Medications to reduce opioid use and promote opioid abstinence

Abstract

The present invention relates to the use of mavoglurant or a pharmaceutically acceptable salt thereof in reducing opioid use in patients with opioid use disorder; in preventing opioid relapse in patients with opioid use disorder; in promoting opioid abstinence in patients with opioid use disorder; and in treating symptoms of depression or anxiety associated with opioid use disorder.

Description

[Technical field]

[0001] The present invention relates to the use of mGluR5 antagonists.

[0002] The present invention relates to the use of an mGluR5 antagonist named mavoglurant, or a pharma- ceutically acceptable salt thereof, in reducing opioid use by patients with opioid use disorder; preventing opioid relapse by patients with opioid use disorder; promoting opioid abstinence by patients with opioid use disorder; treating depression or anxiety symptoms associated with opioid use disorder. In particular, the present invention relates to the use of mavoglurant, or a pharma- ceutically acceptable salt thereof, in reducing opioid use / preventing opioid relapse by patients with opioid use disorder. [Background technology]

[0003] Opioid use disorder is a complex psychiatric disorder (e.g., defined according to DSM-5 criteria, i.e., Diagnostic and Statistical Manual of Mental Disorders. 5th Edition, Washington, DC: American Psychiatric Association, 2013) that continues to grow into a significant global health problem with adverse medical, social, and economic effects (Bahorilk et al J Addict Med. 2017;11(1):3-9). Socioeconomic risks associated with opioid use include increased crime, violence, and overdoses leading to death.

[0004] The mGluR5 receptor (mGluR5) has been implicated in the rewarding effects of various drugs of abuse and drug-seeking behavior. Van der Kam et al. showed that the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) dose-dependently reduced ketamine self-administration (SA) (75%) and modestly reduced heroin SA (20%) in a rat model of drug dependence (Van der Kam et al Behavioural Pharmacology 18(2007)717-724). Brown et al. investigated the effects of mGluR5 antagonism with the selective negative allosteric modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) on operant self-administration of morphine and cue-induced drug seeking in adult CD1 mice. Administration of MTEP (20 mg / kg, ip) attenuated operant responding for morphine (0.1 mg / kg / infusion) and cue-induced morphine seeking after a period of forced withdrawal. Summary of the Invention

[0005] The present invention relates to -In reducing opioid use by patients with opioid use disorder; -In preventing opioid relapse among patients with opioid use disorder; -In promoting opioid abstinence by patients with opioid use disorder; - In the treatment of symptoms of depression or anxiety associated with opioid use disorder The present invention relates to the use of magoglurant or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0006] [Figure 1] FIG. 1 shows the effect of Compound (III) on foot licking latency. [Diagram 2] FIG. 2 shows the effect of Compound (I) on paw licking latency. [Diagram 3]FIG. 3 shows the effects of masvoglurant (3, 10, 30 mg / kg), MPEP (20 mg / kg), and buprenorphine (0.2 mg / kg) on ​​remifentanil self-administration. A) Effect on the number of self-administered infusions of remifentanil per session. B) Effect on lever pressing rate (rate of lever pressing reported as responses / s / session). [Figure 4A] Figure 4A shows the effect of masvoglurant on remifentanil cue-induced reinstatement.Mavoglurant at 10 mg / kg. [Figure 4B] Figure 4B shows the effect of masvoglurant on remifentanil cue-induced reinstatement.Mavoglurant at 3 mg / kg. [Figure 4C] Figure 4C shows the effect of MPEP on remifentanil cue-induced reinstatement. MPEP at 20 mg / kg. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] Mavoglurant may be an ideal candidate for treating said patient population as it has therapeutic benefits for patients diagnosed with opioid use disorder, such as one or more of the following: i) mavoglurant promotes opioid abstinence, e.g., by maintaining abstinence or by reducing the amount or frequency of opioid use, e.g., compared to placebo, as assessed, e.g., by urinalysis (e.g., by measuring urinary opioid metabolites) or by using self-reported opioid use by standardized tools such as timeline followback self-report [Sobell, LC, Sobell, MB (1996) Timeline Followback User's Guide: A Calendar Method for Assessing Alcohol and Drug Use. Addiction Research Foundation, Toronto, Ontario, Canada; J. Anal. Toxicolo., 2002, 26:393-400]; ii) mavoglurant reduces opioid use relapse, e.g., compared to placebo, e.g., mavoglurant increases the time to relapse or patient relapse rate in a treatment program, such as a clinical trial; iii) Mavoglurant reduces (e.g., by eliminating or reducing the intensity, duration, or frequency of) one or more symptoms associated with opioid use disorder selected from the following, e.g., compared to a placebo: a. Depressive symptoms, as assessed, for example, by the Beck Depression Inventory [Beck, AT et al., (1961) An inventory for measuring depression. Archives of General Psychiatry, 4, 561-571; Beck, AT et al., (1988) Psychometric properties of the Beck Depression Inventory: Twenty-five years of evaluation. Clinical Psychology Review, 8(1), 77-100]; and b. For example, the State-Trait Anxiety Inventory [Spielberger, CD (1989). State-Trait Anxiety Inventory: Bibliography (2 nd Anxiety symptoms as assessed by the [Spielberger, CD et al., (1983). Manual for the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press]. iv) mavoglurant increases patient retention in treatment, e.g., compared to placebo, e.g., mavoglurant increases patient retention in a treatment program, such as a clinical trial (e.g., as measured by patient attendance at scheduled clinic visits and / or time to drop out of a clinical protocol); v) mavoglurant improves global functioning, e.g., as assessed by the Clinical Global Impression Scale-Severity (CGI-S) and Improvement (CGI-I) Psychiatry, 2007, 4(7):28-37; or vi) masvoglurant has a favorable therapeutic profile, such as a favorable safety profile or metabolic profile, e.g., a favorable profile with respect to psychiatric adverse events, genotoxicity, or cardiovascular adverse events (e.g., blood pressure, heart rate, electrocardiogram parameters); for example, masvoglurant has a better therapeutic profile (e.g., fewer side effects, reduced toxicity, such as reduced off-target effects or reduced genotoxicity) compared to one or more known therapeutic agents used in the treatment of opioid use disorder.

[0008] The embodiments of the present invention are as follows. Embodiment (a): 1a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in reducing opioid use by a patient with an opioid use disorder. 2a. Mavoglurant, or a pharma- ceutical acceptable salt thereof, for use in preventing opioid relapse in a patient with an opioid use disorder. 3a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in promoting opioid abstinence in a patient with opioid use disorder. 4a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in the treatment of depressive or anxiety symptoms associated with opioid use disorder. 5a. The opioid use disorder is associated with opioid inhalation (i.e. smoking), intravenous opioids, nasal inhalation of opioids (i.e. snorting), or oral formulations of opioids; in particular, mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1a-4a associated with opioid inhalation (i.e. smoking). 6a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a-5a, wherein the opioid use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder. 7a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a to 6a, wherein the use is in combination with standardized psychological treatment, for example at individual or population level. 8a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a to 7a, wherein the use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. 9a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to embodiment 8a, wherein the psychosocial or behavioral therapy is computer-assisted. 10a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a to 9a, wherein the use is carried out in conjunction with methadone or buprenorphine treatment. 11a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a to 10a, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent. 12a. The further active agent may be a GABAergic agent (e.g., topiramate, tiagabine, baclofen, or vigabatrin), a cannabinoid CB1 receptor antagonist, a dual dopamine-serotonin releaser (e.g., PAL-287), a noradregenic agent (e.g., doxazosin, disulfiram, or nepicastat), a 5-HT 1A Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to embodiment 11a, selected from a receptor partial agonist (e.g., buspirone), an MU opioid agonist (e.g., buprenorphine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharma-ceutically acceptable salt thereof. 13a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a-12a, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an opioid use disorder. 14a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a to 13a, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in immediate release or modified release form. 15a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a to 14a, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid. 16a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to embodiment 15a, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal. 17a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to embodiment 15a or 16a, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, with an interval of 12 hours between each administration. 18a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any of the preceding embodiments, wherein the opioid use disorder is associated with recreational drinking.

[0009] Embodiment (b): 1b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient for use in reducing opioid use by a patient with opioid use disorder. 2b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient for use in preventing opioid relapse in a patient with an opioid use disorder. 3b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use in promoting opioid abstinence in a patient with opioid use disorder. 4b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient for use in the treatment of depressive or anxiety symptoms associated with opioid use disorder. 5b. The opioid use disorder is associated with opioid inhalation (i.e. smoking), intravenous opioids, nasal inhalation of opioids (i.e. snorting), or oral formulations of opioids; in particular, a pharmaceutical composition comprising mavoglurant or a pharma- ceutically acceptable salt thereof and at least one pharma-ceutically acceptable excipient for use according to any one of embodiments 1b to 4b, in association with opioid inhalation (i.e. smoking). 6b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for use according to any one of embodiments 1b-5b, wherein the opioid use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder. 7b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for use according to any one of embodiments 1b to 6b, wherein the use is, for example, in combination with standardized psychological treatment at an individual or population level. 8b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for use according to any one of embodiments 1b to 7b, wherein the use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. 9b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to embodiment 8b, wherein the psychosocial or behavioral therapy is computer-assisted. 10b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for use according to any one of embodiments 1b to 9b, wherein the use is in parallel with methadone or buprenorphine treatment. 11b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to any one of embodiments 1b to 10b, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent. 12b. The additional active agent may be a GABAergic agent (e.g., topiramate, tiagabine, baclofen, or vigabatrin), a cannabinoid CB1 receptor antagonist, a dual dopamine-serotonin releaser (e.g., PAL-287), a noradrenaline drug (e.g., doxazosin, disulfiram, or nepicastat), a 5-HT 1A A pharmaceutical composition comprising mavoglurant or a pharma- ceutical acceptable salt thereof and at least one pharma- ceutical acceptable excipient selected from a receptor partial agonist (e.g., buspirone), an MU opioid agonist (e.g., buprenorphine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharma- ceutical acceptable salt thereof, for use according to embodiment 11b. 13b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for use according to any one of embodiments 1b to 12b, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an opioid use disorder. 14b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to any one of embodiments 1b to 13b in immediate release or modified release form. 15b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to any one of embodiments 1b to 14b, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid. 16b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to embodiment 15b, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal. 17b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to embodiment 15b or 16b, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, with an interval of 12 hours between each administration. 18b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to any of the preceding embodiments, wherein the opioid use disorder is associated with recreational drinking.

