such interventions. Summary of the invention

[0010] Summary of the Invention

[0011] The present invention relates to a drug addiction withdrawal program. For withdrawal from opioid use disorders, the program first blocks peripheral opioid receptors with peripheral selective neutral antagonists, starts at a low dose to avoid strong withdrawal in dependent subjects, and then increases the dose level in the stabilization phase, which is largely designed to inhibit peripheral opioid receptors while avoiding central opioid receptors. As recent results show, this second dose level can prevent or regulate opioid hyperalgesia and dependence, in addition to blocking peripheral adverse opioid effects, it can also reduce the dose of opioid agonists designed to reduce opioid drug burden without inducing withdrawal in this second phase. Further, the third step involves subsequent complete withdrawal by increasing the dose of antagonists that penetrate sufficiently into the brain to inhibit the acute effects on central opioid receptors and reduce and eliminate opioid agonists. The optional fourth step involves an opioid antagonist maintenance dose. For the treatment of other addictive conditions that involve indirect activation of opioid signaling pathways in the central nervous system but not in the periphery, including other addictive drugs, such as alcohol use disorder; and stimulant and nicotine dependence; or addictive behaviors, such as eating disorders and gambling, the first treatment step of using very low doses of peripherally selective neutral antagonists can be omitted because peripheral opioid receptors are not sensitized by high circulating levels of opioid drugs, so that doses of neutral antagonists acting in the periphery are well tolerated.

[0012] Therefore, a method for weaning an opioid-dependent subject from opioid addiction is provided below, comprising the following sequential steps:

[0013] a) blocking peripheral opioid receptors of the subject by administering to the subject a therapeutically effective amount of at least one peripherally selective neutral opioid receptor antagonist to block the peripheral opioid receptors;

[0014] b) stabilizing signaling of peripheral opioid receptors produced in a dependent state by maintaining administration of a peripherally selective neutral opioid antagonist at a dose sufficient to block peripheral but not central opioid receptors, thereby reducing hyperalgesia and opioid dependence while simultaneously reducing the dose of the opioid agonist; and

[0015] c) blocking activation of CNS opioid receptors in said subject by opioid drugs or endogenous opioids by adjusting the dose of said opioid receptor antagonist and concomitantly reducing and stopping opioid agonist therapy, thereby weaning said subject from said opioid addiction.

[0016] A further fourth step may include implementing a maintenance strategy designed to prevent relapse through continued administration of the antagonist, with preferred embodiments comprising a dose of a neutral opioid antagonist that reaches the brain, or for long-term preventive treatment, an intermediate dose of said antagonist that is designed to block activation of only peripheral opioid receptors while reducing tolerance and dependence.

[0017] Further provided is a method of reducing reinforcement processing in conditions involving opioid signaling in other drug addictions, such as alcoholism, and addictive behaviors, such as eating disorders, that represent an opioid-dependent state driven by spontaneous / basal activity of μ opioid receptors by reversing the opioid-dependent state with a peripherally selective neutral antagonist at low doses and blocking acute opioid signaling in the CNS at higher doses, such as during binge drinking, comprising the following sequential steps:

[0018] a) reversing the enhanced basal μ opioid receptor signaling produced by the release of endogenous opioids during addictive drugs and behaviors by administering a peripherally selective neutral opioid antagonist at a dose sufficient to block acute activation of peripheral but not central opioid receptors and sufficient to reverse the state of dependence tolerance driven by basally active μ opioid receptors; and

[0019] b) blocking the subject's CNS opioid receptors by modulating a maintenance dose of the opioid receptor antagonist, thereby blocking the acute reinforcing effects of opioid signaling in the CNS during exposure to addictive drugs other than opioids, such as alcohol, and addictive behaviors, such as eating disorders.

[0020] A further fourth step may include implementing a long-term maintenance strategy designed to prevent relapse through continued administration of an antagonist, preferably comprising a peripherally selective neutral opioid antagonist, at a dose that reaches the brain during periods of high recidivism risk, or at a lower dose over a longer period of time to reduce the risk of continued relapse.

[0021] It should be understood that the description of the present invention has been simplified to illustrate the elements relevant to a clear understanding of the present invention, while many other elements found in typical pharmaceutical compositions and stabilization methods have been removed for clarity. One of ordinary skill in the art will recognize that other elements and / or steps are required and / or necessary when implementing the present invention. However, because the elements and steps are well known in the art, and because they cannot promote a better understanding of the present invention, the discussion of the elements and steps is not provided herein. The disclosure herein is directed to all the changes and modifications of the elements and methods known to those skilled in the art. In addition, the embodiments identified and described herein are for exemplary purposes only, and are not intended to be exclusive or limiting in their description of the present invention.

[0022] The present invention is directed to a withdrawal regimen for opioid addiction (opioid use disorder, OUD), and other drug addictions and addictive behaviors involving opioid signaling. The regimen uses a peripherally selective opioid antagonist, such as 6β-naltrexol (1, 2), to first block peripheral opioid agonist effects and reverse the dependence state of the opioid receptor system, and then block acute opioid effects in the central nervous system ("CNS") at increasing doses until the reinforcing process of addiction subsides, reducing the risk of recidivism. In the specific case of opioid drug use disorder, severe withdrawal symptoms are one of the major obstacles to successful withdrawal, and long-term persistent drug-seeking behavior is the main cause of recidivism. Withdrawal can be measured by a variety of symptoms, such as pulse rate, GI discomfort, sweating, tremor, yawning, and pupil size. The Clinical Opioid Withdrawal Scale (COWS; containing 11 symptoms) is commonly used to measure withdrawal (3). Inhibition of peripheral opioid receptors reverses opioid effects in a variety of organs, including the gastrointestinal tract, kidneys, immune cells, and osteoblasts. Typical peripheral withdrawal symptoms include gastrointestinal cramping, accelerated bowel movements, and diarrhea—the 6-β-naltrexol dose is titrated until the patient no longer experiences peripheral withdrawal symptoms. Continued 6β-naltrexol administration will cause a gradual reversal of the dependence state in the periphery, while it also appears to reverse the dependence state of central opioid μ opioid receptor signaling at doses that do not prevent opioid drug-induced analgesia. Withdrawal symptoms mediated by opioid antagonists (naloxone and naltrexone, which readily enter the brain and act as inverse agonists, i.e., they also inhibit spontaneous receptor signaling) are severe even at very low doses and include central and peripheral effects that appear to potentiate each other, including seizures and dramatic gastrointestinal events. Thus, for 6β-naltrexol, as a neutral opioid antagonist that causes less intrinsic withdrawal than the inverse agonists naloxone and naltrexone, the expected withdrawal and abstinence symptoms are manageable at first for peripheral effects, and then at higher doses that penetrate the blood-brain barrier and thus also block acute central opioid effects, as monitored with patient-registered measures of discomfort, and more specifically the COWS scale. Blocking peripheral opioid receptors may first have the additional advantage of interrupting the vicious cycle of interactions between opioid receptors on afferent nociceptors (periphery, in the ascending pathway) and CNS receptors that is reported to contribute to hyperalgesia - one reason for increasing the opioid dose required to achieve the desired effect (an aspect of tolerance) (4,5). As a neutral antagonist, 6β-naltrexol has an additional advantage over inverse agonists such as naltrexone: it allows basal opioid receptor signaling, which has been shown to be physiologically relevant and drive opioid dependence when upregulated (13) and is important in recovery from hypersensitivity / hyperalgesia induced by latent sensitization leading to persistent inflammatory pain in rats (14).On the other hand, the reversal of opioid dependence caused by low-dose 6β-naltrexol suggests that the increased abundance of the μ opioid receptor form responsible for elevated basal signaling in the dependent state is depleted by 6β-naltrexol, which acts as a dependence modulator, in favor of a receptor form that does not have basal signaling activity.

