Use of mGluR5 antagonist for treating analgesic tolerance of opioids

Abstract

The present invention relates to the use of mGluR5 antagonists for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of January 28, 2020, Chinese patent application number 202080008828.5 and an invention name of “Use of mGluR5 antagonists for treating opioid analgesic tolerance”, claiming the priority of US 62 / 798,415. Technical Field

[0002] The present invention relates to the use of mGluR5 antagonists for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain. Background Art

[0003] Pain management is a major healthcare challenge that requires a careful balance between pain control and associated adverse events. In Europe, one fifth of the population suffers from chronic pain. In addition, pain-related diseases are increasing, and only one-third to two-thirds of chronic pain patient populations report >50% pain relief (Trends in Neurosciences, 2014, Vol. 37, No. 3, 146).

[0004] Opioids (such as morphine) are powerful analgesics for treating moderate to severe chronic pain of non-malignant or malignant (i.e., cancer) origin. However, although medical guidelines recommend the use of opioid therapy to manage cancer pain, its use for long-term treatment of non-malignant pain is problematic, particularly due to the many adverse events associated (e.g., nausea, vomiting, itching, drowsiness, cognitive impairment, or dry mouth), the development of analgesic tolerance, and the risk of overdose or opioid use disorder. As described in the 2016 CDC (Centers for Disease Control and Prevention USDepartment of Health and Human Services) Guidelines for prescribing opioids for chronic pain [2016 CDC (U.S. Department of Health and Human Services Centers for Disease Control and Prevention) Chronic Pain Opioid Prescription Guidelines], from 1999 to 2014, in the United States, more than 165,000 people died from overdoses associated with opioid analgesics.

[0005] Opioid analgesic tolerance is a recognized pharmacological phenomenon associated with opioid therapy, and its underlying biological mechanisms are still poorly understood (International Journal of Clinical Pharmacology and Therapeutics, 2004, Vol. 42, No. 4, 191). This phenomenon is characterized by a decrease in analgesic efficacy over time, and therefore requires increased opioid administration to maintain analgesia. As the dose of opioids increases, the likelihood of side effects (e.g., respiratory depression, sedation, dizziness, itching, nausea, vomiting, constipation, immunological and hormonal dysfunction) also increases, and the risk of overdose also increases. As reported by the CDC: 1) Doses ≥50 MME / day increase the risk of overdose by at least two times the risk of <20 MME / day; 2) In a national sample of patients with chronic pain who received opioids from the Veterans Health Administration from 2004-2209, patients who died from overdose were prescribed an average of 98 MME / day. Currently, there are no known treatments to reverse opioid analgesic tolerance associated with chronic opioid use in patients with chronic pain. Therefore, finding pharmacotherapy for the treatment of opioid analgesic tolerance is a high medical need and a major clinical challenge. Morphine tolerance has been treated, for example, with ibudilast, minocycline, fluorocitrate, propentofylline, however, the use of these drugs is associated with significant adverse events. Therefore, there is a need to identify new therapeutic agents that can be used to treat opioid analgesic tolerance, particularly drugs that can reverse established tolerance and more particularly do not increase side effects. Summary of the invention

[0006] The present invention relates to the following uses of an mGluR5 antagonist, e.g. as defined herein:

[0007] - Use in the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain;

[0008] - Use in the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance;

[0009] - Use in the treatment of reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain;

[0010] - Use in treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain;

[0011] - Use in the treatment of chronic pain to reverse opioid analgesic tolerance associated with chronic opioid use;

[0012] - Use in the treatment of opioid analgesic tolerance to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain;

[0013] - Use in treatment for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the opioid dose [e.g., daily opioid dose; such as >50 mg oral morphine / day or a daily isoanalgesic dose of another opioid (i.e., morphine milligram equivalents MME / day), such as from 60 mg oral morphine / day or a daily isoanalgesic dose of another opioid (e.g., hydrocodone or oxycodone) to 100 mg oral morphine / day or a daily isoanalgesic dose of another opioid (e.g., hydrocodone or oxycodone)] administered to the patient is reduced (e.g., reduced by 50% or more, such as reduced by 70% or more, for example reduced by 90% or more), and the opioid analgesic effect (i.e., previously achieved by using a higher opioid dose) is maintained. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 :Effect of compound (III) on paw licking latency

[0015] Figure 2 :Effect of compound (I) on paw-licking latency

[0016] Figure 3 :Effect of compound (II) on paw licking latency DETAILED DESCRIPTION

[0017] It has been discovered that mavoglurant may be an ideal candidate for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain, with therapeutic advantages such as one or more of the following:

[0018] i) For example, it reverses opioid analgesic tolerance associated with chronic use of opioids, for example, compared to placebo: for example, it reduces opioid consumption [e.g., a 50% or greater reduction, such as a 70% or greater reduction, e.g., a 90% or greater reduction, of the original opioid consumption per day or week, as compared to placebo; for example, as assessed by using biomarkers of opioid metabolites or by using a patient's self-reported opioid intake (e.g., by using a Timeline Follow Back opioid self-report diary; e.g., Sobell LC et al., The reliability of the timeline followback method applied to drug, cigarette, and cannabis use. Paper presented at the 30 th The analgesic effect was maintained as assessed by the 30th Annual Meeting of the Association for Advancement of Behavior Therapy, New York, NY, November 1996;

[0019] ii) it reduces opioid consumption and maintains analgesia, e.g., compared to placebo, thereby eliminating or reducing (e.g., one or more) withdrawal symptoms associated with opioid use disorder, e.g., as assessed by the Clinical Opiate Withdrawal Scale (COWS, e.g., in Wesson DR et al., Journal of Psychoactive Drugs, 2003 Apr-Jun;35(2):253-9);

[0020] iii) it reduces opioid consumption and maintains analgesia, e.g., compared to placebo, thereby eliminating or reducing (e.g., one or more) craving symptoms associated with opioid use, e.g., as assessed by the Opioid Craving Scale (OCS, e.g., in McHugh RK et al., Drug and Alcohol Dependency, 2014 Dec 1;145:121-6);

[0021] iv) it reduces opioid consumption and maintains analgesia, e.g., compared to placebo, thereby eliminating or reducing (e.g., one or more) side effects associated with opioid use, e.g., as assessed by the Numerical Opioid Side Effect (NOSE, e.g., in Smith HS et al., Med Clin North Am., 2007, 91(2):213-228);

[0022] v) for example, it eliminates or reduces (e.g., a 10% or greater reduction, such as a 30% or greater reduction) the intensity, duration, or frequency of one or more adverse events associated with chronic use of opioids (e.g., respiratory depression, sedation, dizziness, pruritus, nausea, vomiting, constipation), as compared to placebo;

[0023] vi) for example, it reduces the risk of opioid-related overdose associated with chronic opioid use, e.g., as assessed by the Pasero Opioid-induced Sedation Scale (POSS, e.g., in Pasero C, McCaffery M. Pain Assessment and Pharmacologic Management. St Louis: Mosby / Elsevier; 2011. Section IV, Opioid Analgesics; pp. 277-622, compared to placebo;

[0024] vii) for example, it improves global functioning, for example as assessed by the Clinical Global Impressions Scale severity (CGI-S) and improvement (CGI-I) (Psychiatry, 2007, 4(7):28-37), compared to placebo;

[0025] viii) it has a favorable therapeutic profile, such as a favorable safety profile or metabolic profile; for example a favorable profile with respect to off-target effects, psychiatric adverse events, toxicity (e.g. genotoxicity) or cardiovascular adverse events (e.g. blood pressure, heart rate, electrocardiogram parameters).

[0026] Embodiments of the present invention are described below:

[0027] Embodiment (a):

[0028] Example 1a: An mGluR5 antagonist for use in treating opioid analgesic tolerance associated with chronic opioid use in chronic pain.

[0029] Example 2a: An mGluR5 antagonist for use in treating opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance.

[0030] Example 3a: A mGluR5 antagonist for use in reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain.

[0031] Example 4a: An mGluR5 antagonist for use in a treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

[0032] Example 5a: A mGluR5 antagonist for use in the treatment of chronic pain to reverse opioid analgesic tolerance associated with chronic opioid use.

[0033] Example 6a: An mGluR5 antagonist for use in treating opioid analgesic tolerance to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

[0034] Example 7a: An mGluR5 antagonist for use in reducing opioid consumption in chronic pain.