[0010] Embodiment (c): 1c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use in reducing opioid use by a patient with an opioid use disorder. 2c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use in preventing opioid relapse in a patient with an opioid use disorder. 3c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use in promoting opioid abstinence in a patient with opioid use disorder. 4c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use in the treatment of depressive or anxiety symptoms associated with opioid use disorder. 5c. The opioid use disorder is associated with opioid inhalation (i.e. smoking), intravenous opioids, nasal inhalation of opioids (i.e. snorting), or oral formulations of opioids; in particular, a pharmaceutical combination comprising mavoglurant or a pharma- ceutical acceptable salt thereof and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 4c, associated with opioid inhalation (i.e. smoking). 6c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c-5c, wherein the opioid use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder. 7c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 6c, wherein the use is, for example, in combination with standardized psychological treatment at individual or population level. 8c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 7c, wherein the use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. 9c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to embodiment 8c, wherein the psychosocial or behavioral therapy is computer-assisted. 10c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 9c, wherein the use is carried out in parallel with methadone or buprenorphine treatment. 11c. The further active agent may be a GABAergic agent (e.g., topiramate, tiagabine, baclofen, or vigabatrin), a cannabinoid CB1 receptor antagonist, a dual dopamine-serotonin releaser (e.g., PAL-287), a noradrenaline drug (e.g., doxazosin, disulfiram, or nepicastat), a 5-HT 1A A pharmaceutical combination comprising mavoglurant or a pharma- ceutical acceptable salt thereof and at least one further pharma- ceutical active ingredient selected from a receptor partial agonist (e.g., buspirone), an MU opioid agonist (e.g., buprenorphine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharma- ceutical acceptable salt thereof, for use according to any one of embodiments 1c to 10c. 12c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 11c, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an opioid use disorder. 13c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 12c, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in immediate release or modified release form. 14c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 13c, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, e.g. 200 mg / bid. 15c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to embodiment 14c, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal. 16c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to embodiment 14c or 15c, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, with an interval of 12 hours between each administration. 17c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any of the preceding embodiments, wherein the opioid use disorder is associated with recreational drinking.

[0011] Embodiment (d): 1d. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for reducing opioid use in a patient with opioid use disorder. 2d. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for preventing opioid relapse in a patient with opioid use disorder. 3d. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for promoting opioid abstinence in a patient with opioid use disorder. 4d. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of depression or anxiety symptoms associated with opioid use disorder. 5d. The opioid use disorder is associated with opioid inhalation (i.e. smoking), intravenous opioids, nasal inhalation of opioids (i.e. snorting), or oral formulations of opioids; in particular, the use of mavoglurant or a pharma- ceutically acceptable salt thereof as described in any one of embodiments 1d-4d in association with opioid inhalation (i.e. smoking). 6d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d-5d, wherein the opioid use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder. 7d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 6d, wherein the use is in combination with standardized psychological treatment, for example at individual or population level. 8d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 7d, wherein the use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. 9d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to embodiment 8d, wherein the psychosocial or behavioral therapy is computer-assisted. 10d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 9d, wherein the use is carried out in parallel with methadone or buprenorphine treatment. 11d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 10d, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent. 12d. The further active agent may be a GABAergic agent (e.g., topiramate, tiagabine, baclofen, or vigabatrin), a cannabinoid CB1 receptor antagonist, a dual dopamine-serotonin releaser (e.g., PAL-287), a noradrenaline drug (e.g., doxazosin, disulfiram, or nepicastat), a 5-HT 1A The use of mavoglurant or a pharma- ceutically acceptable salt thereof according to embodiment 11d, selected from a receptor partial agonist (e.g., buspirone), an MU opioid agonist (e.g., buprenorphine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharma- ceutically acceptable salt thereof. 13d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 12d, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an opioid use disorder. 14d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 13d, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in immediate release or modified release form. 15d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 14d, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid. 16d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to embodiment 15d, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal. 17d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to embodiment 15d or 16d, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, with an interval of 12 hours between each administration. 18d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any of the preceding embodiments, wherein the opioid use disorder is associated with recreational drinking.

[0012] Embodiment (e): 1e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for the manufacture of a medicament for reducing opioid use in a patient with opioid use disorder. 2e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for the manufacture of a medicament for preventing opioid relapse in a patient with opioid use disorder. 3e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for the manufacture of a medicament for promoting opioid abstinence in a patient with opioid use disorder. 4e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for the manufacture of a medicament for the treatment of depression or anxiety symptoms associated with opioid use disorder. 5e. The opioid use disorder is associated with opioid inhalation (i.e. smoking), intravenous opioids, nasal inhalation of opioids (i.e. snorting), or oral formulations of opioids; in particular, the use of a pharmaceutical composition comprising mavoglurant or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient as described in any one of embodiments 1e-4e in association with opioid inhalation (i.e. smoking). 6e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to any one of embodiments 1e-5e, wherein the opioid use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder. 7e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient according to any one of embodiments 1e to 6e, wherein the use is, for example, in combination with standardized psychological treatment at individual or population level. 8e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to any one of embodiments 1e to 7e, wherein the use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. 9e. The use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to embodiment 8e, wherein the psychosocial or behavioral therapy is computer-assisted. 10e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to any one of embodiments 1e to 9e, wherein the use is performed in parallel with methadone or buprenorphine treatment. 11e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to any one of embodiments 1e to 10e, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent. 12e. The additional active agent may be a GABAergic agent (e.g., topiramate, tiagabine, baclofen, or vigabatrin), a cannabinoid CB1 receptor antagonist, a dual dopamine-serotonin releaser (e.g., PAL-287), a noradrenaline drug (e.g., doxazosin, disulfiram, or nepicastat), a 5-HT 1A Use of a pharmaceutical composition comprising mavoglurant or a pharma- ceutical acceptable salt thereof as described in embodiment 11e and at least one pharma- ceutical acceptable excipient selected from a receptor partial agonist (e.g., buspirone), an MU opioid agonist (e.g., buprenorphine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharma-ceutical acceptable salt thereof. 13e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient according to any one of embodiments 1e-12e, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an opioid use disorder. 14e. Use of a pharmaceutical composition comprising mavoglurant or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient as described in any one of embodiments 1e to 13e, wherein mavoglurant or a pharma- ceutically acceptable salt thereof is administered in immediate release or modified release form. 15e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to any one of embodiments 1e to 14e, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid. 16e. The use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to embodiment 15e, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal. 17e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to embodiment 15e or 16e, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, with an interval of 12 hours between each administration. 18e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to any of the previous embodiments, wherein the opioid use disorder is associated with recreational drinking.

[0013] Embodiment (f): 1f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient for the manufacture of a medicament for reducing opioid use in a patient with an opioid use disorder. 2f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient for the manufacture of a medicament for the prevention of opioid relapse in a patient with an opioid use disorder. 3f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for the manufacture of a medicament for promoting opioid abstinence in a patient with opioid use disorder. 4f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for the manufacture of a medicament for the treatment of depression or anxiety symptoms associated with opioid use disorder. 5f. The opioid use disorder is associated with opioid inhalation (i.e. smoking), intravenous opioids, nasal inhalation of opioids (i.e. snorting), or oral formulations of opioids; in particular, the use of a pharmaceutical combination comprising mavoglurant or a pharma- ceutically acceptable salt thereof and at least one further pharma- ceutical active ingredient as described in any one of embodiments 1f-4f in association with opioid inhalation (i.e. smoking). 6f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f-5f, wherein the opioid use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder. 7f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f to 6f, wherein the use is, for example, in combination with standardized psychological treatment at individual or population level. 8f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f to 7f, wherein the use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. 9f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to embodiment 8f, wherein the psychosocial or behavioral therapy is computer-assisted. 10f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f to 9f, wherein the use is carried out in parallel with methadone or buprenorphine treatment. 11f. Additional active agents include GABAergic agents (e.g., topiramate, tiagabine, baclofen, or vigabatrin), cannabinoid CB1 receptor antagonists, dual dopamine-serotonin releasers (e.g., PAL-287), noradrenaline drugs (e.g., doxazosin, disulfiram, or nepicastat), 5-HT 1A Use of a pharmaceutical combination comprising mavoglurant or a pharma- ceutical acceptable salt thereof according to any one of embodiments 1f to 10f and at least one further pharma- ceutical active ingredient selected from a receptor partial agonist (e.g., buspirone), an MU opioid agonist (e.g., buprenorphine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharma- ceutical acceptable salt thereof. 12f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f to 11f, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an opioid use disorder. 13f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f to 12f, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in immediate release or modified release form. 14f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1c to 13c, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, e.g. 200 mg / bid. 15f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to embodiment 14f, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal. 16f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to embodiment 14f or 15f, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, with an interval of 12 hours between each administration. 17f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any of the previous embodiments, wherein the opioid use disorder is associated with recreational drinking.

[0014] Embodiment (g): 1g. A method for reducing opioid use by an opioid use disorder patient in need thereof, comprising administering to said opioid use disorder patient an effective amount of mavoglurant or a pharma- ceutically acceptable salt thereof. 2g. A method for the prevention of opioid relapse in an opioid use disorder patient in need thereof, comprising administering to said opioid use disorder patient an effective amount of mavoglurant or a pharma- ceutically acceptable salt thereof. 3g. A method for promoting opioid abstinence by an opioid use disorder patient in need thereof, comprising administering to said opioid use disorder patient an effective amount of mavoglurant or a pharma- ceutically acceptable salt thereof. 4g. A method for the treatment of symptoms of depression or anxiety associated with opioid use disorder by an opioid use disorder patient in need thereof, comprising administering to said opioid use disorder patient an effective amount of mavoglurant or a pharma- ceutically acceptable salt thereof. 5g. The method of any one of embodiments 1g-4g, wherein the opioid use disorder is associated with opioid inhalation (i.e., smoking), intravenous opioids, nasal inhalation of opioids (i.e., snorting), or oral formulations of opioids; particularly, the method is associated with opioid inhalation (i.e., smoking). 6g. The method of any one of embodiments 1g-5g, wherein the opioid use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder. 7g. The method according to any one of embodiments 1g to 6g, wherein the administration of mavoglurant, or a pharma- ceutically acceptable salt thereof, is combined with standardized psychological treatment, for example at an individual or population level. 8g. The method according to any one of embodiments 1g to 7g, wherein the administration of mavoglurant, or a pharma- ceutically acceptable salt thereof, is combined with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. 9g. The method of embodiment 8g, wherein the psychosocial or behavioral therapy is computer-assisted. 10g. The method according to any one of embodiments 1g to 9g, wherein the administration of mavoglurant, or a pharma- ceutically acceptable salt thereof, is performed in parallel with methadone or buprenorphine treatment. 11g. The method according to any one of embodiments 1g to 10g, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent. 12g. The further active agent may be a GABAergic agent (e.g., topiramate, tiagabine, baclofen, or vigabatrin), a cannabinoid CB1 receptor antagonist, a dual dopamine-serotonin releaser (e.g., PAL-287), a noradrenaline drug (e.g., doxazosin, disulfiram, or nepicastat), a 5-HT 1A The method of embodiment 11g, wherein the therapeutic agent is selected from a receptor partial agonist (e.g., buspirone), a MU opioid agonist (e.g., buprenorphine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharmaceutically acceptable salt thereof. 13g. The method of any one of embodiments 1g-12g, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an opioid use disorder. 14g. The method of any one of embodiments 1g-13g, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in immediate release or modified release form. 15g. The method according to any one of embodiments 1g to 14g, wherein masvoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid. 16g. The method according to embodiment 15g, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal. 17g. The method according to embodiment 15g or 16g, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, 12 hours apart. 17g. 18g. The method of any of the preceding embodiments, wherein the opioid use disorder is associated with recreational drinking.