[0023] Because other addictive drugs and addictive behaviors besides opioids also indirectly involve opioid signaling, it can be speculated that the release of endogenous opioids can produce a similar opioid-dependent state of μ opioid receptors that can subsequently drive and promote the addictive behavior. In these cases, peripherally selective neutral opioid antagonists such as 6β-naltrexol can be administered as follows: at a low dose sufficient to block peripheral opioid receptors without causing withdrawal, but sufficient to also reverse the opioid-dependent receptor state in the CNS, followed by a higher dose that also blocks the acute endogenous opioid effects in the CNS, thereby further reducing the rewarding effects of the behavior during the acute episode. Long-term administration of the antagonist can be at this later high dose, or at an initial low dose, to prevent persistent symptoms that promote addictive behavior. The advantage over naltrexone, a drug being tested in the treatment of many addiction conditions, is sustained basal μ-opioid receptor signaling at physiological levels while preventing increased basal signaling known to play a role in the effects of dependence, hyperalgesia, and neuropathic pain.

[0024] In one embodiment of the present invention for opioid use disorder, the withdrawal protocol using 6β-naltrexol involves a 4-step process: Step 1: Gradual withdrawal of the peripheral opioid system; Step 2: Stabilization phase using intermediate doses of 6-β-naltrexol and reduction of the dose of opioid analgesics as tolerated by the patient; Step 3: Beginning with complete withdrawal by increasing the dose of 6-β-naltrexol that can reach the brain while reducing and eliminating the dose of opioid analgesics; Step 4: Maintaining high doses of 6β-naltrexol to prevent relapse without administering opioid analgesics. In this last step, alternative established maintenance means are available, such as the currently used sustained-release naltrexone; however, high-dose 6-β-naltrexol maintenance has the potential to be more effective in balancing the non-dependent opioid system by allowing basal (unliganded) opioid receptor signaling to be blocked by inverse agonists. (13, 14). If pain treatment continues to be required after completion of step 2, the patient may be administered a combination formulation of an opioid analgesic with 6β-naltrexol at a dose that does not block CNS-mediated opioid analgesia but prevents dependence and opioid-induced hyperalgesia and may reduce addiction liability. Thus, the present invention provides a method of utilizing the unique properties of opioid physiology and peripherally selective neutral opioid antagonists such as 6β-naltrexol or analogs and derivatives with similar properties to ease withdrawal and promote a gradual weaning process of abstinence.

[0025] In other addictive conditions such as alcoholism, upregulation of μ opioid receptor signaling creates a general example of treatment with 6β-naltrexol to reduce opioid-dependent receptor states and, at higher doses, prevent the acute increase in opioid signaling triggered by endogenous opioid peptide release. Due to the indirect activation of endogenous opioid signaling in the brain, the peripheral opioid receptor system is less affected than in opioid drug-induced dependence, and the first step of titrating 6β-naltrexol at very low doses is no longer necessary. Therefore, intermediate doses of 6β-naltrexol (step 2 in the opioid withdrawal protocol) would not be expected to cause any withdrawal or rejection that limits the effectiveness of naltrexone, as experienced by the vast majority of subjects with alcohol use disorder.

[0026] Studies have identified the naltrexone metabolite 6β-naltrexol as a neutral opioid antagonist (the parent naltrexone is an inverse agonist in the dependent state) and, in addition, is peripherally selective (in contrast to naltrexone, which readily enters the brain) (1), thus offering the opportunity to prevent peripheral opioid side effects such as opioid-induced intestinal dysfunction / constipation (OIC). Unexpectedly, such peripherally selective dose levels of 6β-naltrexol also reduce hyperalgesia and general dependence, potentially lowering opioid doses and reducing withdrawal symptoms. Because 6-β-naltrexol enters the brain sufficiently at higher doses to block acute opioid effects, and because it has a longer half-life than typical opioid analgesics (9), naltrexol may accumulate in abuse conditions and thereby reduce addiction liability when formulated in an agonist / antagonist combination dose form. These discoveries have resulted in the following patents / applications, all of which are expressly incorporated by reference: US 8,748,448, US 14 / 278576, European Patent EP2214672, US 12 / 288,347\European Patent No. 2214672, US 10 / 544,083, US 8,883,187 and US 9,061,024.

[0027] However, research in this area has not addressed strategies for how individuals in opioid pain therapy or opioid addiction can be withdrawn from opioid use, abuse, or from opioid maintenance programs, typically with methadone or buprenorphine. The present inventors have discovered that any withdrawal regimen needs to take into account peripheral and central opioid signaling in the dependent state, and their interactions, which produce severe withdrawal symptoms upon cessation of opioid use or administration of conventional opioid antagonists (inverse agonists that act centrally and peripherally with equal potency). Peripherally selective neutral antagonists essentially separate the acute opioid effects of central and peripheral opioid receptors and disrupt the interaction between them, while causing acceptable peripheral withdrawal symptoms and reestablishing normal physiological function (9, 11). Recent evidence indicates that blockade of peripheral opioid receptors prevents opioid-induced hyperalgesia (4, 5), which is at least partially responsible for opioid tolerance and results in the need for increasing opioid doses and increased dependence; however, the effects on drug-seeking behavior and intensity of opioid withdrawal in subjects who have previously had peripheral opioid receptor systems blocked remain uncertain. Studies in methadone-maintained subjects have demonstrated that a single intravenous dose of 6-β-naltrexol of 0.5-1 mg reverses opioid-induced constipation with tolerable peripheral side effects and without central withdrawal symptoms (11). Finally, and relevant to the withdrawal protocol proposed here, doses of 6β-naltrexol that selectively block acute opioid drug effects at peripheral opioid receptors without preventing opioid analgesia appear to be sufficient to reverse or prevent opioid dependence, presumably by depleting the enhanced basal active μ opioid receptor form characteristic of the dependent state at high titers. This result suggests that opioid withdrawal is further alleviated.