[0035] Example 8a: An mGluR5 antagonist for use in reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the opioid dose [e.g., daily opioid dose] administered to the patient is reduced (e.g., reduced by 50% or more, such as reduced by 70% or more, for example reduced by 90% or more) and the opioid analgesic effect is maintained (i.e., previously achieved by using a higher opioid dose).

[0036] Embodiment 9a: The mGluR5 antagonist for use according to any of the preceding embodiments, wherein the mGluR5 antagonist is administered to patients receiving an opioid dose of >50 mg oral morphine / day or a daily analgesic dose of another opioid (i.e., morphine milligram equivalents (MME) / day), such as patients receiving an opioid dose of from 60 to 100 mg oral morphine / day or a daily analgesic dose of another opioid.

[0037] Embodiment 10a: An mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the chronic pain is associated with an injury (eg, a wound, a burn, or a bone fracture) or a disease (eg, diabetes, multiple sclerosis, arthritis, an autoimmune disease, or an infection).

[0038] Embodiment 11a: An mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the chronic pain is non-malignant chronic pain.

[0039] Example 12a: An mGluR5 antagonist for use according to Example 11a, wherein the non-malignant chronic pain is chronic back pain, such as chronic lower back pain, eg with or without previous spinal surgery.

[0040] Embodiment 13a: An mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.

[0041] Embodiment 14a: An mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the chronic pain is chronic post-surgical neuropathic pain.

[0042] Embodiment 15a: An mGluR5 antagonist for use according to any of the preceding embodiments, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; in particular a modified release form.

[0043] Embodiment 16a: The mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

[0044] Embodiment 17a: A mGluR5 antagonist for use according to any of the preceding embodiments, wherein the mGluR5 antagonist is administered in combination with one or more additional pharmaceutically active ingredients.

[0045] Embodiment 18a: An mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each case, a pharmaceutically acceptable salt thereof.

[0046] Embodiment 19a: The mGluR5 antagonist for use according to Embodiment 18a, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.

[0047] Embodiment 20a: An mGluR5 antagonist for use according to embodiment 19a, wherein the mGluR5 antagonist is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, such as 200 mg / bid.

[0048] Embodiment 21a: The mGluR5 antagonist for use according to Embodiment 18a, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.

[0049] Embodiment 22a: A mGluR5 antagonist for use according to embodiment 21a, wherein the mGluR5 antagonist is administered in an amount from 1 mg / day to 100 mg / day.

[0050] Embodiment 23a: The mGluR5 antagonist for use according to Embodiment 18a, wherein the mGluR5 antagonist is Compound (III) or a pharmaceutically acceptable salt thereof.

[0051] Example 24a: A combination comprising a mGluR5 antagonist and an opioid.

[0052] Embodiment 25a: The combination according to embodiment 24a, wherein the opioid is selected from the group consisting of alpha methylfentanyl, alfentanil, buprenorphine, butorphanol, codeine, diacetylmorphine, dihydrocodeine, dihydroetorphine, dihydromorphine, ethylmorphine, etorphine, fentanyl, hydrocodone, hydromorphone, L-acetylmethadol, levorphanol, methadone, pethidine, morphine, nicomorphine, normethadone, noroxycodone, normorphine, norlevorphanol, oxycodone, oxymorphone, phenazocine, propoxyphene, remifentanil, tramadol, thebaine, tapentadol, levorphanol, sufentanil, pentazocine The opioids are pentazocine, carfentanyl, ohmfentanyl, nocaine, ketobemidone, allylprodine, prodine, dextropropoxyphene, dextromorphamide, benzitramide, piritramide, dipipanone, loperamide, diphenoxylate, nalbuphine, levomethorpha, dezocine, lefetamine and tildine; in particular, the opioid is selected from the group consisting of hydrocodone and oxycodone.

[0053] Embodiment 26a: The combination according to embodiment 24a or 25a, comprising at least one additional active ingredient selected from the group consisting of antidepressants (e.g. tricyclic antidepressants such as amitriptyline, nortriptyline, doxepin, desipramine, imipramine, protriptyline, trimipramine, clomipramine), serotonin-norepinephrine reuptake inhibitors (e.g. duloxetine, venlafaxine, desvenlafaxine), e), milnacipran, levomilnacipran), serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, vilazodone, vortioxetine), anticonvulsants (e.g., gabapentin, pregabalin, carbamazepine, valproic acid, phenytoin, lamotrigine, tiagabine, lacosamide, topiramate, levetiracetam, oxacarbazepine, zonisamide), nonsteroidal anti-inflammatory drugs (NSAIDs;Such as naproxen, ibuprofen, meloxicam, diclofenac, fenoprofen, flurbiprofen, diflunisal, etodolac, nabumetone, ketoprofen, piroxicam, sulindac, tolmetin, ketorolac, mefenamic, oxaprozin), proton pump inhibitors (e.g. omeprazole, pantoprazole, lansoprazole, dexlansoprazole, esomeprazole, rabeprazole), H2 receptor antagonists (e.g. famotidine, nizatidine, ranitidine, cimetidine) idine), NMDA inhibitors (e.g. ketamine, amantadine, mematine), NO-NSAIDs, COX-2 selective inhibitors, cannabinoid agonists, nitric oxide donors, beta adrenergic agonists, alpha-2 agonists, selective prostanoid receptor antagonists, local anesthetics (e.g. capsaicin, lidocaine), purinergic P2 receptor antagonists, neuronal nicotinic receptor agonists, calcium channel antagonists, sodium channel blockers (e.g. mexiletine, flecainide), superoxide dismutase mimetics, p38 MAP kinase inhibitors, TRPV1 agonists, glycine receptor antagonists, corticosteroids, and acetaminophen. ;

[0054] Embodiment 27a: The combination according to any of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each case, a pharmaceutically acceptable salt thereof.

[0055] Embodiment 28a: The combination according to embodiment 27a, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.

[0056] Embodiment 29a: The combination according to embodiment 27a, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.

[0057] Embodiment 30a: The combination according to embodiment 27a, wherein the mGluR5 antagonist is compound (III) or a pharmaceutically acceptable salt thereof.

[0058] Embodiment (b):

[0059] Example 1b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in treating opioid analgesic tolerance associated with chronic opioid use in chronic pain.

[0060] Example 2b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in treating opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the treatment reverses opioid analgesic tolerance.

[0061] Example 3b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain.

[0062] Example 4b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in a treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

[0063] Example 5b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in treating chronic pain to reverse opioid analgesic tolerance associated with chronic opioid use.

[0064] Example 6b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in treating opioid analgesic tolerance to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

[0065] Example 7b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in reducing opioid consumption in chronic pain.

[0066] Example 8b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the opioid dose [e.g., daily opioid dose] administered to the patient is reduced (e.g., reduced by 50% or more, such as reduced by 70% or more, for example reduced by 90% or more) and the opioid analgesic effect (i.e., previously achieved by using a higher opioid dose) is maintained.

[0067] Embodiment 9b: A pharmaceutical composition for use according to any of the preceding embodiments, comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the mGluR5 antagonist is administered to patients receiving an opioid dose of >50 mg oral morphine / day or a daily analgesic dose of another opioid (i.e., morphine milligram equivalents (MME) / day), such as patients receiving an opioid dose of from 60 to 100 mg oral morphine / day or a daily analgesic dose of another opioid.

[0068] Embodiment 10b: A pharmaceutical composition for use according to any of the preceding embodiments, comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the chronic pain is associated with an injury (e.g., a wound, a burn, or a fracture) or a disease (e.g., diabetes, multiple sclerosis, arthritis, an autoimmune disease, or an infection).

[0069] Embodiment 11b: A pharmaceutical composition for use according to any one of the preceding embodiments, comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the chronic pain is non-malignant chronic pain.

[0070] Embodiment 12b: A pharmaceutical composition for use according to embodiment 11b, comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example with or without previous spinal surgery.

[0071] Embodiment 13b: A pharmaceutical composition for use according to any one of the preceding embodiments, comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the mGluR5 antagonist is administered to an elderly patient.

[0072] Embodiment 14b: A pharmaceutical composition for use according to any one of the preceding embodiments, comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the chronic pain is chronic post-surgical neuropathic pain.

[0073] Embodiment 15b: A pharmaceutical composition for use according to any of the preceding embodiments, comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; in particular a modified release form.

[0074] Embodiment 16b: A pharmaceutical composition for use according to any of the preceding embodiments, comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the mGluR5 antagonist is administered in combination with one or more additional pharmaceutically active ingredients.