[0015] Embodiment (h): 1h. A method for reducing opioid use in a patient with opioid use disorder in need thereof, comprising administering to said patient with opioid use disorder a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient. 2h. A method for preventing opioid relapse in an opioid use disorder patient in need thereof, comprising administering to said opioid use disorder patient a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient. 3h. A method for promoting opioid abstinence in a patient with opioid use disorder in need thereof, comprising administering to said patient with opioid use disorder a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma-ceutical acceptable excipient. 4h. A method for treating depression or anxiety symptoms associated with opioid use disorder in an opioid use disorder patient in need thereof, comprising administering to said opioid use disorder patient a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient. 5h. The method of any one of embodiments 1h-4h, wherein the opioid use disorder is associated with opioid inhalation (i.e., smoking), intravenous opioids, nasal inhalation of opioids (i.e., snorting), or an oral formulation of opioid; particularly, the method is associated with opioid inhalation (i.e., smoking). 6h. The method of any one of embodiments 1h-5h, wherein the opioid use disorder is comorbid with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder. 7h. The method according to any one of embodiments 1h to 6h, wherein the administration of a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, is combined with standardized psychological treatment, e.g., at an individual or population level. 8h. The method according to any one of embodiments 1h to 7h, wherein the administration of a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, is combined with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. 9h. The method of embodiment 8h, wherein the psychosocial or behavioral therapy is computer-assisted. 10h. The method according to any one of embodiments 1h to 9h, wherein the administration of a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient is performed in parallel with methadone or buprenorphine treatment. 11h. The method according to any one of embodiments 1h to 10h, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent. 12h. The further active agent may be a GABAergic agent (e.g., topiramate, tiagabine, baclofen, or vigabatrin), a cannabinoid CB1 receptor antagonist, a dual dopamine-serotonin releaser (e.g., PAL-287), a noradrenaline drug (e.g., doxazosin, disulfiram, or nepicastat), a 5-HT 1A The method of embodiment 11h, wherein the therapeutic agent is selected from a receptor partial agonist (e.g., buspirone), a MU opioid agonist (e.g., buprenorphine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharmaceutically acceptable salt thereof. 13h. The method of any one of embodiments 1h-12h, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an opioid use disorder. 14h. The method of any one of embodiments 1h to 13h, wherein the pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient is in immediate release or modified release form. 15h. The method according to any one of embodiments 1h to 14h, wherein masvoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid. 16h. The method according to embodiment 15h, wherein a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient is administered with a meal. 17h. The method according to embodiment 15h or 16h, wherein a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient is administered in the morning and in the evening, with an interval of 12 hours. 18h. The method of any of the preceding embodiments, wherein the opioid use disorder is associated with recreational drinking.

[0016] Embodiment (j): 1j. A method for reducing opioid use in a patient with opioid use disorder in need thereof, comprising administering to said patient with opioid use disorder a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one additional pharma- ceutical active ingredient. 2j. A method for preventing opioid relapse in a patient with opioid use disorder in need thereof, comprising administering to said patient with opioid use disorder a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one additional pharma- ceutical active ingredient. 3j. A method for promoting opioid abstinence in a patient with opioid use disorder in need thereof, comprising administering to said patient with opioid use disorder a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one additional pharma- ceutical active ingredient. 4j. A method for treating depression or anxiety symptoms associated with opioid use disorder in an opioid use disorder patient in need thereof, comprising administering to said opioid use disorder patient a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one additional pharma- ceutical active ingredient. 5j. The method of any one of embodiments 1j-4j, wherein the opioid use disorder is associated with opioid inhalation (i.e., smoking), intravenous opioids, nasal inhalation (i.e., snorting), or an oral formulation of opioid; particularly, the method is associated with opioid inhalation (i.e., smoking). 6j. The method of any one of embodiments 1j-5j, wherein the opioid use disorder is comorbid with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder. 7j. The method according to any one of embodiments 1j to 6j, wherein the administration of a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient is combined with standardized psychological treatment, e.g., at an individual or population level. 8j. The method according to any one of embodiments 1j to 7j, wherein the administration of a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient is combined with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. 9j. The method of embodiment 8j, wherein the psychosocial or behavioral therapy is computer-assisted. 10j. The method of any one of embodiments 1j-9j, wherein administration of a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient is performed in parallel with methadone or buprenorphine treatment. 11j. Further active agents include GABAergic agents (e.g., topiramate, tiagabine, baclofen, or vigabatrin), cannabinoid CB1 receptor antagonists, dual dopamine-serotonin releasers (e.g., PAL-287), noradrenaline drugs (e.g., doxazosin, disulfiram, or nepicastat), 5-HT 1A The method of embodiment 10j, wherein the therapeutic agent is selected from a receptor partial agonist (e.g., buspirone), a MU opioid agonist (e.g., buprenorphine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharmaceutically acceptable salt thereof. 12j. The method of any one of embodiments 1j-11j, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an opioid use disorder. 13j. The method according to any one of embodiments 1j to 12j, wherein the pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient is in immediate release or modified release form. 14j. The method according to any one of embodiments 1j to 13j, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid. 15j. The method according to embodiment 14j, wherein the pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient is administered with a meal. 16j. The method according to embodiment 14j or 15j, wherein a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient is administered in the morning and evening, with an interval of 12 hours. 17j. The method of any of the preceding embodiments, wherein the opioid use disorder is associated with recreational drinking.

[0017] Embodiment (k): Embodiment 1k: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in reducing opioid use by a patient with an opioid use disorder. Embodiment 2k: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in preventing opioid relapse in a patient with an opioid use disorder. Embodiment 3k: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in promoting opioid abstinence in a patient with an opioid use disorder. Embodiment 4k: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in treating depressive or anxiety symptoms associated with opioid use disorder. Embodiment 5k: The opioid use disorder is associated with opioid inhalation (i.e. smoking), intravenous opioids, nasal inhalation of opioids (i.e. snorting), or oral formulations of opioids; in particular, masvoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1k to 4k, associated with opioid inhalation (i.e. smoking). Embodiment 6k: Mavoglurant or a pharma- tically acceptable salt thereof for use according to any one of embodiments 1k to 5k, wherein the opioid use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder. Embodiment 7k: Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1k to 6k, wherein the use is, for example, in combination with standardized psychological treatment at individual or population level. Embodiment 8k: Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1k to 7k, wherein the use is combined with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. Embodiment 9k: Mavoglurant or a pharma- ceutically acceptable salt thereof for use as described in embodiment 8k, wherein the psychosocial or behavioral therapy is computer-assisted. Embodiment 10k: Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1k to 9k, wherein the use is carried out in parallel with methadone or buprenorphine treatment. Embodiment 11k: Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1k to 10k, wherein mavoglurant or a pharma-ceutically acceptable salt thereof is administered in combination with a further active agent. Embodiment 12k: Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1k to 11k, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an opioid use disorder. Embodiment 13k: Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1k to 12k, wherein the mavoglurant or a pharma-ceutically acceptable salt thereof is administered in immediate release or modified release form. Embodiment 14k: Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1k to 13k, wherein the mavoglurant or a pharma- ceutically acceptable salt thereof is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid, or 200 mg / bid, for example 200 mg / bid. Embodiment 15k: Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1k to 14k, wherein the opioid use disorder is associated with recreational drinking.

[0018] Embodiment (m): 1m. Mavoglurant or a pharma- ceutically acceptable salt thereof for the treatment of opioid use disorder. 2m. The opioid use disorder is associated with opioid inhalation (i.e. smoking), intravenous opioids, nasal inhalation of opioids (i.e. snorting), or oral formulations of opioids; in particular, mavoglurant or a pharma- ceutically acceptable salt thereof for use according to embodiment 1m, associated with opioid inhalation (i.e. smoking). 3m. Mavoglurant or a pharma- tically acceptable salt thereof for use according to any one of embodiments 1m or 2m, wherein the opioid use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder. 4m. Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1m to 3m, wherein the use is, for example, combined with standardized psychological treatment at individual or population level. 5m. Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1m to 4m, wherein the use is combined with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. 6m. The psychosocial or behavioral therapy is computer-assisted. Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to embodiment 5m. 7m. Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1m to 6m, wherein the use is carried out in parallel with methadone or buprenorphine treatment. 8m. Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1m to 7m, wherein the mavoglurant or a pharma- ceutically acceptable salt thereof is administered in combination with a further active agent. 9m. Additional active agents include GABAergic agents (e.g., topiramate, tiagabine, baclofen, or vigabatrin), cannabinoid CB1 receptor antagonists, dual dopamine-serotonin releasers (e.g., PAL-287), noradrenaline drugs (e.g., doxazosin, disulfiram, or nepicastat), 5-HT 1A Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to embodiment 8m, selected from a receptor partial agonist (e.g., buspirone), an MU opioid agonist (e.g., buprenorphine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharma-ceutically acceptable salt thereof. 10m. Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1m to 9m, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an opioid use disorder. 11m. Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1m to 10m, wherein the mavoglurant or a pharma- ceutically acceptable salt thereof is administered in immediate release or modified release form. 12m. Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1m to 11m, wherein the mavoglurant or a pharma- ceutically acceptable salt thereof is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid, or 200 mg / bid, for example 200 mg / bid. 13m. Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to embodiment 12m, wherein the mavoglurant or a pharma- ceutically acceptable salt thereof is administered with a meal. 14m. Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to embodiment 12m or 13m, wherein the mavoglurant or a pharma- ceutically acceptable salt thereof is administered in the morning and in the evening, with an interval of 12 hours between each administration. 15m. Mavoglurant or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1m to 14m, wherein the opioid use disorder is associated with recreational drinking.