[0028] Opioid receptors are present in multiple brain regions and are generally protected by a strong blood-brain barrier that prevents some opioid compounds from entering the brain (central nervous system) (12) or, as observed with 6β-naltrexol, reduces entry into the CNS. These opioid receptors are referred to herein as CNS opioid receptors. Peripheral organs, such as the gastrointestinal tract, kidneys, immune cells, vas deferens, etc., also carry opioid receptors with diverse physiological functions, referred to herein as peripheral opioid receptors. Of the three major receptor types, μ, δ, and κ, the μ opioid receptor is most associated with analgesia and addiction, but other subtypes also contribute. When referring to opioid antagonists, this means antagonism at the μ opioid receptor, but the antagonists of the present invention typically also inhibit the δ and κ receptors to varying degrees due to the similarities between opioid receptor subtypes. The present invention does not require selectivity for only the μ receptor.

[0029] Peripheral opioid receptors, including μ, δ, and κ opioid receptors, are present in many tissues including the gastrointestinal tract, slowing intestinal motility and regulating fluid and electrolyte balance. These receptors are defined as those located outside the blood barrier (BBB), which consists of a tight endothelial cell layer surrounding blood vessels in the brain, and the blood-brain barrier has potent transporters that expel a variety of substances including opioids from the brain - but the extent varies significantly with its chemical structure. Although structurally similar to naltrexone, unlike naltrexone, 6β-naltrexol is largely expelled from the brain at low doses that saturate peripheral opioid receptors, which is attributed to the reduction of the C-6 position and the tilt of the ring structure, causing interactions with the efflux pumps in the blood-brain barrier - features shared between analogs with the same C-6 reduction. Nevertheless, 6β-naltrexol appears to act with high potency in reversing opioid dependence - centrally mediated - at low doses that fail to block acute opioid effects (such as centrally mediated analgesia), indicating the presence of a receptor form associated with dependence. Central opioid receptors exist in the brain with the BBB, where μ opioid receptors (OPRM or MOR) are the main targets of opioid analgesics and the main judge of opioid addiction. After long-term opioid use, peripheral and central opioid receptors, their cell signaling pathways and neuronal networks change to produce dependence and tolerance states. Only recently has the interaction between peripheral and central signaling pathways been studied, but it seems to play a key role in maintaining opioid dependence / tolerance states and hyperalgesia states (4, 5). The withdrawal protocol definition in the present invention is designed to enable the reversal of dependence / tolerance states under tolerable withdrawal symptoms, and thereafter maintain abstinence from opioid abuse. Similarly, reversing opioid dependence states indirectly caused by other drug use disorders and addictive behaviors other than OUD with 6β-naltrexol and its analogs has the potential to reduce the addictive behavior by removing the driving force that promotes it.

[0030] Both peripheral and central opioid receptor systems are highly activated in states of opioid dependence, and the two interact by influencing opioid tolerance, dependence, and possibly craving, all key elements of opioid addiction. Novel strategies to inhibit peripheral opioid systems must first reflect their activation state, so that even neutral opioid antagonists must be slowly titrated in OUD (replacing a small fraction of the opioid agonist already elicits a physiological response). The same is true for subsequent withdrawal of central opioid receptor systems under the 6-β-naltrexol / opioid anesthetic-analgesic regimen, except that in the absence of agonist-dependent peripheral opioid receptor signaling, and thus reduced opioid-induced hyperalgesia, dose reduction of the 6-β-naltrexol / opioid anesthetic-analgesic regimen may be feasible in a subset of subjects (due to reduced tolerance and dependence), thereby reducing overall opioid exposure. Complete withdrawal can then be achieved by increasing the 6-β-naltrexol dose and reducing the 6-β-naltrexol / opioid narcotic-analgesic dose in stages, followed by continued 6β-naltrexol administration.

[0031] This 4-step, orchestrated withdrawal approach is novel because it is the first to intentionally disrupt the interaction between peripheral and central opioid signaling, targeting hyperalgesia and dependence - an area that has only recently become a focus in biomedical research. If long-term 6β-naltrexol / opioid analgesia is medically necessary, blocking the peripheral opioid receptor system with 6-β-naltrexol has many additional benefits, such as inhibiting opioid effects on the gastrointestinal tract (GI tract), opioid-induced bone loss, immune disruption, renal effects, etc. After the initial titration of 6β-naltrexol, the preferred 6β-naltrexol / opioid agonist regimen is an oral combination formulation, as described in the combination product patent. In other drug use disorder and addictive behavior treatments, the peripheral opioid receptor system is unlikely to be activated, making the first step of treating OUD with very low doses of 6β-naltrexol to avoid peripheral withdrawal symptoms no longer necessary.

[0032] In one embodiment, the present invention can be used to treat alcohol addiction. In addition to opioid use disorder (OUD), the endogenous opioid system is involved in various types of addiction symptoms and behaviors. Specifically, alcohol use disorder (AUD) is associated with similar abnormal opioid signaling observed in OUD, and opioid and alcohol use disorder (OAUD) overlap in parallel. As a result, opioid antagonists such as naltrexone and nalmefene have been tested and shown to not only effectively prevent narcotic abuse, but also effectively reduce AUD including excessive drinking, while the literature on the efficacy of nalmefene is less, and a large part of the treatment is interrupted. In order to prevent recidivism in OUD and improve AUD, a sustained-release formulation of naltrexone (XRNTX) has been developed, which can maintain naltrexone blood levels>1ng / ml within several months, and successfully prevent OUD and reduce AUD. Naltrexone is metabolized to 6β-naltrexol, which reaches blood levels 5-10 times higher than naltrexone due to its longer half-life. Whether 6β-naltrexol contributes to or mediates the effects of naltrexone has not been definitively determined, as 6β-naltrexol is considered less potent than naltrexone in antagonizing the acute effects of opioid analgesics (less than 1 / 100 in guinea pigs and non-human primates) and has a slightly lower affinity for the μ opioid receptor (MOR) than naltrexone in vitro. This view is reinforced by studies comparing the effects of 6β-naltrexol and naltrexone on alcohol consumption (rats do not metabolize naltrexone to 6β-naltrexol) showing that 6β-naltrexol is 1 / 25 times more potent than naltrexone. However, in that study, the antagonist was given 15 minutes before the alcohol consumption test in rats habituated to high alcohol consumption, Stromberg MF, Rukstalis MR, Mackler SA, Volpicelli JR, O'Brien CP (2002). A comparison of the effects of 6-beta naltrexol and naltrexone on the consumption of ethanol or sucrose using a limited-access procedure in rats. Pharmacol Biochem Behav 72:483-490., to block the acute reinforcing effects of drinking (Strromberg et al.).