[0075] Embodiment 17b: A pharmaceutical composition for use according to any of the preceding embodiments, comprising an mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the mGluR5 antagonist is selected from the group consisting of compound (I), compound (II), and compound (III); or in each case, a pharmaceutically acceptable salt thereof.

[0076] Embodiment 18b: A pharmaceutical composition for use according to Embodiment 17b, comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.

[0077] Example 19b: A pharmaceutical composition for use according to Example 18b, comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the mGluR5 antagonist is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, such as 200 mg / bid.

[0078] Embodiment 20b: A pharmaceutical composition for use according to embodiment 17b, comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the mGluR5 antagonist is compound (II) or a pharmaceutically acceptable salt thereof.

[0079] Embodiment 21b: A pharmaceutical composition for use according to embodiment 20b, comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the mGluR5 antagonist is administered in an amount from 1 mg / day to 100 mg / day.

[0080] Embodiment 22b: A pharmaceutical composition for use according to embodiment 17b, comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, wherein the mGluR5 antagonist is compound (III) or a pharmaceutically acceptable salt thereof.

[0081] Embodiment (c):

[0082] Example 1c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, for use in the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain.

[0083] Example 2c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient for use in the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance.

[0084] Example 3c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, for use in reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain.

[0085] Example 4c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, for use in a treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

[0086] Example 5c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient for use in the treatment of chronic pain to reverse opioid analgesic tolerance associated with chronic opioid use.

[0087] Example 6c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, for use in treating opioid analgesic tolerance to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

[0088] Example 7c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, for use in reducing opioid consumption in chronic pain.

[0089] Example 8c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, for use in reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the opioid dose [e.g., daily opioid dose] administered to the patient is reduced (e.g., reduced by 50% or more, such as reduced by 70% or more, for example reduced by 90% or more) and the opioid analgesic effect is maintained (i.e., previously achieved by using a higher opioid dose).

[0090] Embodiment 9c: The pharmaceutical combination for use according to any of the preceding embodiments, comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, wherein the mGluR5 antagonist is administered to patients receiving an opioid dose of >50 mg oral morphine / day or a daily analgesic dose of another opioid (i.e., morphine milligram equivalents (MME) / day), such as patients receiving an opioid dose of from 60 to 100 mg oral morphine / day or a daily analgesic dose of another opioid.

[0091] Embodiment 10c: The pharmaceutical combination for use according to any of the preceding embodiments, comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, wherein the chronic pain is associated with an injury (e.g., a wound, burn, or fracture) or a disease (e.g., diabetes, multiple sclerosis, arthritis, an autoimmune disease, or an infection).

[0092] Embodiment 11c: A pharmaceutical combination for use according to any one of the preceding embodiments, comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, wherein the chronic pain is non-malignant chronic pain.

[0093] Example 12c: A pharmaceutical combination for use according to Example 11b, comprising a mGluR5 antagonist, and at least one further pharmaceutically active ingredient, wherein the non-malignant chronic pain is chronic back pain, such as chronic low back pain, e.g. with or without previous spinal surgery.

[0094] Embodiment 13c: A pharmaceutical combination for use according to any of the preceding embodiments, comprising a mGluR5 antagonist, and at least one further pharmaceutically active ingredient, wherein the mGluR5 antagonist is administered to an elderly patient.

[0095] Embodiment 14c: A pharmaceutical combination for use according to any one of the preceding embodiments, comprising a mGluR5 antagonist, and at least one further pharmaceutically active ingredient, wherein the chronic pain is chronic post-surgical neuropathic pain.

[0096] Embodiment 15c: A pharmaceutical combination for use according to any of the preceding embodiments, comprising a mGluR5 antagonist, and at least one further pharmaceutically active ingredient, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; in particular a modified release form.

[0097] Embodiment 16c: The drug combination for use according to any of the preceding embodiments, comprising an mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, wherein the mGluR5 antagonist is selected from the group consisting of compound (I), compound (II), and compound (III); or in each case, a pharmaceutically acceptable salt thereof.

[0098] Embodiment 17c: A pharmaceutical combination for use according to embodiment 16c, comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.

[0099] Example 18c: A pharmaceutical combination for use according to Example 17c, comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, wherein the mGluR5 antagonist is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, such as 200 mg / bid.

[0100] Embodiment 19c: A pharmaceutical combination for use according to embodiment 16c, comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, wherein the mGluR5 antagonist is compound (II) or a pharmaceutically acceptable salt thereof.

[0101] Embodiment 20c: The pharmaceutical combination for use according to embodiment 19c, comprising a mGluR5 antagonist, and at least one further pharmaceutically active ingredient, wherein the mGluR5 antagonist is administered in an amount from 1 mg / day to 100 mg / day.

[0102] Embodiment 21c: A pharmaceutical combination for use according to embodiment 16c, comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient, wherein the mGluR5 antagonist is compound (III) or a pharmaceutically acceptable salt thereof.

[0103] Embodiment (d):

[0104] Example 1d: A method for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain in a subject in need thereof, the method comprising administering to the subject an effective amount of an mGluR5 antagonist.

[0105] Example 2d: A method for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain in a subject in need thereof, the treatment reversing opioid analgesic tolerance, the method comprising administering to the subject an effective amount of an mGluR5 antagonist.

[0106] Example 3d: A therapeutic method for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain in a subject in need thereof, the therapeutic method comprising administering to the subject an effective amount of an mGluR5 antagonist.

[0107] Example 4d: A therapeutic method for reducing the risk of opioid-related overdose associated with chronic opioid use in chronic pain in a subject in need thereof, the therapeutic method comprising administering to the subject an effective amount of an mGluR5 antagonist.

[0108] Example 5d: A method of treating chronic pain in a subject in need thereof to reverse opioid analgesic tolerance associated with chronic opioid use, the method comprising administering to the subject an effective amount of an mGluR5 antagonist.

[0109] Example 6d: A method of treating opioid analgesic tolerance in a subject in need thereof to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain, the method comprising administering to the subject an effective amount of an mGluR5 antagonist.

[0110] Example 7d: A therapeutic method for reducing opioid consumption in chronic pain in a subject in need thereof, comprising administering to the subject an effective amount of an mGluR5 antagonist.

[0111] Example 8d: A therapeutic method for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain in a subject in need thereof, the method comprising administering to the subject an effective amount of an mGluR5 antagonist, whereby the opioid dose [e.g., daily opioid dose] administered to the patient is reduced (e.g., reduced by 50% or more, such as reduced by 70% or more, for example reduced by 90% or more) and the opioid analgesic effect (i.e., previously achieved by using a higher opioid dose) is maintained.

[0112] Embodiment 9d: A method according to any of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient receiving an opioid dose of >50 mg oral morphine / day or a daily analgesic dose of another opioid (i.e., morphine milligram equivalents (MME) / day), such as a patient receiving an opioid dose of from 60 to 100 mg oral morphine / day or a daily analgesic dose of another opioid.

[0113] Embodiment 10d: The method according to any one of the preceding embodiments, wherein the chronic pain is associated with an injury (eg, a wound, a burn, or a fracture) or a disease (eg, diabetes, multiple sclerosis, arthritis, an autoimmune disease, or an infection).

[0114] Embodiment 11d: The method according to any one of the preceding embodiments, wherein the chronic pain is non-malignant chronic pain.

[0115] Embodiment 12d: The method of Embodiment 11d, wherein the non-malignant chronic pain is chronic back pain, such as chronic lower back pain, for example with or without prior spinal surgery.

[0116] Embodiment 13d: The method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.

[0117] Embodiment 14d: The method according to any one of the preceding embodiments, wherein the chronic pain is chronic post-surgical neuropathic pain.

[0118] Embodiment 15d: The method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; in particular a modified release form.

[0119] Embodiment 16d: The method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

[0120] Embodiment 17d: The method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in combination with one or more additional pharmaceutically active ingredients.

[0121] Embodiment 18d: The method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each case, a pharmaceutically acceptable salt thereof.

[0122] Embodiment 19d: The method according to embodiment 18d, wherein the mGluR5 antagonist is compound (I) or a pharmaceutically acceptable salt thereof.

[0123] Embodiment 20d: The method according to embodiment 19d, wherein the mGluR5 antagonist is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, such as 200 mg / bid.

[0124] Embodiment 21d: The method according to embodiment 18d, wherein the mGluR5 antagonist is compound (II) or a pharmaceutically acceptable salt thereof.