[0019] Embodiment (n): 1n. Use of mavoglurant or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of opioid use disorder. 2n. The opioid use disorder is associated with opioid inhalation (i.e., smoking), intravenous opioids, nasal inhalation of opioids (i.e., snorting), or oral formulations of opioids; in particular, the use of mavoglurant or a pharma- ceutically acceptable salt thereof as described in embodiment 1n in association with opioid inhalation (i.e., smoking). 3n. The use of mavoglurant or a pharma- ceutically acceptable salt thereof according to embodiment 1n or 2n, wherein the opioid use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder. 4n. The use of mavoglurant or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1n to 3n, wherein the use is combined with standardized psychological treatment, for example at individual or population level. 5n. The use of mavoglurant or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1n to 4n, wherein the use is combined with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. 6n. The psychosocial or behavioral therapy is computer-assisted using mavoglurant or a pharma- ceutically acceptable salt thereof as described in embodiment 5n. 7n. The use of mavoglurant or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1n to 9n, wherein the use is carried out in parallel with methadone or buprenorphine treatment. 8n. The use of mavoglurant or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1n to 7n, wherein mavoglurant or a pharma- ceutically acceptable salt thereof is administered in combination with a further active agent. 9n. Additional active agents include GABAergic agents (e.g., topiramate, tiagabine, baclofen, or vigabatrin), cannabinoid CB1 receptor antagonists, dual dopamine-serotonin releasers (e.g., PAL-287), noradrenaline drugs (e.g., doxazosin, disulfiram, or nepicastat), 5-HT 1A The use of mavoglurant or a pharma- ceutically acceptable salt thereof according to embodiment 8n, selected from a receptor partial agonist (e.g., buspirone), an MU opioid agonist (e.g., buprenorphine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharma- ceutically acceptable salt thereof. 10n. The use of mavoglurant or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1n to 9n, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an opioid use disorder. 11n. The use of mavoglurant or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1n to 10n, wherein mavoglurant or a pharma- ceutically acceptable salt thereof is administered in immediate release or modified release form. 12n. The use of mavoglurant or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1n to 11n, wherein mavoglurant or a pharma- ceutically acceptable salt thereof is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid, or 200 mg / bid, for example 200 mg / bid. 13n. The use of mavoglurant or a pharma- ceutically acceptable salt thereof according to embodiment 12n, wherein mavoglurant or a pharma- ceutically acceptable salt thereof is administered with a meal. 14n. The use of mavoglurant or a pharma- ceutically acceptable salt thereof according to embodiment 12n or 13n, wherein mavoglurant or a pharma- ceutically acceptable salt thereof is administered in the morning and in the evening, with an interval of 12 hours between each administration. 15n. The use of mavoglurant or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1n to 14n, wherein the opioid use disorder is associated with recreational drinking.

[0020] Embodiment (p): 1p. A method for treating an opioid use disorder in a patient in need thereof, comprising administering to said patient an effective amount of mavoglurant or a pharma- ceutically acceptable salt thereof. 2p. The method of embodiment 1p, wherein the opioid use disorder is associated with opioid inhalation (i.e., smoking), intravenous opioids, nasal inhalation of opioids (i.e., snorting), or oral formulations of opioids; particularly, with opioid inhalation (i.e., smoking). 3p. The method of embodiment 1p or 2p, wherein the opioid use disorder is comorbid with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder. 4p. The method according to any one of embodiments 1p to 3p, wherein the administration of mavoglurant or a pharma- ceutically acceptable salt thereof is combined with standardized psychological treatment, for example at an individual or population level. 5p. The method according to any one of embodiments 1p to 4p, wherein the administration of mavoglurant or a pharma- ceutically acceptable salt thereof is combined with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. 6p. The method of embodiment 5p, wherein the psychosocial or behavioral therapy is computer-assisted. 7p. The method of any one of embodiments 1p-6p, wherein administration of mavoglurant or a pharma- ceutically acceptable salt thereof is performed in parallel with methadone or buprenorphine treatment. 8p. The method of any one of embodiments 1p-7p, wherein mavoglurant or a pharma- ceutically acceptable salt thereof is administered in combination with a further active agent. 9p. Additional active agents include GABAergic agents (e.g., topiramate, tiagabine, baclofen, or vigabatrin), cannabinoid CB1 receptor antagonists, dual dopamine-serotonin releasers (e.g., PAL-287), noradrenaline drugs (e.g., doxazosin, disulfiram, or nepicastat), 5-HT1A The method of embodiment 8p, wherein the therapeutic agent is selected from a receptor partial agonist (e.g., buspirone), a MU opioid agonist (e.g., buprenorphine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharmaceutically acceptable salt thereof. 10p. The method of any one of embodiments 1p-9p, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an opioid use disorder. 11p. The method of any one of embodiments 1p-10p, wherein mavoglurant or a pharma- ceutically acceptable salt thereof is administered in immediate release or modified release form. 12p. The method according to any one of embodiments 1p to 11p, wherein magglurant or a pharma- ceutically acceptable salt thereof is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid, or 200 mg / bid, for example 200 mg / bid. 13p. The method of embodiment 12p, wherein mavoglurant or a pharma- ceutically acceptable salt thereof is administered with a meal. 14p. The method according to embodiment 12p or 13p, wherein mavoglurant or a pharma- ceutically acceptable salt thereof is administered in the morning and evening, 12 hours apart. 15p. The method of any one of embodiments 1p-14p, wherein the opioid use disorder is associated with recreational drinking.

[0021] common terms The term "opioid use disorder" or "OUD" as used herein is defined according to DSM-5 criteria (i.e., in accordance with the Diagnostic and Statistical Manual of Mental Disorders. 5th Edition, Washington, DC: American Psychiatric Association, 2013), the entire contents of which are incorporated herein by reference. As used herein, the term "opioid use disorder" is defined as a problematic pattern of opioid use leading to clinically significant impairment or distress occurring within a 12-month period, as manifested by at least two of the following: 1) Opioids are often taken in larger amounts or for longer periods than intended. 2) Persistent cravings for opioid use or unsuccessful efforts to reduce or suppress them. 3) Excessive time is spent in activities necessary to obtain opioids, use opioids, or recover from their effects. 4) Craving or strong desire or urge to use opioids. 5) Recurrent opioid use that prevents the patient from fulfilling major role responsibilities at work, school, or home. 6) Continued opioid use despite persistent or recurring social or interpersonal problems caused or exacerbated by the effects of the opioid. 7) Important social, occupational, or recreational activities are forfeited or reduced due to opioid use. 8) Repeated opioid use in physically dangerous situations. 9) Continued opioid use despite knowledge of persistent or recurring physical or psychological problems likely caused or exacerbated by opioids. 10) Tolerance, as defined by any of the following: a) the need for significantly increased doses of opioid to achieve intoxication or the desired effect; b) a significantly decreased effect with regular use of the same amount of opioid. 11) Withdrawal, as manifested by any of the following: a) Characteristic opioid withdrawal syndrome: i) Cessation (or reduction) of chronic opioid use; ii) Dysphoric mood and two (or more) of the following physiological changes that occur within hours to days after cessation (or reduction) of opioid use: fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; psychomotor retardation or agitation. b) Opioids are taken to relieve or avoid withdrawal symptoms.

[0022] "Opioid use disorder" may be divided into three categories: mild (i.e., having two or three symptoms defined according to DSM-5 criteria), moderate (i.e., having four or five symptoms defined according to DSM-5 criteria), and severe (i.e., having six or more symptoms defined according to DSM-5 criteria). In one embodiment, "opioid use disorder" as used herein refers to "mild opioid use disorder", "moderate opioid use disorder", and "severe opioid use disorder". In a further embodiment, "opioid use disorder" as used herein refers to "mild opioid use disorder", "moderate opioid use disorder", or "severe opioid use disorder".

[0023] The term "opioid use disorder patient" refers to a patient diagnosed with OUD as defined herein. In one embodiment, the term "opioid use disorder patient" refers to a patient diagnosed with OUD who is abstinent from opioids, for example, for at least one day, for example, three or more days. The term "opioid use disorder patient abstinent from opioids" refers to a patient diagnosed with OUD who is abstinent from opioids for a period of time, for example, for at least one day. The term "opioid use disorder associated with recreational drinking" refers to a patient diagnosed with opioid use disorder who is an alcohol abuser (i.e., a heavy drinker). As explained at http: / / drugabuse.com / library / alcohol-abuse / , an alcohol abuser may not drink alcohol all the time, for example, only once a week, but when they do drink, they may drink heavily, which causes problems, such as developing alcoholism. For purposes of clarity, as used herein, an alcohol abuser is not an individual with an alcohol use disorder (i.e., does not meet criteria for an alcohol use disorder as defined according to DSM-5 criteria). The term "heavy drinker" refers to an individual with a pattern of heavy alcohol use. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the Substance Abuse and Mental Health Services Administration (SAMHSA) defines "heavy alcohol use" as recreational drinking on 5 or more days in the past month. The NIAAA defines recreational drinking as a pattern of drinking that leads to a blood alcohol concentration (BAC) value of 0.08 g / dL. This typically occurs after 4 alcoholic drinks for women and 5 alcoholic drinks for men in approximately 2 hours.The Substance Abuse and Mental Health Services Administration (SAMHSA) defines "recreational drinking" as 5 or more alcoholic drinks for men or 4 or more alcoholic drinks for women on the same occasion (i.e., at the same time or within a few hours of each other) on at least one day in the past month. The term "alcohol" as used herein with reference to, for example, a "drink," an "alcoholic drink," or an "alcoholic drink," refers to ethyl alcohol (i.e., ethanol). The terms "alcoholic drink," "drink," or "alcoholic drink," as used herein, are understood in the context of a "standard drink," such as a distilled liquor or blend intended for human consumption, where a "standard drink" is equal to 12 grams of ethanol.