[0033] It is demonstrated in the present invention that 6β-naltrexol has extremely high potency in preventing the opioid dependence state when co-administered with opioids several days prior to assessing dependence. This high potency can be attributed to the ability of 6β-naltrexol to maintain or re-establish a MOR conformational state / equilibrium that is closely associated with the non-dependent state - hence the term 6β-naltrexol as an addiction or dependence modulator. 6β-naltrexol appears to exert its effects in a non-competitive manner at low doses to modulate the addiction state - proposed for the first time here. Although 6β-naltrexol is effective at low doses, it can also be administered at increasing doses that inhibit the acute effects of opioids both peripherally and centrally (drugs and endogenous opioids), but the low-dose paradigm is designed to prevent or reverse the addiction state in which basal activity of the μ opioid receptor MOR drives long-term dependence and its sequelae.

[0034] When treating alcoholism with XRNTX, some evidence supports the view that its metabolite 6β-naltrexol contributes to the clinical outcome (reduced alcohol consumption) because the extent to which test subjects 'like' alcohol correlates with 6β-naltrexol levels. However, naltrexone itself is extremely potent and acts as an inverse agonist, preferentially binding to the basal active MORs characteristic of the dependence state. As alcohol consumption indirectly activates the endogenous opioid system, it is hypothesized that the MORs will exist in this basal active dependence state in AUD, which then itself drives further alcohol use. Therefore, 6β-naltrexol may be effective at low doses, which conventional antagonists would not be considered active because they would fail to antagonize acute central opioid agonist effects. If 6β-naltrexol actually contributes to the efficacy of naltrexone in reducing binge drinking, this could prove superior to nalmefene, which cannot be metabolized to a neutral antagonist with a structure similar to 6β-naltrexol (nalmefene has a non-metabolically reduced C-6C=C bond), but the distinction between naltrexone and nalmefene remains unclear (Yelel-Okouma et al. 2017. Fundam Clin Pharmacol. 2017 Oct;31(5):574-579. Digital Object Identifier: 10.1111 / fcp.12286. Epub 2017 May 9. Opioid substitution therapy or hidden opioids are a minefield for nalmefene: an atypical case series of 11 patients in Lorraine. Yéléhé-Okouma M 1 , MartiniH 2 , Lemarié J 3 , LabrocaP 4 , PetitpainN 1 , GibajaV 5 , Paille F 2 , Gillet P 1 )).

[0035] Taken together, the results suggest that low-dose 6β-naltrexol will be effective in modulating the dependence state of the opioid receptor system, thereby reducing compulsive alcohol consumption in AUD, and in other pathologies with up-regulation of basal MOR signaling.

[0036] In a specific embodiment of the invention, 6β-naltrexol is administered at a dose high enough to antagonize acute opioid effects in the CNS caused by opioid drugs or by endogenous opioid release. This approach is used to prevent recidivism during the high-risk period after cessation of addictive drug use; however, this approach can cause anhedonia and low compliance in the long term. For example, 6β-naltrexol blocks acute intake of alcohol and sucrose, but only at high doses (17). It is proposed herein that prevention of opioid dependence states with low doses of 6β-naltrexol is preferred for long-term intervention.

[0037] While 6-β-naltrexol is one compound that can be used in withdrawal protocols, other naltrexol and naloxone derivatives, analogs and / or metabolites, such as those specified in US8,748,448, US14 / 278576, European Patent No. EP2214672, and US12 / 288,347 (all of which are expressly incorporated by reference, including routes of administration and sustained release formulations) also have neutral antagonist properties and the same structure as 6β-naltrexol that is recognized by the export pumps in the blood-brain barrier, indicating that they may also be peripherally selective. The present invention embodies the use of any of these compounds or their derivatives or metabolites. For example, 6α-naltrexol, 6α- and β-naloxol and their derivatives (including pegylated derivatives) and 6α / β-naltrexamine and 6α / β-naloxamine, and especially 6β-naltrexamide, all show neutral antagonism. 6β-naltrexamide has also been shown to have strong peripheral selective activity (internal results). In combination, any opioid analgesic is a viable component embodied in the above combination patents. One example is the combination product of oxycodone or hydrocodone with 6β-naltrexol.

[0038] 6β-naltrexol was also tested in 4 methadone substitution patients who were sensitive to 0.05 mg intravenous naloxone. These subjects tolerated 6β-naltrexol at intravenous doses up to 1 mg, causing bowel movements and some additional peripheral but no central withdrawal symptoms (one subject withdrew from the study after the 0.5 mg dose) [11, internal data obtained from AIKO Biotechnology], these results show the good pharmacological properties of 6β-naltrexol even after the first dose of 6BN in highly dependent methadone patients, while typical opioid antagonists (naloxone and naltrexone) will cause severe withdrawal at equivalent doses.

[0039] Therefore, in one embodiment of the present invention, a method for a drug-dependent subject to quit drug dependence is provided, which comprises the following steps in sequence:

[0040] a) blocking peripheral opioid receptors of the subject by administering to the subject in need thereof a therapeutically effective amount of at least one peripherally selective opioid receptor antagonist to block the peripheral opioid receptors;

[0041] b) stabilizing signaling of peripheral opioid receptors by maintaining administration of a peripherally selective opioid antagonist at a dose sufficient to block peripheral but not central opioid receptors, preventing peripheral opioid adverse effects and resulting in a reduction in opioid-induced hyperalgesia and dependence while simultaneously reducing the dose of the opioid agonist;

[0042] c) blocking the subject's CNS opioid receptors by adjusting the dose of the opioid receptor antagonist and concomitantly reducing and discontinuing opioid agonist therapy, thereby weaning the subject from opioid addiction; and

[0043] d) administering a maintenance dose of said antagonist at a dose sufficient to block peripheral opioid receptor activation: a dose sufficient to block central opioid receptors during the high relapse risk phase and an intermediate dose sufficient to block peripheral opioid receptors long-term.

[0044] In one embodiment, the peripheral opioid receptor is a μ opioid receptor.

[0045] In one embodiment, the drug addiction is alcohol addiction or other drug use disorders involving upregulation of opioid receptor signaling similar to the situation of opioid dependence, such as nicotine and stimulants, further comprising hyperalgesia and chronic neuropathic pain.

[0046] In one embodiment, the peripherally selective opioid receptor antagonist is a neutral peripherally selective opioid receptor antagonist.

[0047] In one embodiment, the neutral peripheral selective opioid receptor antagonist is 6α / β-naltrexol or 6α / β-naloxol, 6α / β-naltrexone or 6α / β-naloxone, or an analog, derivative or metabolite thereof.