[0125] Embodiment 22d: The method according to embodiment 21d, wherein the mGluR5 antagonist is administered in an amount from 1 mg / day to 100 mg / day.

[0126] Embodiment 23d: The method according to embodiment 18d, wherein the mGluR5 antagonist is compound (III) or a pharmaceutically acceptable salt thereof.

[0127] Embodiment (e):

[0128] Example 1e: A method for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient.

[0129] Example 2e: A method for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain in a subject in need thereof, wherein the treatment reverses opioid analgesic tolerance, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient.

[0130] Example 3e: A therapeutic method for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain in a subject in need thereof, the therapeutic method comprising administering to the subject a pharmaceutical composition comprising an effective amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient.

[0131] Example 4e: A therapeutic method for reducing the risk of opioid-related overdose associated with chronic opioid use in chronic pain in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient.

[0132] Example 5e: A method of treating chronic pain in a subject in need thereof to reverse opioid analgesic tolerance associated with chronic opioid use, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient.

[0133] Example 6e: A method for treating opioid analgesic tolerance in a subject in need thereof to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient.

[0134] Example 7e: A therapeutic method for reducing opioid consumption in chronic pain in a subject in need thereof, the therapeutic method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a mGluR5 antagonist and at least one pharmaceutically acceptable excipient.

[0135] Example 8e: A therapeutic method for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient, whereby the opioid dose [e.g., daily opioid dose] administered to the patient is reduced (e.g., reduced by 50% or more, such as reduced by 70% or more, for example reduced by 90% or more) and the opioid analgesic effect (i.e., previously achieved by using a higher opioid dose) is maintained.

[0136] Embodiment 9e: The method according to any of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient receiving an opioid dose of >50 mg oral morphine / day or a daily analgesic dose of another opioid (i.e., morphine milligram equivalents (MME) / day), such as a patient receiving an opioid dose of from 60 to 100 mg oral morphine / day or a daily analgesic dose of another opioid.

[0137] Embodiment 10e: The method according to any one of the preceding embodiments, wherein the chronic pain is associated with an injury (eg, a wound, a burn, or a fracture) or a disease (eg, diabetes, multiple sclerosis, arthritis, an autoimmune disease, or an infection).

[0138] Embodiment 11e: The method according to any one of the preceding embodiments, wherein the chronic pain is non-malignant chronic pain.

[0139] Embodiment 12e: The method according to Embodiment 11e, wherein the non-malignant chronic pain is chronic back pain, such as chronic lower back pain, for example, with or without previous spinal surgery.

[0140] Embodiment 13e: A mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.

[0141] Embodiment 14e: The method according to any one of the preceding embodiments, wherein the chronic pain is chronic post-surgical neuropathic pain.

[0142] Embodiment 15e: The method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; in particular a modified release form.

[0143] Embodiment 16e: The method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in combination with one or more additional pharmaceutically active ingredients.

[0144] Embodiment 17e: The method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each case, a pharmaceutically acceptable salt thereof.

[0145] Embodiment 18e: The method according to embodiment 17e, wherein the mGluR5 antagonist is compound (I) or a pharmaceutically acceptable salt thereof.

[0146] Embodiment 19e: The method according to embodiment 18e, wherein the mGluR5 antagonist is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, such as 200 mg / bid.

[0147] Embodiment 20e: The method according to embodiment 17e, wherein the mGluR5 antagonist is compound (II) or a pharmaceutically acceptable salt thereof.

[0148] Embodiment 21e: The method according to embodiment 20e, wherein the mGluR5 antagonist is administered in an amount from 1 mg / day to 100 mg / day.

[0149] Embodiment 22e: The method according to embodiment 17e, wherein the mGluR5 antagonist is compound (III) or a pharmaceutically acceptable salt thereof.

[0150] Embodiment (f):

[0151] Example 1f: A method for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain in a subject in need thereof, the method comprising administering to the subject a pharmaceutical combination comprising an effective amount of an mGluR5 antagonist and at least one additional pharmaceutically active ingredient.

[0152] Example 2f: A method for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain in a subject in need thereof, wherein the treatment reverses opioid analgesic tolerance, the method comprising administering to the subject a drug combination comprising an effective amount of an mGluR5 antagonist and at least one additional pharmaceutically active ingredient.

[0153] Example 3f: A therapeutic method for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain in a subject in need thereof, the therapeutic method comprising administering to the subject a pharmaceutical combination comprising an effective amount of an mGluR5 antagonist and at least one additional pharmaceutically active ingredient.

[0154] Example 4f: A therapeutic method for reducing the risk of opioid-related overdose associated with chronic opioid use in chronic pain in a subject in need thereof, the therapeutic method comprising administering to the subject a pharmaceutical combination comprising an effective amount of an mGluR5 antagonist and at least one additional pharmaceutically active ingredient.

[0155] Example 5f: A method of treating chronic pain in a subject in need thereof to reverse opioid analgesic tolerance associated with chronic opioid use, the method comprising administering to the subject a pharmaceutical combination comprising an effective amount of an mGluR5 antagonist and at least one additional pharmaceutically active ingredient.

[0156] Example 6f: A method for treating opioid analgesic tolerance in a subject in need thereof to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain, the method comprising administering to the subject a pharmaceutical combination comprising an effective amount of an mGluR5 antagonist and at least one additional pharmaceutically active ingredient.

[0157] Example 7f: A therapeutic method for reducing opioid consumption in chronic pain in a subject in need thereof, comprising administering to the subject a pharmaceutical combination comprising an effective amount of a mGluR5 antagonist and at least one additional pharmaceutically active ingredient.

[0158] Example 8f: A therapeutic method for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain in a subject in need thereof, the method comprising administering to the subject a drug combination comprising an effective amount of an mGluR5 antagonist and at least one additional pharmaceutically active ingredient, whereby the opioid dose [e.g., daily opioid dose] administered to the patient is reduced (e.g., reduced by 50% or more, such as reduced by 70% or more, for example reduced by 90% or more) and the opioid analgesic effect (i.e., previously achieved by using a higher opioid dose) is maintained.

[0159] Embodiment 9f: The method according to any of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient receiving an opioid dose of >50 mg oral morphine / day or a daily analgesic dose of another opioid (i.e., morphine milligram equivalents (MME) / day), such as a patient receiving an opioid dose of from 60 to 100 mg oral morphine / day or a daily analgesic dose of another opioid.

[0160] Embodiment 10f: The method according to any one of the preceding embodiments, wherein the chronic pain is associated with an injury (eg, a wound, a burn, or a fracture) or a disease (eg, diabetes, multiple sclerosis, arthritis, an autoimmune disease, or an infection).

[0161] Embodiment 11f: The method according to any one of the preceding embodiments, wherein the chronic pain is non-malignant chronic pain.

[0162] Embodiment 12f: The method of Embodiment 11f, wherein the non-malignant chronic pain is chronic back pain, such as chronic lower back pain, for example with or without prior spinal surgery.

[0163] Embodiment 13f: A mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.

[0164] Embodiment 14f: The method according to any one of the preceding embodiments, wherein the chronic pain is chronic post-surgical neuropathic pain.

[0165] Embodiment 15f: The method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; in particular a modified release form.

[0166] Embodiment 16f: The method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each case, a pharmaceutically acceptable salt thereof.

[0167] Embodiment 17f: The method according to embodiment 16f, wherein the mGluR5 antagonist is compound (I) or a pharmaceutically acceptable salt thereof.

[0168] Embodiment 18f: The method according to embodiment 17f, wherein the mGluR5 antagonist is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, such as 200 mg / bid.

[0169] Embodiment 19f: The method according to embodiment 16f, wherein the mGluR5 antagonist is compound (II) or a pharmaceutically acceptable salt thereof.

[0170] Embodiment 20f: The method according to embodiment 19f, wherein the mGluR5 antagonist is administered in an amount from 1 mg / day to 100 mg / day.

[0171] Embodiment 21f: The method according to embodiment 16f, wherein the mGluR5 antagonist is compound (III) or a pharmaceutically acceptable salt thereof.

[0172] Embodiment (g):

[0173] Example 1g: Use of a mGluR5 antagonist for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain.

[0174] Example 2g: Use of a mGluR5 antagonist for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance.

[0175] Example 3g: Use of a mGluR5 antagonist for the manufacture of a medicament for treatment to reverse opioid analgesic tolerance associated with chronic opioid use in chronic pain.