[0024] The term "opioid," as used herein, refers to both natural (opiate) or synthetic (opioid) forms and natural or synthetic mixed opioid agonists / antagonists, including, without limitation, alphamethylfentanyl, alfentanil, buprenorphine, butorphanol, codeine, diacetylmorphine, dihydrocodeine, dihydroetorphine, dihydromorphine, ethylmorphine, etorphine, fentanyl, hydrocodone, hydromorphone, L-acetylmethadol, levorphanol, methadone, meperidine, morphine, nicomorphine, normethadone, noroxycodone, normorphine, norlevorpha, In one embodiment, the "opioid" is selected from the group consisting of morphine, hydrocodone, oxycodone, and codeine; in particular, the opioid is selected from the group consisting of hydrocodone and oxycodone. In one embodiment, the opioid is hydrocodone. In another embodiment, the opioid is oxycodone.

[0025] The term "opioid craving," as used herein, refers to a conscious desire or urge to consume an opioid.

[0026] The term "opioid use," as used herein, refers to opioid consumption.

[0027] The terms "reducing opioid use" or "reducing opioid use" as used herein refer to a reduction in the amount or frequency of opioid use as assessed, for example, by urinalysis (e.g., by measuring urinary opioid metabolites) or by using self-reported opioid use by standardized tools such as the Timeline FollowBack Self-Report (Sobell LC, Sobell MB, 1996, Timeline FollowBack user's guide: A calendar method for assessing alcohol and drug use. Addiction Research Foundation, Toronto, Ontario, Canada; J. Anal. Toxicolo., 2002, 26:393-400).

[0028] The term "opioid abstinence" or "withdrawing from opioids" as used herein refers to not taking opioids. The term "promoting opioid abstinence" or "promoting opioid abstinence" as used herein refers to helping maintain abstinence from opioid use, especially after not taking opioids for at least one day, e.g., for a period of at least one week, two weeks, three weeks, one month, three months, six months or more, especially at least one week or more, e.g., two weeks.

[0029] The term "opioid use relapse" or "opioid consumption relapse", as used herein, refers to opioid intake (i.e., taking an opioid) after a period of opioid abstinence, e.g., after at least one day or more, e.g., 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months or more of opioid abstinence.

[0030] The term "preventing opioid use relapse" or "preventing opioid consumption relapse" as used herein refers to the prevention of opioid intake by an OUD patient after the patient has stopped taking opioids, particularly after one or more days of not taking opioids. In some embodiments, the term encompasses a permanent cessation of opioid intake. In other embodiments, the term encompasses a delay in resumption of opioid intake compared to the time to resumption by a subject not administered a compound of the invention. The delay in resumption may be, for example, several days (e.g., 2, 3, 4, 5, 6, 7 days), several weeks (e.g., 1, 2, 3 weeks), several months (e.g., 1, 2, 3, 4, 5, 6 months), or longer.

[0031] The term "psychosocial or behavioral therapy" as used herein includes, but is not limited to, cognitive behavioral therapy (e.g., as described in Arch. Gen. Psychiatry 1999;56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav 2009;23(1):168-174), contingency management-based therapy (e.g., as described in Psychol Addict Behav 2009;23(1):168-174; J. Consul. Clin. Psychol. 2005;73(2):354-59; or Case Reports in Psychiatry, Vol. 2012, Article ID 731638), community reinforcement approach-based therapy (e.g., Drug Alcohol Dependence Therapy, Vol. 2012, Article ID 731638), and therapies based on the psychiatric treatment (e.g., Drug Alcohol Dependence Therapy, Vol. 2012, Article ID 731638). 2004;74:1-13), motivational interviewing-based therapies (e.g. as described in J. Consul. Clin. Psychol. 2001;69(5):858-62), motivational enhancement-based therapies (e.g. as described in Drug Alcohol Depend 2007,91:97-101) or meditation-based therapies, such as transcendental meditation-based therapies (e.g. as described in Addiction 2004;99(7):862-874 or J. Consul. Clin. Psychol. 2000;68(3):515-52); in particular contingency management-based therapies.

[0032] The term "standardized psychological treatment" or "standardized psychological support" as used herein refers to standard counseling sessions, e.g., once a week, particularly counseling focused on opioid consumption.

[0033] The term "computer-assisted" in the phrase "psychosocial or behavioral therapy is computer-assisted" as used herein refers to psychosocial or behavioral therapy that includes the use of electronic tools, such as online tools, smartphones, wireless devices, or health applications. In one embodiment, the term "computer-assisted" in the phrase "psychosocial or behavioral therapy is computer-assisted" as used herein should be understood as "computer-implemented" (i.e., the psychosocial or behavioral therapy is computer-implemented).

[0034] The term "administered with a meal" refers to any food with caloric content, e.g., solid or liquid. A dosage of mavoglurant, or a pharma- ceutically acceptable salt thereof, may be administered to a subject, e.g., 30 minutes before a meal to, e.g., 1 hour after a meal. In particular, administration of mavoglurant, or a pharma- ceutically acceptable salt thereof, occurs immediately after a meal to up to about 30 minutes after a meal.

[0035] The term "genetic variation" refers to a change in a gene sequence compared to a reference sequence (e.g., a commonly found and / or wild type sequence). A genetic variation can be a recombination event or a mutation, such as a substitution / deletion / insertion event, such as a point mutation and a splice site mutation. In one embodiment, the genetic variation is a genetic variation of mGluR5.

[0036] The terms "treat", "treating", "treatment" or "therapy" as used herein mean to achieve a beneficial or desired result, e.g., a clinical result. A beneficial or desired result can include, but is not limited to, the alleviation of one or more symptoms, such as anxiety or depression symptoms associated with opioid use disorder, by a patient with opioid use disorder as defined herein, particularly a patient with opioid use disorder abstinent from opioids as defined herein. One aspect of treatment is, for example, that the treatment should have minimal adverse effects on the patient, e.g., the drug used should have a high safety level, e.g., without causing side effects of previously known treatment regimens. The term "alleviation", as used herein, e.g., with respect to symptoms of a condition, refers to reducing at least one of the frequency and breadth of the symptoms of the condition in the patient.

[0037] The term "concurrent" as used herein refers to both simultaneous and sequential administration, for example, with respect to "concurrent with methadone or buprenorphine treatment."

[0038] As used herein, the term "subject" refers to a mammalian organism, preferably a human being, male or female.

[0039] As used herein, the term "patient" refers to a subject suffering from a disease and who may benefit from treatment.

[0040] As used herein, a subject is "in need of" a treatment if such subject (patient) would benefit biologically, medically, or in terms of quality of life from the treatment.

[0041] The term "pharmaceutical composition" is defined herein to refer to a mixture or solution containing at least one active ingredient or therapeutic agent that is administered to a subject to treat a particular condition (i.e., a disease, disorder or condition or at least one of its clinical symptoms) that affects the subject.

[0042] As used herein, the term "pharmaceutically acceptable excipient" includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as would be known to one of skill in the art (see, e.g., Remington's Pharmaceutical Sciences, 22). nd (See Ed. Mack Printing Company, 2013, pp. 1049-1070.) Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

[0043] The terms "drug", "active substance", "active ingredient", "pharmaceutical active ingredient", "active agent", or "therapeutic agent" should be understood to mean a compound in free form or in the form of a pharmaceutically acceptable salt, particularly a compound of the type specified herein. In particular, reference to mavoglurant or a pharmaceutically acceptable salt thereof in combination with a further active agent as used herein (e.g., in any of the above embodiments (a)-(j) or in any of the claims below) includes, but is not limited to, a GABAergic agent (e.g., topiramate, tiagabine, baclofen, or vigabatrin), a cannabinoid CB1 receptor antagonist, a dual dopamine-serotonin releaser (e.g., PAL-287), a noradrenaline drug (e.g., doxazosin, disulfiram, or nepicastat), a 5-HT 1A It refers to masvoglurant in combination with at least one further active agent selected from the group consisting of a receptor partial agonist (e.g., buspirone), an MU opioid agonist (e.g., buprenorphine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharmaceutically acceptable salt thereof.

[0044] The term "immediate release form" refers to a pharmaceutical composition designed to release an active agent immediately after administration in vivo.

[0045] The term "modified release form" refers to a pharmaceutical composition that does not release an active agent immediately, but rather provides a sustained, delayed, continuous, gradual, extended or pulsed release, thus characteristically altering drug plasma levels compared to immediate release forms. The term "modified release form" includes controlled release forms, sustained release forms, extended release forms, and long acting forms; particularly forms described as sustained release forms.

[0046] The term "combination" or "pharmaceutical combination" refers to either a mixed combination in one unit dosage form (e.g., capsule, tablet, caplet, or granule), a non-mixed combination, or a kit-of-parts for combination administration, wherein a compound of the present invention and one or more combination partners (e.g., another drug as specified herein, also referred to as a "pharmaceutical active ingredient," "therapeutic agent," or "co-drug") may be administered independently simultaneously or separately within time intervals, particularly those time intervals that allow the combination partners to exhibit a cooperative effect, e.g., a synergistic effect. The terms "co-administration" or "co-administration," and the like, as used herein, are meant to encompass administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include therapeutic regimens in which the agents are not necessarily administered by the same route of administration or are not administered simultaneously. The term "mixed combination" means that the active ingredients, e.g., a compound of the present invention, and one or more combination partners are both administered simultaneously to a patient in the form of a single entity or dosage. The term "non-multidrug combination" means that the active ingredients, e.g., a compound of the present invention and one or more combination partners, are either both administered simultaneously to a patient as separate entities or administered sequentially without any particular time limit, where such administration provides therapeutically effective levels of the two compounds in the patient's body.

[0047] The compounds of the present invention may be administered separately by the same or different routes of administration, or together in the same pharmaceutical composition as the other agent. In the combination therapy of the present invention, the compounds of the present invention and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compounds of the present invention and the other therapeutic agent may be combined into a combination therapy: (i) before release of the combination product to the physician (e.g., in the case of a kit containing the compounds of the present invention and the other therapeutic agent); (ii) by the physician (or under the physician's guidance) immediately prior to administration; (iii) within the patient's own body, for example, during sequential administration of the compounds of the present invention and the other therapeutic agent.

[0048] As used herein, the terms "a," "an," "the," and similar terms used in connection with the present invention (particularly in connection with the claims) are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0049] Any examples provided herein, or the use of illustrative language (e.g., "such as"), are intended merely to better clarify the invention, and do not pose limitations on the scope of the invention as originally claimed.