[0048] In one embodiment, in step a), blockade of the peripheral opioid receptors is measured by restoration of gut motility in opioid use disorder in the absence of central opioid withdrawal symptoms.

[0049] In one embodiment, in step 1), the therapeutically effective amount of 6-β-naltrexol is 0.5 to 40 mg.

[0050] In one embodiment, in step 1), 0.5 to 10 mg of 6β-naltrexol is orally administered once or twice daily for 2 to 4 days, followed by 2 to 20 mg once or twice daily for 4 to 8 days.

[0051] In one embodiment, in step 2), 4 to 50 mg of 6β-naltrexol is orally administered once or twice daily for 1 to 4 weeks or more, and the dose of the opioid agonist is reduced until the first sign of withdrawal symptoms occurs.

[0052] In one embodiment, in step 3), the dose of the opioid receptor antagonist is increased in an amount sufficient to block the CNS opioid receptors, wherein 10 to 80 mg, preferably 20 mg 6β-naltrexol is orally administered twice daily for 4 to 8 days, followed by 20 to 120 mg, preferably 40 mg, once or twice daily for 1 to 4 weeks, and further increased to a range of 40 to 300 mg, preferably 100 mg, once or twice daily for maintenance, while the dose of the opioid agonist is reduced and discontinued at a rate that induces only mild tolerable withdrawal symptoms.

[0053] In one embodiment, the derivative or metabolite is 6β-naltrexol.

[0054] In one embodiment, the method further comprises administering an opioid antagonist maintenance regimen long-term until the risk of recidivism is deemed low.

[0055] In one embodiment, in step 4), a maintenance dose of 6-β-naltrexol is chronically administered at a dose ranging from 40 to 300 mg, preferably 100 mg / day, orally.

[0056] In one embodiment, for long-term maintenance of reduced risk of recidivism, the dose of 6β-naltrexol is reduced to 4 to 50 mg / day.

[0057] In one embodiment, a method of treating a condition other than opioid use disorder in an individual in need thereof, the condition involving upregulation of basal signaling of the μ opioid receptor (MOR) system, is provided, the method comprising administering to the individual a therapeutically effective amount of 6β-naltrexol.

[0058] In one embodiment, the condition involving upregulation of basal signaling of the μ opioid receptor (MOR) system is alcohol use disorder, opioid dependence, hyperalgesia, chronic neuropathic pain, alcoholism, nicotine addiction, cocaine and stimulant abuse, anorexia, bulimia, gambling, and excessive sexual behavior, further comprising hyperalgesia and chronic neuropathic pain.

[0059] In one embodiment, the condition involving upregulation of basal signaling of the mu opioid receptor (MOR) system is a combination of alcohol use disorder and opioid disorder.

[0060] In another embodiment of the present invention, a method for abstinence of a subject from drug use disorder or addictive compulsive behavior associated with up-regulation of opioid receptor signaling is provided, comprising the following sequential steps:

[0061] a) administering to said subject a therapeutically effective amount of at least one peripherally selective opioid receptor antagonist (step 2) to modulate an opioid receptor dependence state, the antagonist selected being highly effective in reversing or preventing said dependence state while causing minimal withdrawal;

[0062] (b) selectively blocking signaling at peripheral opioid receptors by maintaining administration of said peripherally selective opioid antagonist at a dose sufficient to inhibit the effects of the opioid drug at peripheral but not central opioid receptors to reverse the dependent signaling state of the μ opioid receptor;

[0063] c) blocking the subject's CNS opioid receptors (step 3) by adjusting the dose of the opioid receptor antagonist to prevent acute endogenous opioid signaling during the episode of addictive behavior (optionally while simultaneously reducing and stopping opioid agonist treatment, thereby weaning the subject from the opioid addiction); and

[0064] d) chronically administering the opioid receptor antagonist (step 4) at doses high enough to effectively prevent relapse to drug use or addictive behavior by rendering the opioid drug ineffective, and subsequently at doses low enough to prevent or reverse dependence (step 2).

[0065] The present invention will now be further described in the following examples, which are intended to be illustrative only and not to limit the scope of the present invention. DETAILED DESCRIPTION

[0066] The inventors have exploited the deliberate separation of peripheral and central opioid receptor systems to improve immediate withdrawal symptoms and facilitate long-term abstinence. Thus, the present invention provides a multi-step opioid addiction withdrawal regimen that uses a peripherally selective neutral opioid antagonist, such as 6β-naltrexol, in the first step to block the peripheral opioid receptor system. In the second step, stabilization at an intermediate 6β-naltrexol dose allows for a gradual reversal of the dependence state of the peripheral opioid system—which can last for several weeks—which also allows the opioid agonist dose to be reduced as hyperalgesia decays. In addition, the intermediate dose also appears to reverse the dependence opioid receptor state in the CNS at doses that are insufficient to block acute opioid effects such as analgesia. If pain therapy needs to be continued after completion of step 2 or at any other time, an opioid analgesic / 6-β-naltrexol combination product designed to reduce peripheral side effects and addiction liability is a preferred embodiment. Step 3 involves applying increasing doses of 6β-naltrexol, gradually inhibiting central opioid effects, while gradually weaning off opioid analgesics, with tolerable withdrawal symptoms if performed over a sufficient period of time, such as two weeks. Administration of increasing doses of 6β-naltrexol will further reduce the risk of relapse, as opioid agonists become relatively ineffective centrally - thus administration of 6β-naltrexol (rather than opioid dose reduction alone) is required during this third withdrawal process to prevent relapse during withdrawal (during which inverse agonists will still cause significant withdrawal). In an additional step 4, 6β-naltrexol is then administered at high doses sufficient to block any opioid effects both peripherally and centrally, with continued high risk of relapse, for long-term prevention of relapse after opioid cessation. For long-term treatment, an intermediate dose of 6β-naltrexol sufficient to block peripheral opioid receptors (step 2) may be a preferred embodiment, which minimally interferes with the physiological effects of the opioid system. After complete withdrawal, other long-term strategies are possible, such as extended-release naltrexone formulations. When treating other drug addictions or addictive behaviors involving opioid signaling, low-dose 6β-naltrexol administration can be eliminated when peripheral withdrawal is not expected (step 1).

[0067] Example 1

[0068] Blockade of peripheral opioid receptors. Step 1.