[0176] Example 4g: Use of a mGluR5 antagonist for the manufacture of a medicament for treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

[0177] Example 5g: Use of a mGluR5 antagonist for the manufacture of a medicament for the treatment of chronic pain to reverse opioid analgesic tolerance associated with chronic opioid use.

[0178] Example 6g: Use of a mGluR5 antagonist for the manufacture of a medicament for treating opioid analgesic tolerance to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

[0179] Example 7g: Use of a mGluR5 antagonist for the manufacture of a medicament for use in treatment to reduce opioid consumption in chronic pain.

[0180] Example 8g: Use of a mGluR5 antagonist for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the opioid dose [e.g., daily opioid dose] administered to the patient is reduced (e.g., reduced by 50% or more, such as reduced by 70% or more, for example reduced by 90% or more) and the opioid analgesic effect (i.e., previously achieved by using a higher opioid dose) is maintained.

[0181] Embodiment 9g: Use of an mGluR5 antagonist according to any one of the preceding embodiments for the manufacture of a medicament, wherein the mGluR5 antagonist is administered to patients receiving an opioid dose of >50 mg oral morphine / day or a daily analgesic dose of another opioid (i.e., morphine milligram equivalents MME / day), such as patients receiving an opioid dose of from 60 to 100 mg oral morphine / day or a daily analgesic dose of another opioid.

[0182] Embodiment 10g: Use of an mGluR5 antagonist according to any one of the preceding embodiments for the manufacture of a medicament, wherein the chronic pain is associated with an injury (eg, a wound, a burn, or a fracture) or a disease (eg, diabetes, multiple sclerosis, arthritis, an autoimmune disease, or an infection).

[0183] Embodiment 11g: Use of the mGluR5 antagonist according to any one of the preceding embodiments for the manufacture of a medicament, wherein the chronic pain is non-malignant chronic pain.

[0184] Embodiment 12g: Use of the mGluR5 antagonist according to embodiment 11g for the manufacture of a medicament, wherein the non-malignant chronic pain is chronic back pain, such as chronic lower back pain, for example with or without previous spinal surgery.

[0185] Embodiment 13g: Use of the mGluR5 antagonist according to any one of the preceding embodiments for the manufacture of a medicament, wherein the mGluR5 antagonist is administered to an elderly patient.

[0186] Embodiment 14g: Use of an mGluR5 antagonist according to any one of the preceding embodiments for the manufacture of a medicament, wherein the chronic pain is chronic post-surgical neuropathic pain.

[0187] Embodiment 15g: Use of the mGluR5 antagonist according to any one of the preceding embodiments for the manufacture of a medicament, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; in particular a modified release form.

[0188] Embodiment 16g: Use of the mGluR5 antagonist according to any one of the preceding embodiments for the manufacture of a medicament, wherein the mGluR5 antagonist is administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

[0189] Embodiment 17g: Use of a mGluR5 antagonist according to any of the preceding embodiments for the manufacture of a medicament, wherein the mGluR5 antagonist is administered in combination with one or more additional pharmaceutically active ingredients.

[0190] Embodiment 18g: Use of an mGluR5 antagonist according to any one of the preceding embodiments for the manufacture of a medicament, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each case, a pharmaceutically acceptable salt thereof.

[0191] Embodiment 19g: Use of the mGluR5 antagonist according to Embodiment 18g for the manufacture of a medicament, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.

[0192] Embodiment 20g: Use of the mGluR5 antagonist according to embodiment 19g for the manufacture of a medicament, wherein the mGluR5 antagonist is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, such as 200 mg / bid.

[0193] Embodiment 21g: Use of the mGluR5 antagonist according to Embodiment 18g for the manufacture of a medicament, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.

[0194] Embodiment 22g: Use of the mGluR5 antagonist according to embodiment 21g for the manufacture of a medicament, wherein the mGluR5 antagonist is administered in an amount from 1 mg / day to 100 mg / day.

[0195] Embodiment 23g: Use of the mGluR5 antagonist according to Embodiment 18g for the manufacture of a medicament, wherein the mGluR5 antagonist is Compound (III) or a pharmaceutically acceptable salt thereof.

[0196] Embodiment (h):

[0197] Example 1h: Use of a pharmaceutical composition comprising an mGluR5 antagonist, and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain.

[0198] Example 2h: Use of a pharmaceutical composition comprising an mGluR5 antagonist, and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance.

[0199] Example 3h: Use of a pharmaceutical composition comprising an mGluR5 antagonist, and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for treatment to reverse opioid analgesic tolerance associated with chronic opioid use in chronic pain.

[0200] Example 4h: Use of a pharmaceutical composition comprising an mGluR5 antagonist, and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

[0201] Example 5h: Use of a pharmaceutical composition comprising an mGluR5 antagonist, and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for treating chronic pain to reverse opioid analgesic tolerance associated with chronic opioid use.

[0202] Example 6h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for treating opioid analgesic tolerance to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

[0203] Example 7h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for treatment to reduce opioid consumption in chronic pain.

[0204] Example 8h: Use of a pharmaceutical composition comprising an mGluR5 antagonist, and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the opioid dose [e.g., daily opioid dose] administered to the patient is reduced (e.g., reduced by 50% or more, such as reduced by 70% or more, for example reduced by 90% or more) and the opioid analgesic effect (i.e., previously achieved by using a higher opioid dose) is maintained.

[0205] Embodiment 9h: Use of a pharmaceutical composition comprising an mGluR5 antagonist according to any one of the preceding embodiments and at least one pharmaceutically acceptable excipient for the manufacture of a medicament, wherein the mGluR5 antagonist is administered to patients receiving an opioid dose of >50 mg oral morphine / day or a daily analgesic dose of another opioid (i.e., morphine milligram equivalents MME / day), such as patients receiving an opioid dose of from 60 to 100 mg oral morphine / day or a daily analgesic dose of another opioid.

[0206] Embodiment 10h: Use of a pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient according to any one of the preceding embodiments for the manufacture of a medicament, wherein the chronic pain is associated with an injury (e.g., a wound, a burn, or a fracture) or a disease (e.g., diabetes, multiple sclerosis, arthritis, an autoimmune disease, or an infection).

[0207] Embodiment 11h: Use of a pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient according to any one of the preceding embodiments for the manufacture of a medicament, wherein the chronic pain is non-malignant chronic pain.

[0208] Embodiment 12h: Use of a pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient according to embodiment 11h for the manufacture of a medicament, wherein the non-malignant chronic pain is chronic back pain, such as chronic lower back pain, for example with or without previous spinal surgery.

[0209] Embodiment 13h: Use of a pharmaceutical composition comprising a mGluR5 antagonist and at least one pharmaceutically acceptable excipient according to any one of the preceding embodiments for the manufacture of a medicament, wherein the mGluR5 antagonist is administered to an elderly patient.

[0210] Embodiment 14h: Use of a pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient according to any one of the preceding embodiments for the manufacture of a medicament, wherein the chronic pain is chronic postoperative neuropathic pain.

[0211] Embodiment 15h: Use of a pharmaceutical composition comprising a mGluR5 antagonist and at least one pharmaceutically acceptable excipient according to any one of the preceding embodiments for the manufacture of a medicament, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; in particular a modified release form.

[0212] Embodiment 16h: Use of a pharmaceutical composition comprising a mGluR5 antagonist and at least one pharmaceutically acceptable excipient according to any one of the preceding embodiments for the manufacture of a medicament, wherein the mGluR5 antagonist is administered in combination with one or more additional pharmaceutically active ingredients.

[0213] Embodiment 17h: Use of a pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient according to any one of the preceding embodiments for the manufacture of a medicament, wherein the mGluR5 antagonist is selected from the group consisting of compound (I), compound (II), and compound (III); or in each case, a pharmaceutically acceptable salt thereof.

[0214] Embodiment 18h: Use of the pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient according to Embodiment 17h for the manufacture of a medicament, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.

[0215] Embodiment 19h: Use of the pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient according to Embodiment 18h for the manufacture of a medicament, wherein the mGluR5 antagonist is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, such as 200 mg / bid.

[0216] Embodiment 20h: Use of the pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient according to Embodiment 17h for the manufacture of a medicament, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.

[0217] Embodiment 21h: Use of the pharmaceutical composition comprising a mGluR5 antagonist and at least one pharmaceutically acceptable excipient according to embodiment 20h for the manufacture of a medicament, wherein the mGluR5 antagonist is administered in an amount from 1 mg / day to 100 mg / day.