[0050] As used herein, the compound of the present invention, also known as Compound (I), as used herein above and hereinafter, has the formula: [ka] The mGluR5 antagonist (-)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester, also referred to as (-)-(3aR,4S,7aR)-4-hydroxy-4-[2-(3-methylphenyl)ethynyl]perhydroindole-1-carboxylic acid methyl ester, also known as masvoglurant, can be prepared, for example, as described in WO 2003 / 047581, for example in Example 1, or as described in WO 2010 / 018154. WO 2003 / 047581 (incorporated herein by reference) also describes its in vitro biological data, as per page 7. As used herein, masvoglurant refers to the free form, and any reference to its pharmaceutically acceptable salt refers to its pharmaceutically acceptable acid addition salt. Thus, as used herein, the term mavoglurant, or a salt thereof, e.g. a pharma- ceutically acceptable salt thereof, as used in the context of the present invention (particularly in the context of any of the above or following embodiments and claims), unless otherwise indicated herein, should be interpreted as encompassing both the free form and a pharma- ceutically acceptable salt thereof.

[0051] In one embodiment, compound (I) is also intended to represent an isotopically labeled form. Isotopically labeled compounds have the structure depicted in the formula above, except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen, i.e., the formula: [ka] [In the formula, each R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R18 , R 19 , R 20 , R 21 , R 22 and R 23 are independently selected from H or deuterium; provided that at least one deuterium is present in the compound. In other embodiments, multiple deuterium atoms are present in the compound.

[0052] In addition, certain isotopes, especially deuterium (i.e. 2 Incorporation of H or D) may provide certain therapeutic advantages resulting from increased metabolic stability, for example increased in vivo half-life or reduced dosage requirements or improved therapeutic index or tolerability. It is understood that deuterium in this context is considered a substituent of the compounds of the present invention. The concentration of deuterium may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a designated isotope. When a substituent in a compound of the present invention is designated as deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0053] Other examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen other than deuterium, isotopes of carbon, nitrogen, oxygen, and fluorine, e.g., 3 H, 11 C. 13 C. 14 C.15 N, 18 Thus, the present invention relates to, for example, 3 H and 14 Radioisotopes such as C, or 2 H and 13 It should be understood that the present invention includes compounds incorporating one or more of any of the aforementioned isotopes, including those in which a non-radioactive isotope such as C is present. Such isotopically labeled compounds may be used for metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H or 3 3H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiation treatment of patients. In particular, PET or SPECT studies include 18 F or labeled compounds may be particularly desirable. Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to the described preparations of the compounds of the invention, by substituting the appropriate isotopically labeled reagent for the non-labeled reagent previously used.

[0054] As used herein, the term "free form" or "free forms" refers to a compound in a non-salt form, such as the base free form or the acid free form of the respective compound, e.g., a compound specified herein (e.g., mavoglurant or a further pharma- ceutical active ingredient, e.g., as defined herein).

[0055] As used herein, the term "salt", "salts" or "salt form" refers to an acid addition salt or a base addition salt of the respective compound, for example, a compound specified herein (e.g., mavoglurant or a further medicament active ingredient, e.g., as defined herein). "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compound, which are typically not biologically or otherwise undesirable. A compound as specified herein (e.g., mavoglurant or a further medicament active ingredient, e.g., as defined herein) may be capable of forming acid salts and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. The compounds of the present invention are capable of forming acid addition salts, and therefore, as used herein, the term pharmaceutically acceptable salts of mavoglurant means pharmaceutically acceptable acid addition salts of mavoglurant.

[0056] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0057] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0058] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0059] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0060] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of Groups I to XII of the Periodic Table, in certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts.

[0061] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Some organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0062] Pharmaceutically acceptable salts can be synthesized from basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of an appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.) or by reacting the free base form of the compound with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where feasible. Further lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 22 nd edition, Mack Publishing Company (2013); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, 2011, 2 nd For more information, please refer to the IEEE International Conference on Statistical English (ISI) .

[0063] The compounds specified herein (e.g., mavoglurant or further medicament active ingredients, e.g., as defined herein) can be administered by conventional routes, in particular orally, such as in the form of tablets, capsules, caplets or granules, which can be prepared according to pharmaceutical techniques as known in the art (see, e.g., "Remington Essentials of Pharmaceutics, 2013, 1 st Edition, edited by Linda Felton, Pharmaceutical Press 2012, ISBN 978 0 85711 105 0; in particular Chapter 30), where pharmaceutical excipients are, for example, those described in “Handbook of Pharmaceutical Excipients, 2012, 7 th Edition, edited by Raymond C. Rowe, Paul J. Sheskey, Walter G. Cook and Marian E. Fenton, ISBN 978 0 85711 027 5. In particular, WO 2014 / 199316 describes formulations comprising mavoglurant, in particular modified release formulations thereof, and more particularly the Examples, Detailed Description and Claims therein are incorporated herein by reference.

[0064] The pharmaceutical composition or combination of the present invention may be in a unit dosage form (e.g., tablet, capsule, caplet or granule) containing 1 mg to 300 mg, in particular 50 mg to 200 mg, for example 50 mg to 100 mg, more particularly 200 mg, of mavoglurant (based on the amount of mavoglurant in free form, if a salt thereof is used, this amount will be adapted accordingly; in particular mavoglurant is in free form). For the above-mentioned uses / treatment methods, the appropriate dosage may vary depending on various factors, such as age, weight, sex, route of administration or salt used. For example, for a patient weighing 50 to 70 kg, the indicated daily dosage is, for example, 200 mg / bid (based on the amount of mavoglurant in free form, if a salt thereof is used, this amount will be adapted accordingly).

[0065] Abbreviation BE=benzoylecgonine EtG = ethyl glucuronide CM = Contingency Management DSM 5=Diagnostic and Statistical Manual of Mental Disorders,5th Ed OUD = Opioid Use Disorder PK = pharmacokinetics TLFB=Timeline Follow Back mg = milligrams bid=bid=twice a day (2 times) mmHg = millimeter of mercury msec=milliseconds HIV = Human Immunodeficiency Virus ELISA = Enzyme-Linked Immunosorbent Assay ECG = electrocardiogram QT = time between the beginning of the Q wave and the end of the T wave T wave = positive deflection after each QRS complex ST wave = the time between the start of the S wave and the end of the T wave QRS = time between the start of the Q wave and the end of the T wave QTcF = Fridericia QT correction formula SoA = standard of care SSRI = selective serotonin reuptake inhibitors C-SSRS = Columbia Suicide Severity Rating Scale hCG = human chorionic gonadotropin AST = aspartate aminotransferase ALT = alanine aminotransferase ULN = upper limit of normal GGT = gamma-glutamyl transpeptidase AV block = atrioventricular block UDS=urine drug screen MDMA = 3,4-methylenedioxy-methamphetamine MDEA = 3,4-methylenedioxy-N-ethylamphetamine MDA = 3,4-methylenedioxy-amphetamine ℃ = degrees Celsius cm = centimeters ip=intraperitoneal po = by mouth, orally PEG = Evaluation of Pain Intensity (P), Enjoyment of Life (E), and General Activity (G) NRS = Numeric Rating Scale TLFB-Opioid = A longitudinal self-report diary of opioid use COWS=Clinical Opiate Withdrawal Scale OCS = Opioid Craving Scale NOSE = Numerical Opioid Adverse Reactions QTcF = QT interval corrected by Fridericia's formula QTcB = QT interval corrected by Bazett's formula GGT = gamma glutamyltransferase ULN = upper limit of normal hCG = human chorionic gonadotropin FDA = Food and Drug Administration

[0066] The following examples are offered to illustrate the invention without limiting its scope. EXAMPLES

[0067] Example 1: The term "Compound (I)" (i.e., mavoglurant) as used in connection with these examples refers to the free form. The term "Compound (III)" refers to 2-methyl-6-(phenylethynyl)-pyridine (i.e., MPEP) as used in connection with these examples refers to the free form.

[0068] Example 1a: Opiate Tolerance Test in Mice (Hot Plate) The method for detecting tolerance to analgesia follows that described by Fernandes et al. (Naunyn-Schmiedeberg's Arch. Pharmacol., 297, 53-60, 1977).

[0069] Mice were placed on a hot metal plate maintained at 54°C and surrounded by a Plexiglas cylinder (height: 13 cm; diameter: 19 cm) (Bioseb: model PE34). The latency to the first paw lick was measured (maximum: 30 sec). Morphine (32 mg / kg ip) or vehicle was administered twice daily for 6 days (at approximately 9:00 and 15:00), followed by morphine 8 mg / kg ip (or saline) 30 min before testing on the 7th day to assess morphine tolerance.

[0070] Compound (I) was evaluated at three doses (1, 3, and 10 mg / kg) administered acutely po to morphine-tolerant mice 60 min prior to testing on day 7. The experiment included an appropriate control group to evaluate possible effects of the test substance on morphine tolerance. Compound (III) was evaluated at one dose (10 mg / kg) administered under the same experimental conditions and used as a comparison substance.

[0071] Ten mice were tested per group. Studies were performed in a blinded manner. Data were analyzed by comparing appropriate control and treatment groups using unpaired Student's t-test.

[0072] result: Compound (III) (10 mg / kg) administered po 60 min prior to testing on day 7 significantly increased paw lick latency (+32%, p<0.05) in animals receiving vehicle po and morphine (32 mg / kg) ip twice daily on days 1 through 6 compared to animals receiving morphine on days 1 through 6 (Figure 1).

[0073] Compound (I) (1 mg / kg) administered po 60 min prior to testing on day 7 significantly increased paw lick latency (+44%, p<0.01) in animals receiving vehicle po and morphine (32 mg / kg) ip twice daily on days 1 through 6 compared to animals receiving morphine on days 1 through 6. There were no significant effects at 3 or 10 mg / kg (Figure 2).

[0074] Conclusion: These results suggest that acute po administration of Compound (I) (1 mg / kg) and Compound (III) (10 mg / kg) significantly reduced the development of morphine tolerance.

[0075] Example 1b: Assessment of the efficacy of masvoglurant on reinstatement of opiate dependence using an intravenous self-administration model in Sprague-Dawley rats Several preclinical models have been developed to assess the abuse liability of compounds and / or to determine their effectiveness in treating drug dependence.Intravenous self-administration is widely recognized as a valid model for assessing the abuse liability of various drugs.For example, this model can be used to assess whether compounds are effective in reducing opiate self-administration.This model can also be used to determine the effectiveness of compounds in preventing relapse after extinction of conditioned response to opiates.

[0076] method: Surgery and Opiate Training: Rats were trained to press a lever for food and then fitted with an intravenous catheter. After acquiring the lever-press response, rats were allowed to self-administer opiates (e.g., morphine, heroin, remifentanil) by pressing a lever that had been previously paired with food in exchange for drug solution (FR1-3, i.e., 1-3 lever presses per opiate infusion).