[0069] This step is applicable to opioid use disorders. Slowly increasing doses of 6β-naltrexol are administered orally in amounts sufficient to gradually overcome peripheral opioid effects in addicted / dependent subjects, causing mild withdrawal characterized by restoration of bowel activity without excessive cramping or diarrhea, without central withdrawal symptoms. The recommended initial dose is 2 mg naltrexol orally (assuming approximately 30% oral bioavailability; estimated dose range 0.5 to 10 mg) once or twice daily for 2 to 4 days, followed by 6 mg once or twice daily for 4 to 8 days (estimated dose range 2-20 mg twice daily). Step 1 is designed to inhibit the peripheral effects of opioid drugs with minimal peripheral withdrawal symptoms, and at least partially reverse opioid dependence.

[0070] Example 2

[0071] Stabilization of peripheral opioid receptor signaling. Step 2.

[0072] Step 1 is followed by administration of 6-β-naltrexol, 10 mg, once or twice daily (estimated dose range 4-50 mg twice daily), for 1-4 weeks. This dose can be maintained to prevent peripheral side effects and reverse hyperalgesia and the dependent opioid state at peripheral opioid receptors. Because opioid-induced hyperalgesia is expected to be at least partially reversed during step 2, if withdrawal symptoms do not occur, the dose of the opioid agonist should be reduced and maintained at a lower dose. The goal is to reduce the burden of opioid exposure during step 2.

[0073] Patients who require continued pain therapy after completing step 2 can be administered a maintenance dose consisting of a 6-β-naltrexol / opioid analgesic combination formulation containing a dose of 6-β-naltrexol sufficient to block peripheral effects without interfering with opioid analgesia while reducing addiction liability, as described in the patent for the combination formulation. Patients who are willing to proceed with further opioid use withdrawal, whether or not they are taking opioids as part of their pain therapy, have an opioid use disorder, or are on an opioid maintenance program (methadone and butyl morphine), proceed to step 3 of the withdrawal regimen.

[0074] Example 3

[0075] Blockade of CNS opioid receptors and complete withdrawal. Step 3.

[0076] Blockade of peripheral opioid receptors is followed by administration of increasing doses of 6-β-naltrexol to subjects, gradually inhibiting the CNS effects of opioid analgesics. The recommended dose is 20 mg (range 10 to 80 mg) once or twice daily for 4 to 8 days, followed by 40 mg (range 20 to 120 mg) once or twice daily for 1 to 4 weeks, and further escalated to 100 mg (range 40 to 300 mg) once or twice daily for maintenance as necessary. A single dose of 20 mg intravenous naltrexol in opioid naive subjects The analgesia induced by 10 mg intravenous morphine was not blocked in 10 mg intravenous morphine; the IC50 for blocking morphine-induced slowing of bowel movements was about 3 mg intravenous naltrexol; the peripheral / central potency ratio of naltrexol was about 10 in mice, but may be higher in humans. In addition to increasing doses of 6-β-naltrexol, individuals will achieve a gradual complete cessation of opioid administration. The dosing schedule can be achieved by designing a sustained release formulation as described in the previously incorporated patents.

[0077] Example 4

[0078] Antagonist maintenance therapy after completion of opioid abstinence for relapse prevention. Step 4.

[0079] Opioid antagonist maintenance with 6-β-naltrexol may require 100 mg (dose range 40 to 300 mg) orally daily (assuming 20 to 40% bioavailability). Following withdrawal, an alternative preventive maintenance regimen (e.g., sustained release naltrexone) may replace 6-β-naltrexol in subjects who do not experience naltrexone rejection. Any benefit of long-term use of 6β-naltrexol (neutral antagonist) instead of naltrexone (inverse agonist) requires further testing - considering the physiological role of basal μ opioid receptor signaling in pain perception and dependence (13, 14). For long-term treatment, the lower doses of 6β-naltrexol described in step 3 may be preferred to minimize interference with physiological opioid function while reducing opioid dependence. Complete cessation of opioid use must be medically supervised for at least one year to determine recidivism rates.

[0080] Criteria for success in step 1 include normalization of bowel function without excessive withdrawal symptoms, resulting in high compliance with the use of 6β-naltrexol. In step 2, tolerance of 6-β-naltrexol dose escalation without further withdrawal symptoms (or only minimal symptoms), and the ability to reduce the opioid agonist dose without triggering withdrawal. In step 3, success will be measured by the ability of the individual to experience complete abstinence with tolerable withdrawal symptoms, and the success rate compared to other withdrawal programs. Additional medications currently used to promote abstinence (such as alpha-2 adrenergic agonists) can be added to the abstinence step. In step 4, the reduction in recidivism rate compared to the standard withdrawal / maintenance strategy will be a measure of success.

[0081] Example 5

[0082] Treatment of other drug addiction or addictive behaviors

[0083] Because these conditions indirectly involve enhanced opioid signaling in the CNS and the dependent opioid state contributes to addiction, the same multi-step protocol of administering 6β-naltrexone or its analogs and derivatives can be applied - but step 1 is no longer required because no peripheral adverse effects are expected and the withdrawal risk of blocking CNS opioid receptors in step 3 is minimal. Steps 2-4 are designed to modulate the μ opioid receptor state, promote one in which the opioid-independent state predominates, and at higher doses prevent any effects of acute upregulation of endogenous opioid signaling. Treatment of alcohol addiction is the primary goal of this treatment strategy, but other drug use disorders (e.g., nicotine, stimulants) and addictive behaviors can be similarly treated with 6β-naltrexone and its analogs, maintaining the physiological effects of spontaneous μ opioid receptor signaling in the non-dependent state with fewer adverse effects.

[0084] The present invention is further described by, but not limited to, the following numbered paragraphs:

[0085] 1. A method for a drug-dependent subject to quit drug dependence or addictive behavior, comprising the following steps in order:

[0086] a) blocking peripheral opioid receptors of the subject by administering to the subject in need thereof a therapeutically effective amount of at least one peripherally selective neutral opioid receptor antagonist to block the peripheral opioid receptors;

[0087] b) stabilizing peripheral opioid receptor signaling by maintaining administration of a peripherally selective neutral opioid antagonist at a dose sufficient to block peripheral but not central opioid receptors, thereby reducing opioid-induced hyperalgesia and dependence while simultaneously reducing the dose of the opioid agonist; and

[0088] c) blocking said subject's CNS opioid receptors by adjusting said dosage of said opioid receptor antagonist and concomitantly reducing and discontinuing opioid agonist therapy, thereby weaning said subject from said opioid addiction.

[0089] 2. The method according to paragraph 1, wherein the peripheral opioid receptor is a μ opioid receptor.

[0090] 3. The method according to paragraph 1, wherein the drug addiction is alcohol addiction or opioid dependence, or addiction to other drugs of abuse including nicotine and stimulants.

[0091] 3a. A method according to paragraph 1, wherein the addiction is a compulsive behavior, such as an eating disorder or gambling.

[0092] 4. The method according to paragraph 1, wherein the peripherally selective opioid receptor antagonist is a neutral peripherally selective opioid receptor antagonist.