[0218] Embodiment 22h: Use of the pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient according to Embodiment 17h for the manufacture of a medicament, wherein the mGluR5 antagonist is Compound (III) or a pharmaceutically acceptable salt thereof.

[0219] Embodiment (j):

[0220] Example 1j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutically active ingredient for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain.

[0221] Example 2j: Use of a pharmaceutical combination comprising an mGluR5 antagonist, and at least one additional pharmaceutically active ingredient for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance.

[0222] Example 3j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient for the manufacture of a medicament for treatment to reverse opioid analgesic tolerance associated with chronic opioid use in chronic pain.

[0223] Example 4j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient for the manufacture of a medicament for treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

[0224] Example 5j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient for the manufacture of a medicament for the treatment of chronic pain to reverse opioid analgesic tolerance associated with chronic opioid use.

[0225] Example 6j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one additional pharmaceutically active ingredient for the manufacture of a medicament for treating opioid analgesic tolerance to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

[0226] Example 7j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutically active ingredient for the manufacture of a medicament for treatment to reduce opioid consumption in chronic pain.

[0227] Example 8j: Use of a pharmaceutical combination comprising an mGluR5 antagonist, and at least one additional pharmaceutically active ingredient for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the opioid dose [e.g., daily opioid dose] administered to the patient is reduced (e.g., reduced by 50% or more, such as reduced by 70% or more, for example reduced by 90% or more) and the opioid analgesic effect (i.e., previously achieved by using a higher opioid dose) is maintained.

[0228] Embodiment 9j: Use of a pharmaceutical combination comprising an mGluR5 antagonist according to any one of the preceding embodiments and at least one additional pharmaceutically active ingredient for the manufacture of a medicament, wherein the mGluR5 antagonist is administered to patients receiving an opioid dose of >50 mg oral morphine / day or a daily analgesic dose of another opioid (i.e., morphine milligram equivalents MME / day), such as patients receiving an opioid dose of from 60 to 100 mg oral morphine / day or a daily analgesic dose of another opioid.

[0229] Embodiment 10j: Use of a pharmaceutical combination comprising an mGluR5 antagonist according to any one of the preceding embodiments and at least one additional pharmaceutically active ingredient for the manufacture of a medicament, wherein the chronic pain is associated with an injury (e.g., a wound, a burn, or a fracture) or a disease (e.g., diabetes, multiple sclerosis, arthritis, an autoimmune disease, or an infection).

[0230] Embodiment 11j: Use of a pharmaceutical combination comprising a mGluR5 antagonist according to any one of the preceding embodiments, and at least one additional pharmaceutically active ingredient for the manufacture of a medicament, wherein the chronic pain is non-malignant chronic pain.

[0231] Embodiment 12j: Use of a pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutically active ingredient according to embodiment 11j for the manufacture of a medicament, wherein the non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example with or without previous spinal surgery.

[0232] Embodiment 13j: Use of a pharmaceutical combination comprising a mGluR5 antagonist according to any one of the preceding embodiments, and at least one further pharmaceutically active ingredient for the manufacture of a medicament, wherein the mGluR5 antagonist is administered to an elderly patient.

[0233] Embodiment 14j: Use of a pharmaceutical combination comprising a mGluR5 antagonist according to any one of the preceding embodiments, and at least one additional pharmaceutically active ingredient for the manufacture of a medicament, wherein the chronic pain is chronic post-surgical neuropathic pain.

[0234] Embodiment 15j: Use of a pharmaceutical combination comprising a mGluR5 antagonist according to any one of the preceding embodiments and at least one further pharmaceutically active ingredient for the manufacture of a medicament, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; in particular a modified release form.

[0235] Embodiment 16j: Use of a pharmaceutical combination comprising an mGluR5 antagonist according to any one of the preceding embodiments and at least one additional pharmaceutically active ingredient for the manufacture of a medicament, wherein the mGluR5 antagonist is selected from the group consisting of compound (I), compound (II), and compound (III); or in each case, a pharmaceutically acceptable salt thereof.

[0236] Embodiment 17j: Use of the pharmaceutical combination comprising a mGluR5 antagonist and at least one additional pharmaceutically active ingredient according to Embodiment 16j for the manufacture of a medicament, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.

[0237] Embodiment 18j: Use of the pharmaceutical combination comprising a mGluR5 antagonist and at least one additional pharmaceutically active ingredient according to embodiment 17j for the manufacture of a medicament, wherein the mGluR5 antagonist is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, such as 200 mg / bid.

[0238] Embodiment 19j: Use of the pharmaceutical combination comprising a mGluR5 antagonist and at least one additional pharmaceutically active ingredient according to Embodiment 16j for the manufacture of a medicament, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.

[0239] Embodiment 20j: Use of a pharmaceutical combination comprising a mGluR5 antagonist according to embodiment 19j, and at least one further pharmaceutically active ingredient for the manufacture of a medicament, wherein the mGluR5 antagonist is administered in an amount from 1 mg / day to 100 mg / day.

[0240] Embodiment 21j: Use of the pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutically active ingredient according to Embodiment 16j for the manufacture of a medicament, wherein the mGluR5 antagonist is Compound (III) or a pharmaceutically acceptable salt thereof.

[0241] General terms

[0242] As used herein, the term "opioid" or "opioid analgesic" refers to natural (opiate) or synthetic (opioid) forms, as well as natural or synthetic mixed opioid agonists / antagonists, and includes, but is not limited to, alpha methylfentanyl, alfentanil, buprenorphine, butorphanol, codeine, diacetylmorphine, dihydrocodeine, dihydroetorphine, dihydromorphine, ethylmorphine, etorphine, fentanyl, hydrocodone, hydromorphone, L-acetylmethadol, levorphanol, methadone, pethidine, morphine, , nicomorphine, normethadone, noroxycodone, normorphine, norlevorphanol, oxycodone, oxymorphone, phenazocine, propoxyphene, remifentanil, tramadol, thebaine, tapentadol, levorphanol, sufentanil, pentazocine, carfentanil, omefentanyl, nocaine, ketobemidone, allylprodine, prodinil, dextropropoxyphene, dextromorphamide, cypermethrin, pirithromide, dipipanone, loperamide, diphenoxylate, nalbuphine, levormethophan, dezocine, levophenidine and tilidine. 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.

[0243] As used herein, the term "chronic opioid use" or "chronic use of opioids" refers to opioid treatment / therapy (eg, daily) that lasts for more than 6 months, wherein the opioid is, eg, as defined herein. In one embodiment, "chronic opioid use" refers to chronic alpha methylfentanyl use, chronic alfentanil use, chronic buprenorphine use, chronic butorphanol use, chronic codeine use, chronic diacetylmorphine use, chronic dihydrocodeine use, chronic dihydroetorphine use, chronic dihydromorphine use, chronic ethylmorphine use, chronic etorphine use, chronic fentanyl analgesic use, chronic hydrocodone use, chronic hydromorphone use, chronic L-acetylmethadol use, chronic levorphanol use, chronic methadone use, chronic meperidine use, chronic morphine use, chronic nicomorphine use, chronic normethadone use, chronic noroxycodone use, chronic normorphine use, chronic norlevorphanol use, chronic oxycodone use, chronic oxymorphone use, chronic phenazocine use Chronic propoxyphene use, chronic remifentanil use, chronic tramadol use, chronic thebaine use, chronic tapentadol use, chronic levorphanol use, chronic sufentanil use, chronic pentazocine use, chronic carfentanil use, chronic omfentanyl use, chronic nocaine use, chronic ketobemidone use, chronic allylprodine use, chronic prodin use, chronic dextropropoxyphene use, chronic dextromorphamide use, chronic cypermethrin use, chronic pirithramide use, chronic dipipanone use, chronic loperamide use, chronic diphenoxylate use, chronic nalbuphine use, chronic levomethophallen use, chronic dezocine use, chronic leptomycin use, and chronic tilidine use; wherein the term "chronic" in each case refers to use lasting for more than 6 months (e.g., daily). In another embodiment, "chronic opioid use" refers to chronic morphine use, chronic hydrocodone use, chronic oxycodone use, or chronic codeine use, in one embodiment, chronic hydrocodone use, in another embodiment, chronic oxycodone use; wherein the term "chronic" in each case refers to use (e.g., daily) that lasts for more than 6 months.