[0077] Test Compound Mavoglurant (free form) can be formulated in 0.5% methylcellulose (MC) at 1, 3, and 10 mg / kg and administered orally in a dose volume of 1 ml / kg 60 minutes prior to testing.

[0078] MPEP can be formulated in 0.5% methylcellulose (MC) at 10 mg / kg and administered orally in a dose volume of 1 ml / kg 30 minutes prior to testing.

[0079] method: Phase I: Acute effects of mavoglurant on opiate self-administration in rats After stable responding is established for the training substances, vehicle, mavoglurant (1, 3, 10 mg / kg), MPEP (20 mg / kg ip 30 min) are assessed during a single test session.

[0080] Phase II: Effects of mavoglurant on cue-induced reinstatement of self-administered responding Feeding training, catheterization, flushing, and injection verification methods will be the same as in Phase I.

[0081] Extinction and cue-induced reinstatement After a stable rate of opiate self-administration is achieved, rats undergo an extinction procedure that is similar to acquisition training except that pressing the active lever results in an injection of saline instead of opiate.

[0082] Once extinction is achieved (eg, a significant reduction in active lever pressing), rats are pretreated with vehicle, test article, or comparator prior to the cued reinstatement session (tone and light cue).

[0083] Conclusion: As shown in Example 1a above herein, mavoglurant reduces the tolerance to the analgesic effect of opioids (morphine). The long-term use or misuse of opioid drugs is closely related to the development of addiction, dependence and tolerance (Morgan&Christie Brit J Pharm 2011,164:1322-1334). Tolerance is characterized by the reduction in drug efficacy and the need for increased drug doses. Based on this knowledge and the results of Example 1a, it is therefore plausible that mavoglurant is effective in models of opiate self-administration and opiate relapse.

[0084] Example 2: Assessment of the effects of mavoglurant on opioid dependence using a remifentanil intravenous self-administration model in Sprague-Dawley rats animal Adult male Sprague-Dawley rats (220-320 g on arrival) from Harlan Laboratory (Indiana, USA) were used. From the time of arrival until the end of the study, rats were housed singly in macrolon cages (SAFE, 89290 Augy, France) lined with wood litter. Additional environmental enrichment (nesting material, gnawing material, and tunnels, up to the surgical stage) was provided. The animal room was maintained under artificial lighting (12 h) between 07:00 and 19:00, with a controlled ambient temperature of 22 ± 2 °C and a relative humidity between 30 and 70%.

[0085] Test Compound Remifentanil hydrochloride (Ultiva®), (3.2 μg / kg / infusion) was dissolved in saline and administered iv in a dose volume of 0.519 mL / kg (0.9% NaCl).

[0086] Mavoglurant (free form) was formulated in 0.5% methylcellulose (MC) at 3, 10, and 30 mg / kg and administered orally in a dose volume of 5 ml / kg 30 minutes before testing.

[0087] MPEP hydrochloride [2-methyl-6-(phenylethynyl)-pyridine HCl] was formulated in 0.5% methylcellulose (MC) at 20 mg / kg and administered orally in a dose volume of 5 ml / kg 30 minutes prior to testing.

[0088] Buprenorphine hydrochloride (Buprecare® or bupaq® Multidose 0.3 mg / mL) was diluted in saline and administered subcutaneously in a dose volume of 5 ml / kg.

[0089] Device Experiments are conducted in 25.5 x 29.5 x 19 cm high operant chambers (MED Associates, Inc., St. Albans, Vermont, USA) placed in soundproof, ventilated cubicles. Each chamber is equipped with a single lever located to the right of a 5 x 5 cm opening through which pelleted food is dispensed from the food hopper. A 2.5 cm translucent stimulus light source is located above the food hopper. Experimental events are managed and monitored, and data are collected and stored by a computer system (MED-PCIV, MED Associates, Inc.) and associated interfaces (MED Associates, Inc.).

[0090] method Acute effects of mavoglurant on remifentanil self-administration in rats Feeding training and surgery Upon arrival, rats are food restricted (15 g / rat / day, then 18 g / rat / day post-surgery) for 5-7 days, after which lever training begins under a fixed-ratio reinforcement 1 (FR1) schedule of food pellet presentation (AIN-76A Rodent Tablet 45 mg, Cambridge University). A daily session comprises 45 min or 20 food presentations, whichever occurs first. Once rats have received 20 food pellets in a single session under the FR1 schedule (typically within 5 days), food training is stopped and a chronic indwelling iv femoral catheter is implanted.

[0091] Acquisition of remifentanil self-administration At least 3 days after surgery, daily sessions (usually of maximum duration 120 min) were performed during which rats received up to 50 iv infusions of training substance (remifentanil 3.2 μg / kg / infusion) under a fixed ratio reinforcement (FR1) schedule. Just before the start of the daily session, rats received one non-contingent (i.e., priming) infusion of remifentanil 3.2 μg / kg / infusion. A distinctive visual cue was presented for the period allowing for the iv infusion. Each infusion was followed by a 30 s time-out during which the chamber was kept dark and no consequences were set for lever pressing.

[0092] Pharmacological treatment with mavoglurant After responding to the training substance (remifentanil 3.2 μg / kg / infusion) had stabilized (i.e., the number of infusions delivered per session did not vary by more than ±30% over three consecutive sessions), vehicle (po-30 min), three doses of mavoglurant (3, 10, and 30 mg / kg po 30 min), a dose of MPEP (20 mg / kg po 30 min), and a dose of buprenorphine (0.4 mg / kg sc 30 min) were assessed during one test session. N=14 (total number of rats) Vehicle (0.5% methylcellulose) Mavoglurant 3mg / kg Mavoglurant 10mg / kg Mavoglurant 30 mg / kg MPEP 20mg / kg Buprenorphine 0.4 mg / kg

[0093] result: Effect of mavoglurant on remifentanil self-administration As shown in Figure 3A, mavoglurant (3, 10, or 30 mg / kg) administered po 30 min prior to one remifentanil 3.2 μg / kg / infusion session did not significantly affect the mean number of remifentanil infusions. Lever pressing rate (rate of lever pressing reported as number of responses / second / session) was dose-dependently reduced by treatment with mavoglurant (3, 10, and 30 mg / kg; 0.048 ± 0.019, 0.035 ± 0.010, and 0.026 ± 0.007, respectively) compared with remifentanil 3.2 μg / kg / infusion or vehicle placebo treatment (0.077 ± 0.031), but did not reach statistical significance (P > 0.05) (Figure 3B).

[0094] The mGluR5 antagonist MPEP, 20 mg / kg administered po 30 min prior to one remifentanil 3.2 μg / kg / infusion session, did not significantly affect the mean number of remifentanil infusions (FIG. 3A). The lever pressing rate was also not significantly reduced (0.039 ± 0.011 responses per second) (p > 0.05) compared to the previous remifentanil 3.2 μg / kg / infusion only phase or compared to the vehicle test session (FIG. 3B).

[0095] The opioid receptor partial agonist buprenorphine markedly and significantly reduced the mean number of remifentanil infusions (Figure 3A). Lever press rate was reduced by 0.038 ± 0.025 responses per second, but this did not reach statistical significance (p>0.05, compared to the previous remifentanil 3.2 μg / kg / infusion only phase or compared to the vehicle test session) (Figure 3B).

[0096] Example 3: Evaluation of Mavoglurant in Cue-Induced Reinstatement of Remifentanil Seeking in Rats Feeding training and surgery The methods of feeding training, catheter surgery, flushing, and injection confirmation were the same as those in Example 2.

[0097] Acquisition of remifentanil self-administration Beginning at least 3 days after surgery, daily 2-h sessions (Monday through Friday) were conducted during which rats received up to 200 iv infusions of baseline drug (remifentanil, 3.2 μg / kg / infusion) under a FR1 schedule of lever pressing. Only one lever was active per rat. Responses on the inactive lever were recorded, but no consequences were assigned to responses. Just before the start of the daily session, rats received a noncontingent (i.e., priming) infusion of remifentanil 3.2 μg / kg / infusion. The room lights were turned on for the period during which iv infusions were allowed. During these sessions, if the rat pressed the active lever, a cue light was turned on for 3 seconds. Two seconds after the cue light was turned on, a tone signal (2900 Hz sonalert, approximately 79 dB) was turned on for 1 second, along with activation of the infusion pump. Each injection was followed by a 30-second time-out during which the chamber was kept dark and no consequences were established for lever pressing. During the time-out period, responses on the active lever were recorded, but no pump actuation / remifentanil injection occurred.

[0098] Extinction and cue-induced reinstatement Animals that reached the criteria described above were included in the first extinction phase. Although rats were connected to the infusion pump during these sessions, extinction sessions differed from self-administration sessions in that active lever pressing no longer resulted in drug infusion, cue light / tone presentation, or infusion pump noise (pump was turned off). These sessions lasted 2 hours and were conducted daily (Monday to Friday) for up to 15 days. During one of these extinction sessions, rats were pretreated with vehicle (po) to habituate to drug administration. Rats were considered to have extinguished behavior when, during two consecutive sessions, they exhibited an average of less than 12 active lever presses or a maximum of 25% of the number of active lever presses that occurred during the last two sessions of remifentanil self-administration, whichever occurred first.

[0099] First cue-induced reinstatement: On the next working day, rats are pretreated with vehicle, macoglurant (3 and 10 mg / kg), MPEP (20 mg / kg / ) po 30 min prior to the cued reinstatement session. The cued reinstatement session is initiated with a tone (1 s) and a cue light (3 s). The remainder of the 2-h session is identical to the self-administration session except that no remifentanil is administered and there is no 30 s time-out (cue light and tone are presented simultaneously with the active lever press). Lever presses were recorded.

[0100] Second extinction: rats were subjected to a second extinction period for up to 15 days. As with the first extinction period, rats were connected to the infusion pump during these sessions, but extinction sessions differed from self-administration sessions in that active lever pressing no longer resulted in drug infusion, presentation of a cue light / tone, or infusion pump noise (the pump was turned off).

[0101] Second cue-induced reinstatement: As in the first cue-induced reinstatement session, rats were pretreated with vehicle, mavoglurant (3 and 10 mg / kg), or MPEP (20 mg / kg / ) po 30 min prior to the cued reinstatement session. The cued reinstatement session was initiated by a tone (1 s) and a cue light (3 s). The remainder of the 2-h session was identical to the self-administration session, except that no remifentanil was administered and there was no 30 s time-out (cue light and tone presented simultaneously with the active lever press). Lever presses were recorded. The number of active lever presses obtained during the reinstatement session was compared to the extinct lever response, which was considered as the criterion of reinstatement.