[0093] 5. The method according to paragraph 4, wherein the neutral peripheral selective opioid receptor antagonist is 6-β-naltrexol or 6-β-naloxol, or 6α-naltrexol or 6α-naloxol, or 6α / β-naltrexamide or 6α / β-naltrexamide, or a derivative or metabolite thereof, including 6β-naltrexamide.

[0094] 6. The method according to paragraph 1, regarding opioid use disorder, wherein in step 1), the blockade of the peripheral opioid receptors is measured by restoration of bowel activity in the absence of central opioid withdrawal symptoms.

[0095] 7. The method according to paragraph 1, regarding opioid use disorder, wherein in step 1), the therapeutically effective amount of 6β-naltrexol is 0.5 to 20 mg.

[0096] 8. The method according to paragraph 1, regarding opioid use disorder, wherein in step 1), 0.5 to 10 mg of 6β-naltrexol is orally administered twice a day for 2 to 4 days, followed by 2 to 20 mg once or twice a day for 4 to 8 days.

[0097] 9. The method according to paragraph 1, regarding opioid use disorder, wherein in step 2), 4 to 50 mg of 6-β-naltrexol is orally administered once or twice daily for 1 to 4 weeks or more, and the dose of the opioid agonist is reduced until the first sign of withdrawal symptoms occurs.

[0098] 10. The method according to paragraph 1, regarding opioid use disorder, wherein in step 3), the dose of the opioid receptor antagonist is increased in an amount sufficient to block the CNS opioid receptors, wherein 10 to 80 mg, preferably 20 mg 6-β-naltrexol is orally administered twice daily for 4 to 8 days, followed by 20 to 120 mg, preferably 40 mg, twice daily for 1 to 4 weeks, and further increased to a range of 40 to 300 mg, preferably 100 mg, once or twice daily for maintenance, while the dose of the opioid agonist is reduced and discontinued at a rate that induces only mild tolerable withdrawal symptoms.

[0099] 11. The method according to paragraph, wherein the derivative or metabolite is 6β-naltrexol.

[0100] 12. The method according to paragraph 1, further comprising step 4): long-term implementation of a high-dose opioid antagonist maintenance regimen until the risk of recidivism is deemed low.

[0101] 13. The method according to paragraph, wherein in step 4), the maintenance dose of 6β-naltrexol is orally administered in a dose ranging from 40 to 300 mg, preferably 100 mg / day during the period of high risk of relapse, until long-term treatment with an intermediate dose can be continued in a dose range of 4 to 50 mg once or twice daily when the risk of recidivism decreases.

[0102] 14. A method of treating an addiction condition involving upregulation of basal signaling of the μ opioid receptor (MOR) system in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of 6β-naltrexol.

[0103] 15. The method according to paragraph, wherein the condition involving upregulation of basal signaling of the μ opioid receptor (MOR) system is alcohol use disorder, opioid dependence, hyperalgesia, chronic neuropathic pain, alcoholism, nicotine addiction, cocaine and stimulant abuse, anorexia, bulimia, gambling and excessive sexual behavior.

[0104] 16. The method according to paragraph, wherein the condition involving upregulation of basal signaling of the μ opioid receptor (MOR) system is a combination of alcohol use disorder and opioid dependence.

[0105] 17. A method for weaning an opioid-dependent subject from drug addiction or addictive behavior, comprising the following steps in order:

[0106] a) administering to said subject a therapeutically effective amount of at least one peripherally selective opioid receptor neutral antagonist to modulate the opioid dependence state, the antagonist selected being highly effective in reversing or preventing dependence while causing minimal withdrawal;

[0107] b) selectively blocking signaling at peripheral opioid receptors while reducing a dependence-like opioid state by maintaining administration of said peripherally selective neutral opioid antagonist at a dose sufficient to inhibit the effects of the opioid drug at peripheral but not central opioid receptors, wherein 4 to 50 mg of 6-β-naltrexol is administered orally once or twice daily for 1-4 weeks or more;

[0108] c) blocking the CNS opioid receptors of the subject by adjusting the dose of the opioid receptor antagonist, thereby preventing endogenous opioids from activating central opioid receptors, wherein in step 4), a maintenance dose of 6β-naltrexol is orally administered once or twice daily in a dose ranging from 40 to 300 mg, preferably 100 mg, for a long term, thereby weaning the subject from the addiction; and

[0109] d) When the risk of recidivism decreases, the opioid receptor antagonist may be continued to be administered chronically at an intermediate dose ranging from 4 to 50 mg once or twice daily (step 2), effectively reducing the risk of recidivism.

[0110] References

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[0112] 2. Yancey-Wrona, JE, Raymond, TJ, Mercer, HK, Sadee, W and Bilsky, EJ (2009). 6b-naltrexol preferentially antagonizes opioid effects on gastrointestinal transit compared to anti nociception in mice. Life Science, 85, 413-420.

[0113] 3. Wesson DR and Ling W (2003) The Clinical Opioid Withdrawal Scale (COWS). J Psychoact Drugs 35, 253-259.

[0114] 4.Araldi D 1 , Ferrari LF, Levine JD (2017) Hyperalgesic priming (type II) induced by repeated opioid exposure: maintenance mechanisms. Pain 158: 1204-1216.

[0115] 5. Corder G, Tawfik VL, Wang D, Sypek EI, Low SA, Dickinson JR, Sotoudeh C, Clark JD, Barres BA, Bohlen CJ, Scherrer (2017). Loss of μ-opioid receptor signaling in nociceptors, but not microglial cells, abolishes morphine tolerance without impairing analgesia. Nature Medicine 23:164-173.

[0116] 6. Porter SJ, Somogyi AA, White JM. (2002) In vivo and in vitro potency studies of 6β-naltrexol, the major human metabolite of naltrexone. Addiction Biology 7, 219-225.

[0117] 7. Raehal KM, Lowery JJ, Bhamidipati CM, Paolino RM, Blair JR, Wang D, Sadée W, Bilsky EJ. (2005). In vivo characterization of the opioid ligand 6β-naltrexol with less inverse agonist activity than naltrexone and naloxone in opioid-dependent mice. Journal of Pharmacology and Experimental Therapeutics 313, 1150-1162.

[0118] 8. Sirohi S, Dighe SV, Madia PA, Yoburn BC (2009) The relative potency of inverse opioid agonists and a neutral opioid antagonist inprecipitated withdrawal and antagonism of analgesia and toxicity. Journal of Pharmacology and Experimental Therapeutics 330, 513-519.

[0119] 9. Yancey-Wrona, J, Dallaire, B, Bilsky, E, Bath, B, Burkart, J, Wenster, L, Magiera, D, Yang, X, Phelps, M and Sadee, W. (2011) 6β-naltrexol, a peripherally selective opioid antagonist that inhibits morphine induced slowing of gastrointestinal transit: an exploratory study. Pain Medicine 12, 1727-1737.