[0244] As used herein, the term "chronic opioid use in chronic pain" is to be understood as "chronic opioid use" as defined herein by a patient suffering from chronic pain. The term "chronic opioid user" refers to a chronic pain patient who receives opioids as defined herein (e.g., daily) for more than 6 months.

[0245] As used herein, the term "opioid treatment" or "opioid therapy" refers to analgesic treatment of chronic pain with, e.g., an opioid as defined herein [see, e.g., the Interagency Guideline on Prescribing Opioids for Pain, 3rd edition, July 2015; or the Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain, 2016; or The Journal of Pain, 2009, 10(2), 113-130; the entire contents of each of which are incorporated herein by reference].

[0246] As used herein, the term "tolerance" is understood, for example, according to the definition of the National Institute on Drug Abuse (NIDA), as a state in which a patient no longer responds to a drug and requires higher doses (e.g., higher daily doses) to achieve an effect. Thus, tolerance is a phenomenon in the body over time in which one or more effects of a drug diminish with repeated use at the same dose, and higher doses are required to achieve a result (e.g., an increased dose is required to maintain an analgesic effect).

[0247] As used herein, the term "opioid tolerance" or "opioid analgesic tolerance" refers to chronic use of opioids that results in gradual dose increases (e.g., daily dose increases) of opioids to maintain analgesic effects. Signs of tolerance can be assessed, for example, according to the PEG scale [i.e., assessment of pain intensity (P), enjoyment of life (E), general activity (G); the PEG scale has been shown to be sensitive to changes and distinctions between patients with and without pain improvement; for example, at http: / / mytopcare.org / wp-content / uploads / 2013 / 06 / PEG-Pain-Screening-Tool1.pdf, Krebs EE et al. J. Gen. Intern. Med [Journal of General Internal Medicine], 2009, 24, 733-8]. In one embodiment, "opioid analgesic tolerance" is selected from the group consisting of alpha-methylfentanyl analgesic tolerance, alfentanil analgesic tolerance, buprenorphine analgesic tolerance, butorphanol analgesic tolerance, codeine analgesic tolerance, diacetylmorphine analgesic tolerance, dihydrocodeine analgesic tolerance, dihydroetorphine analgesic tolerance, dihydromorphine analgesic tolerance, ethylmorphine analgesic tolerance, etorphine analgesic tolerance, fentanyl analgesic tolerance, hydrocodone analgesic tolerance, hydromorphone analgesic tolerance, L-acetylmethadol analgesic tolerance, levorphanol analgesic tolerance, methadone analgesic tolerance, pethidine analgesic tolerance, morphine analgesic tolerance, nicomorphine analgesic tolerance, normethadone analgesic tolerance, noroxycodone analgesic tolerance, normorphine analgesic tolerance, norlevorphanol analgesic tolerance, oxycodone analgesic tolerance Tolerance, oxymorphone analgesic tolerance, phenazocine analgesic tolerance, propoxyphene analgesic tolerance, remifentanil analgesic tolerance, tramadol analgesic tolerance, thebaine analgesic tolerance, tapentadol analgesic tolerance, levorphanol analgesic tolerance, sufentanil analgesic tolerance, pentazocine analgesic tolerance, carfentanil analgesic tolerance, omefentanyl analgesic tolerance, nocaine analgesic tolerance, ketobemidone analgesic tolerance The analgesic tolerance of opioids is selected from the group consisting of morphine analgesic tolerance, hydrocodone analgesic tolerance, oxycodone analgesic tolerance and codeine analgesic tolerance; in particular, selected from the group consisting of hydrocodone analgesic tolerance and oxycodone analgesic tolerance; in one embodiment, hydrocodone analgesic tolerance; in another embodiment, oxycodone analgesic tolerance.

[0248] As used herein, the terms "for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain", "reverses / reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain" should be understood as reversing existing (i.e., established) opioid analgesic tolerance as defined herein in a chronic pain patient who is a chronic opioid user as defined herein. In particular, it refers to the ability of, for example, an active ingredient as defined herein (such as an mGluR5 antagonist) to reduce the opioid dose of the opioid administered to the chronic pain patient [e.g., daily opioid dose, such as >50 mg oral morphine / day or daily isoanalgesic dose of another opioid (i.e., morphine milligram equivalents MME / day)] [e.g., a 50% or greater reduction in the original opioid consumption / day or week, such as a 70% or greater reduction, such as a 90% or greater reduction; for example, as assessed by using a biomarker of an opioid metabolite or as assessed by using a patient's self-reported opioid intake (e.g., by using a timeline tracking opioid self-report diary)], and maintain analgesia (i.e., maintain analgesia previously achieved by using a larger dose of the opioid (such as a larger daily dose)). Opioid reduction can be assessed, for example, by using a biomarker of an opioid metabolite or by using a patient's self-reported opioid intake.

[0249] As used herein, the term "PEG scale" refers to the PEG three-item scale (i.e., as defined, for example, in http: / / mytopcare.org / wp-content / uploads / 2013 / 06 / PEG-Pain-Screening-Tool1.pdf, KrebsEE et al. J. Gen. Intern. Med [Journal of General Internal Medicine], 2009, 24, 733-8 (incorporated herein by reference)). The scale is a 3-item clinical interview that assesses the following items: i) "Pain average" (P) from 1 to 10, ii) "Interference with enjoyment of life" (E) from 1 to 10, and iii) "Interference with general activities" from 1 to 10. The scale has been shown to be sensitive to changes between subjects with and without pain improvement, and can distinguish between these subjects.

[0250] In particular, as used herein, the term "for use in reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain" should be understood as "for use in a treatment to reverse opioid analgesic tolerance associated with chronic opioid use in chronic pain" or "for use in a therapeutic method to reverse opioid analgesic tolerance associated with chronic opioid use in chronic pain."

[0251] As used herein, the term "analgesic equivalent dose of another opioid" is to be understood as morphine milligram equivalents MME / day, as calculated, for example, according to the United States Department of Health and Human Services Centers for Disease Control and Prevention guideline (see, e.g., https: / / www.cdc.gov / drugoverdose / pdf / calculating_total_daily_dose-a.pdf; the entire contents of which are incorporated herein by reference), whereby morphine equivalent dosing is calculated based on the following conversion factor:

[0252]

[0253]

[0254] Thus, 50 MME / day refers to, for example, 50 mg of hydrocodone, 33 mg of oxycodone, or 12 mg of methadone per day; and 90 MME / day refers to, for example, 90 mg of hydrocodone, 60 mg of oxycodone, or about 20 mg of methadone per day.

[0255] The term MME refers to the milligram equivalent dose of morphine.

[0256] As used herein, the term "to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain" is understood to be a reduction in the risk of overdose associated with chronic opioid use in patients with chronic pain. The risk of overdose can be, for example, compared to placebo, for example, according to the Pasero Opioid Induction Sedation Scale (POSS; For example, in Pasero C, McCaffery M. Pain Assessment and Pharmacologic Management. St Louis: Mosby / Elsevier; 2011. Section IV, Opioid Analgesics; In pages 277-622) to assess.

[0257] As used herein, the terms "to reduce opioid consumption in chronic pain", "reduces / reducing opioid consumption in chronic pain" refer to a reduction in opioid consumption in a patient suffering from chronic pain. In one embodiment, the term is understood to be a reduction in the dose of opioids being administered to a patient suffering from chronic pain who is a chronic opioid user as defined herein (e.g., a reduction in the daily opioid dose). In another embodiment, the term is understood to be a reduction in the disease state of opioid use (e.g., from a moderate state to a mild state according to the DMS-V diagnostic criteria for opioid use disorder). In particular, the reduction in opioid consumption in patients suffering from chronic pain is while maintaining analgesic effect.

[0258] In particular, "reduction in opioid consumption in chronic pain" or "reduction in opioid consumption in patients suffering from chronic pain" refers to a 50% opioid reduction in the original opioid dose, such as a 50% opioid reduction in the original opioid dose when the initial opioid dose is from 60 mg to 100 mg oral morphine / day or a daily isoanalgesic dose of another opioid; for example, a 50% opioid reduction in the original opioid dose over a 5 week period, such as a 50% opioid reduction in the original opioid dose over a 5 week period when the initial opioid dose is from 60 mg to 100 mg oral morphine / day or a daily isoanalgesic dose of another opioid.