[0102] result: Effects of mavoglurant on cue-induced reinstatement of self-administration MPEP at 20 mg / kg significantly reduced the number of active lever presses compared to the vehicle condition (p<0.05), but did not significantly affect the number of inactive lever presses compared to vehicle (Figure 4C).

[0103] Mavoglurant at 10 mg / kg significantly decreased the number of active lever presses compared to the vehicle condition (p<0.01). Similarly, mavoglurant at 10 mg / kg significantly decreased the number of inactive lever presses compared to the vehicle condition (p<0.05) (Figure 4A). No significant effect was observed in the group treated with mavoglurant at 3 mg / kg po (Figure 4B).

[0104] This study demonstrated that 10 mg / kg masvoglurant was effective in reducing cue-induced relapse to remifentanil self-administration. Based on these results, it is therefore plausible that masvoglurant attenuates opioid relapse in patients with opioid use disorder.

[0105] [Table 1]

[0106] Test Design This will be a randomized, investigator-blinded, parallel-group, placebo-controlled study in patients with OUD. The study will consist of: a screening period of approximately 21 days, followed by a 7-day baseline; a 98-day outpatient treatment period (a 14-day escalation dose regimen, followed by an 84-day maintenance dose), and finally, an end-of-study visit approximately 14 days after the last test medication administration. The total duration for each patient in the study will be up to approximately 20 weeks.

[0107] Test Visit (Days 1-112): Study visits will be conducted twice weekly as outpatient visits. During these visits, urine samples will be collected for drug testing (opioid and other drug metabolites) as well as safety / efficacy assessments.

[0108] Screening (days -28 to -8):Patients will be initially eligible for inclusion in the study, including safety testing and other clinical trials. Patients who meet the eligibility criteria at screening will be allowed to undergo baseline evaluations.

[0109] Baseline (days -7 to -1): In addition to safety assessments, patient self-assessments on a variety of scales and questionnaires will be included. During baseline, a self-reported opioid history (TLFB) and two urine samples will be collected on two different days, with the second sample being collected 3 days prior to randomization to indicate abstinence from opioid use.

[0110] Treatment (Days 1-98): On Day 1 after baseline, eligible patients will be randomized in a 1:1 ratio to receive magoglurant (free form) or placebo. Group A - Mavoglurant (free form): for the first 2 weeks, titration regimen: 50 mg bid on days 1 to 7, 100 mg bid on days 8 to 14, then 200 mg bid for 84 days. The dose selected for evaluation in this study (200 mg bid / modified release formulation) was chosen based on safety, tolerability, and pharmacokinetic data from completed mavoglurant studies. · Group B: matching placebo.

[0111] Test Drugs: Take twice daily (bid) with meals, in the morning and evening (approximately 12 hours apart). For all outpatient morning visits, including any test evaluations or PK / urine sample collections, test medication will be self-administered by the patient at the test center and supervised by test personnel. On these days, a standard breakfast will be provided at the test center and consumed by the patient between medication intakes. During the treatment period, patients will also undergo evaluations with various scales and questionnaires, as well as safety assessments and pharmacokinetic sampling 2±1 hours before and after dosing per SoA.

[0112] Urine Sample (Days 1-113):Samples are collected twice per week at the testing center, with tests at least 48 hours apart, e.g., Tuesday and Friday or Monday and Thursday or Tuesday morning and Thursday afternoon. Sample collection is monitored by staff and quantitatively assayed for the presence of opioid and alcohol metabolites [e.g., ethyl glucuronide (EtG)]. Urine samples are collected during the test run: 28 samples from patients continuing treatment for 14 weeks (4 samples at weeks 1-2 of titration); 24 samples at weeks 3-14 (maintenance dose); 4 samples at weeks 15-16 (follow-up), and finally, 1 sample at the end-of-study visit. If a patient is unable to attend the clinic or refuses to provide a sample on the scheduled test date, the sample is considered positive unless an exemption from attendance is given (e.g., illness, other personal reasons). In case of missed or refused samples, samples are collected the next day, if possible.

[0113] Clinical support to ensure medication and protocol compliance: Medication Compliance: Patients will be present at the test facility at the time of test medication administration for the morning dose on PK collection days and all other days including urine sampling assessments. On these days, self-administration of test medication will be supervised by the test personnel and compliance will be ensured by mouth check after medication has been swallowed. To monitor compliance, patients will be provided with an individual medication diary (booklet) to record administration of test medication. Medication compliance will be monitored at least weekly by the investigator and / or test personnel using the number of tablets(s). Medication compliance will be verified by comparing the patient's self-reported data from the medication diary with the total number of tablets in the returned bottle or blister (depending on packaging format). Compliance will be calculated as the total amount of tablets taken divided by the total amount planned to be taken during the treatment phase. If the investigator deems appropriate, patients may be contacted further during outpatient periods to confirm compliance.

[0114] Group Patients aged 18-65 years who use opioids and have been diagnosed with OUD will be included in the study.

[0115] Statistical models and analytical methods Key variables: The percentage of days of opioid use during the treatment period (days 1 to 98)

[0116] For each patient, the percentage of days of opioid use is calculated by dividing the number of days of opioid use during the treatment period, i.e., 98 days for completers and, in case of early discontinuation of test treatment, the number of days between day 1 and the last dose. This is considered a continuous variable. Opioid consumption is recorded daily using the TLFB during the entire test (yes / no).

[0117] A Bayesian analysis is performed on the percentage of days of opioid use, which is assumed to be a continuous outcome with normally distributed errors. A linear model is fitted with treatment factor and past consumption of opioids as a covariate. Non-informative priors are used for all parameters. Past consumption of opioids is the percentage of days of opioid use over the 3 months preceding the screening visit, which is assessed using TLFB. The model determines the posterior probability that the difference in the percentage of days of opioid use between mavoglurant and placebo is <0 and that it is <-10%. Based on the literature in this indication, a difference of 10% in days is considered a minimally clinically meaningful effect, and a difference of 20% is a very promising effect. The test shows positive evidence of efficacy if the following two criteria are met: 1. There is at least a 90% probability that the difference in the proportion of opioid use days between mavoglurant and placebo is <0 2. There is at least a 50% probability that the difference in the proportion of opioid use days between mavoglurant and placebo will be <-10%

[0118] If the distribution of the data is not normal, sensitivity analyses will be performed using other models such as negative binomial regression. In addition, profiles of consumption over time will be compared between treatment groups through the analysis of longitudinal data (weekly use) using repeated measures mixed models.

[0119] Secondary variables: The proportion of negative UDS over the treatment period will be analyzed in the same manner as the primary variable. Safety and PK are secondary endpoints for this study.

Claims

1. A compound comprising magglurant or a pharma- ceutical acceptable salt thereof. Medications for reducing opioid use by people with opioid use disorder.

2. A compound comprising magglurant or a pharma- ceutical acceptable salt thereof. Medications for facilitating opioid abstinence in patients with opioid use disorder.

3. A pharmaceutical for reducing opioid use by a patient with opioid use disorder as described in claim 1, or a pharmaceutical for promoting opioid abstinence by a patient with opioid use disorder as described in claim 2, Opioid use disorder is associated with inhaling opioids (i.e., smoking), intravenous opioids, nasal inhalation of opioids, or oral formulations of opioids.

4. A pharmaceutical for reducing opioid use by a patient with opioid use disorder as described in claim 1, or a pharmaceutical for promoting opioid abstinence by a patient with opioid use disorder as described in claim 2, Medications where the opioid use disorder is comorbid with a psychiatric disorder selected from the group consisting of antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, and recreational eating disorder.

5. A pharmaceutical for reducing opioid use by a patient with opioid use disorder as described in claim 1, or a pharmaceutical for promoting opioid abstinence by a patient with opioid use disorder as described in claim 2, A pharmaceutical agent, wherein said pharmaceutical agent is administered in combination with a standardized psychological treatment.

6. A pharmaceutical for reducing opioid use by a patient with opioid use disorder as described in claim 1, or a pharmaceutical for promoting opioid abstinence by a patient with opioid use disorder as described in claim 2, The pharmaceutical agent is used in combination with a psychosocial or behavioral therapy or a combination thereof.

7. A pharmaceutical for reducing opioid use by a patient with opioid use disorder as described in claim 1, or a pharmaceutical for promoting opioid abstinence by a patient with opioid use disorder as described in claim 2, The pharmaceutical agent is used in combination with a psychosocial or behavioral therapy or a combination thereof; The pharmaceutical product, wherein the psychosocial therapy or the behavioral therapy is computer-assisted.

8. A pharmaceutical for reducing opioid use by a patient with opioid use disorder as described in claim 1, or a pharmaceutical for promoting opioid abstinence by a patient with opioid use disorder as described in claim 2, The pharmaceutical agent, wherein said pharmaceutical agent is used in combination with methadone or buprenorphine treatment.

9. A pharmaceutical for reducing opioid use by a patient with opioid use disorder as described in claim 1, or a pharmaceutical for promoting opioid abstinence by a patient with opioid use disorder as described in claim 2, A pharmaceutical product in which magglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent.

10. A pharmaceutical for reducing opioid use by a patient with opioid use disorder as described in claim 1, or a pharmaceutical for promoting opioid abstinence by a patient with opioid use disorder as described in claim 2, The pharmaceutical agent, wherein the patient has a genetic variation associated with a substance use disorder.

11. A pharmaceutical for reducing opioid use by a patient with opioid use disorder as described in claim 1, or a pharmaceutical for promoting opioid abstinence by a patient with opioid use disorder as described in claim 2, A pharmaceutical product in which magglurant, or a pharma- ceutically acceptable salt thereof, is administered in an immediate release or modified release form.

12. A pharmaceutical for reducing opioid use by a patient with an opioid use disorder as described in claim 1, or a pharmaceutical for promoting opioid abstinence by a patient with an opioid use disorder as described in claim 2, A pharmaceutical product, wherein magglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / b.i.d. to 200 mg / b.i.d.

13. A pharmaceutical for reducing opioid use by a patient with opioid use disorder as described in claim 1, or a pharmaceutical for promoting opioid abstinence by a patient with opioid use disorder as described in claim 2, Opioid use disorder associated with recreational drinking, medicines.

Images