[0120] 10. Ko MC, Divin MF, Lee H, Woods JH, Traynor JR. (2006) Differential in vivo potencies of naltrexone and 6beta-naltrexol in the monkey. Journal of Pharmacology and Experimental Therapeutics 316, 772-779.

[0121] 11. Mendelson J, Li L, Flower K, Harris W, Coyle JR et al. (2011) The Effects of 6β-Naltrexol, a Putative Neutral Opioid Antagonist, in Opioid-Dependent Subjects: A Proof-of-Concept Trial. J Addict Res Ther 2:108. DOI: 10.4172 / 2155-6105.1000108.AIKO Biotechnology. "APhase-I, Two-Stage, Double-Blind, Placebo-Controlled, Pharmacokinetic and Pharmacodynamic Trial of Low Doses of Intravenous 6β-Naltrexol (AIKO-150) in Opioid-Dependent Subjects." ClinicalTrials.gov. January 2009.

[0122] 12. Kalvass JC, Olson ER, Cassidy MP, Selley DE, Pollack GM. (2007) Pharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice: assessment of unbound brain EC50, and correlation of in vitro, preclinical, and clinical data. Journal of Pharmacology and Experimental Therapeutics, 323, 346-355.

[0123] 13. Corder G, Doolen S, Donahue RR, Winter M, Jutras B, He Y, Hu X, Wieskopf JS, Mogil JS, Storm DR, Wang ZJ, McCarson KE and Taylor BK. Constitutive μ-opioid receptor activity produces long-term endogenous analgesia and dependence. Science 2013;341, 1394-1399.

[0124] 14.Walwyn WM,Chen C,Kim H,Minasyan A,Ennes HS,McRoberts JA,Marvizon JCG. Sustained suppression of hyperalgesia during latent sensitization by mu-, delta-,and kappa-opioid receptors and 2A-adrenergic receptors: role of constitutive activity. Neurobiol. Dis. 36:204-221 (2016).

[0125] ***

[0126] It is to be understood that the present invention is not limited to the particular embodiments of the invention described above, as variations may be made thereto and still fall within the scope of the appended claims.

Claims

1. A method for weaning a drug-dependent subject from drug dependence, comprising the following steps in order: a) blocking peripheral opioid receptors of the subject by administering to the subject in need thereof a therapeutically effective amount of at least one peripherally selective opioid receptor antagonist to block the peripheral opioid receptors; b) stabilizing signaling of peripheral opioid receptors by maintaining administration of a peripherally selective opioid antagonist at a dose sufficient to block peripheral but not central opioid receptors, preventing peripheral opioid adverse effects and resulting in a reduction in opioid-induced hyperalgesia and dependence while simultaneously reducing the dose of the opioid agonist; c) blocking the subject's CNS opioid receptors by adjusting the dose of the opioid receptor antagonist and concomitantly reducing and discontinuing opioid agonist therapy, thereby weaning the subject from opioid addiction; and d) administering a maintenance dose of said antagonist at a dose sufficient to block peripheral opioid receptor activation: a dose sufficient to block central opioid receptors during the high relapse risk phase and an intermediate dose sufficient to block peripheral opioid receptors long-term.

2. The method of claim 1, wherein the peripheral opioid receptor is a μ opioid receptor.

3. The method of claim 1, wherein the drug addiction is alcohol addiction or other drug use disorders involving upregulation of opioid receptor signaling similar to the situation of opioid dependence, such as nicotine and stimulants, further comprising hyperalgesia and chronic neuropathic pain.

4. The method of claim 1, wherein the peripherally selective opioid receptor antagonist is a neutral peripherally selective opioid receptor antagonist.

5. The method of claim 4, wherein the neutral peripheral selective opioid receptor antagonist is 6α / β-naltrexol or 6α / β-naloxol, 6α / β-naltrexone or 6α / β-naloxone, or an analog, derivative or metabolite thereof.

6. The method of claim 1, wherein in step a), blockade of the peripheral opioid receptors is measured by restoration of gut motility in opioid use disorder in the absence of central opioid withdrawal symptoms.

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

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

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

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

11. The method of claim 5, wherein the derivative or metabolite is 6β-naltrexol.

12. The method according to claim 1, further comprising: The following steps are involved: An opioid antagonist maintenance program is implemented long-term until the risk of recidivism is deemed low.

13. The method according to claim 12, wherein the maintenance dose of 6-β-naltrexol is administered chronically in a dose ranging from 40 to 300 mg, preferably 100 mg / day orally.

14. The method of claim 12, wherein for long-term maintenance of reduced risk of recidivism, the dose of 6β-naltrexol is reduced to 4 to 50 mg / day.

15. A method of treating a condition other than opioid use disorder in an individual in need thereof, the condition involving upregulation of basal signaling of the μ opioid receptor (MOR) system, the method comprising administering to the individual a therapeutically effective amount of 6β-naltrexol.

16. The method of claim 15, wherein the condition involving upregulation of basal signaling of the μ opioid receptor (MOR) system is alcohol use disorder, opioid dependence, hyperalgesia, chronic neuropathic pain, alcoholism, nicotine addiction, cocaine and stimulant abuse, anorexia, bulimia, gambling, and excessive sexual behavior, further comprising hyperalgesia and chronic neuropathic pain.

17. The method of claim 15, wherein the condition involving upregulation of basal signaling of the μ opioid receptor (MOR) system is a combination of alcohol use disorder and opioid disorder.

18. A method for abstinence from drug use disorder or addictive compulsive behavior associated with upregulated opioid receptor signaling in a subject, comprising the following sequential steps: a) administering to said subject a therapeutically effective amount of at least one peripherally selective opioid receptor antagonist to modulate an opioid receptor dependence state, the selected antagonist being highly effective in reversing or preventing said dependence state while causing minimal withdrawal; (b) selectively blocking signaling at peripheral opioid receptors by maintaining administration of said peripherally selective opioid antagonist at a dose sufficient to inhibit the effects of the opioid drug at peripheral but not central opioid receptors to reverse the dependent signaling state of the μ opioid receptor; c) blocking the subject's CNS opioid receptors by modulating the dose of the opioid receptor antagonist to prevent acute endogenous opioid signaling during episodes of addictive behavior, optionally while simultaneously reducing and stopping opioid agonist therapy, thereby weaning the subject from the opioid addiction; and d) chronically administering the opioid receptor antagonist at doses initially high enough to effectively prevent relapse to drug use or addictive behavior by rendering the opioid drug ineffective, and subsequently at doses low enough to prevent or reverse dependence.