[0259] In particular, as used herein, the term "opioid dose" refers to a daily opioid dose. As used herein, the term "daily opioid dose" refers to a daily isoanalgesic dose of mg oral morphine / day or another opioid (i.e., morphine milligram equivalent MME / day). In one embodiment, the daily opioid dose is, for example, >50 mg oral morphine / day or a daily isoanalgesic dose of another opioid (i.e., morphine milligram equivalent MME / day), such as from 60 mg oral morphine / day or a daily isoanalgesic dose of another opioid (e.g., hydrocodone or oxycodone) to 100 mg oral morphine / day or a daily isoanalgesic dose of another opioid (e.g., hydrocodone or oxycodone).

[0260] In particular, the daily opioid dose administered to the chronic pain patient is reduced by 50% or more, such as by 70% or more, for example by 90% or more. In another embodiment, the daily opioid dose administered to the chronic pain patient is reduced by 50% over a 5-week period, such as a 50% opioid reduction over a 5-week period of the original opioid dose when the starting opioid dose is from 60 mg to 100 mg oral morphine / day or a daily isoanalgesic dose of another opioid. Opioid reduction is assessed, for example, by using biomarkers of metabolites of opioids or by using a patient's self-reported opioid intake (e.g., by using a timeline tracking opioid self-report diary).

[0261] In particular, as used herein, the term "for use in reducing opioid consumption in chronic pain" should be understood as "for use in a treatment for reducing opioid consumption in chronic pain" or "for use in a treatment method for reducing opioid consumption in chronic pain."

[0262] In particular, as used herein, the term "for use in the reduction of opioid consumption in chronic pain" should be understood as "for use in a treatment for the reduction of opioid consumption in chronic pain" or "for use in a treatment method for the reduction of opioid consumption in chronic pain."

[0263] As used herein, the term "chronic pain" should be understood as, for example, defined by the American Chronic Pain Association (ACPA) Resource Guide to Chronic Pain Management, 2017 edition, i.e., it is understood as persistent or recurrent pain that lasts beyond the usual course of acute disease or injury or exceeds 6 months and adversely affects the health of the individual. Typically, chronic pain is classified by pathophysiology (functional changes associated with disease or injury or caused by disease or injury) as nociceptive pain (due to persistent tissue damage), neuropathic pain (caused by brain, spinal cord or peripheral nerve damage) or a mixture of these pains. As used herein, the term "chronic pain" can be understood as "performed by patients suffering from chronic pain" or "patients suffering from chronic pain".

[0264] As used herein, the term "non-malignant chronic pain" refers to non-cancer chronic pain, including, for example, post-herpetic neuralgia, degenerative joint disease (DJD; osteoarthritis), diabetic neuropathy, neuroma pain, central pain, sympathetic dystrophy, chronic musculoskeletal pain, migraine, fibromyalgia, rheumatoid arthritis, spinal stenosis, and low back pain. In particular, non-malignant chronic pain refers to chronic postoperative neuropathic pain. In another embodiment, non-malignant chronic pain refers to back pain, such as chronic low back pain. As used herein, the term "low back pain" or "chronic low back pain" refers to pain that persists for 12 weeks or longer, even after the initial injury or underlying cause of the acute low back pain has been treated (e.g., see, e.g., North America Spine Society Diagnosis (NASS) and Treatment of Low-Back Pain Evidence-Based Guideline, 2016; or Guideline for the Evaluation and Management of Low Back Pain: Evidence Review, R. Chou, L. Hoyt Huffman, American Pain Society).

[0265] As used herein, the term "malignant chronic pain" refers to chronic pain of cancer (e.g., chronic pain syndromes as described in Appendix E of the Interagency Guideline on Prescribing Opioids for Pain, 3rd Edition, June 2015, the entire contents of which are incorporated herein by reference).

[0266] As used herein, with respect to a disease or disorder, the term "treat / treating / treatment" refers, in one embodiment, to improving a disease or disorder (i.e., slowing down or preventing or reducing the development of a disease or at least one of its clinical symptoms). In another embodiment, "treat / treating / treatment" refers to alleviating or improving at least one physical parameter, including those that cannot be discerned by the patient. In yet another embodiment, "treat / treating / treatment" refers to regulating a disease or disorder physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of physical parameters) or both. In one embodiment, as used herein, the term "method for treating ..." refers to "method for treating ...".

[0267] As used herein, the term "elderly patient" refers to a patient who is sixty-five years of age or older.

[0268] As used herein, "bid," "bid," or "bid" means twice / two times a day (eg, 200 mg bid = 400 mg / day), such as in the morning and evening (eg, separated by about 12 hours).

[0269] As used herein, the term "patient" refers to a subject who is ill and will benefit from treatment. As used herein, the term "chronic pain patient" or "patient with chronic pain" refers to a subject suffering from chronic pain (i.e., diagnosed with chronic pain as defined herein). In one embodiment, the term "patient" refers to a subject diagnosed with chronic pain as defined herein, who is a chronic opioid user and is an opioid dependent (i.e., has withdrawal symptoms after opioid cessation, but does not meet the DSM-V opioid use disorder criteria). In another embodiment, the term "patient" refers to a subject diagnosed with chronic pain as defined herein, who meets the DSM-V opioid use disorder criteria for mild or moderate.

[0270] As used herein, the term "subject" refers to a mammal, preferably a human (male or female).

[0271] As used herein, a subject (patient) is "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0272] The term "therapeutically effective amount" of a compound of the invention refers to an amount of the compound of the invention that will elicit a biological or medical response (eg, improvement of symptoms, alleviation of a condition, etc.) in a subject.

[0273] As used herein, the term "opioid use disorder" or "OUD" refers to the DSM-5 criteria for opioid use disorder (i.e., according to the Diagnostic and Statistical Manual of Mental Disorders. 5th ed., Washington, DC: American Psychiatric Association, 2013; the entire contents of which are incorporated herein by reference), which can be divided into the following three categories: mild (i.e., the presence of 2 to 3 symptoms, as defined by the DSM-5 criteria), moderate (i.e., the presence of 4 to 5 symptoms, as defined by the DSM-5 criteria), and severe (i.e., the presence of 6 or more symptoms, as defined by the DSM-5 criteria). Thus, as used herein, the term "opioid use disorder" is defined as a problematic pattern of opioid use that occurs over a 12-month period that causes clinically significant impairment or distress, as manifested by at least two of the following:

[0274] 1) Opioids are often taken in larger amounts or over longer periods of time than intended.

[0275] 2) The presence of a persistent desire to use opioids or unsuccessful efforts to reduce or control opioid use.

[0276] 3) Spending a significant amount of time in activities required to obtain opioids, use opioids, or recover from their effects.

[0277] 4) Craving, or a strong desire or need to use opioids.

[0278] 5) Recurrent opioid use resulting in an inability to fulfill major role obligations at work, school, or home.

[0279] 6) Continued opioid use despite persistent or recurring social or interpersonal problems caused or exacerbated by the effects of opioids.

[0280] 7) Giving up or reducing important social, occupational, or recreational activities because of opioid use.

[0281] 8) Repeated use of opioids in situations that are harmful to the body.

[0282] 9) Continuing to use opioids despite knowledge of persistent or recurring physical or psychological problems that may be caused or exacerbated by opioids.

[0283] 10) Tolerance, as defined by any of the following: a) the need for significantly increasing amounts of opioids to achieve intoxication or a desired effect; b) significantly diminished effects with continued use of the same amount of opioid.

[0284] 11) Withdrawal symptoms, as manifested by any of the following:

[0285] a) Typical opioid withdrawal syndrome (referring to DSM-5 Criteria A and B of the opioid withdrawal symptom set).

[0286] b) Taking opioids (or closely related substances) to relieve or avoid withdrawal symptoms.

[0287] The term "pharmaceutical composition" is defined herein to mean a mixture or solution containing at least one active ingredient or therapeutic agent to be administered to a subject to treat a specific condition (ie, a disease, disorder or condition or at least one clinical symptom thereof) affecting the subject.

[0288] The Opioid Craving Scale (OCS) is a modified version of the Cocaine Craving Scale and is a short-form 3-item reported outcome used to assess craving experiences during opioid consumption. The 3-item scale includes a visual analog scale from 1 to 10 and is used to indicate how much the opioid user craves for opioids; how strong the opioid user's desire to use opioids was during the previous day; and whether the opioid user wants to take opioids at the same time of the day. Based on responses on a 1 to 10 scale for these three items, each unit increase in score is associated with a 17% greater odds of using opioids in the next week (e.g., McHugh RK, et al., Assessing craving and its relationship to subsequent prescription opioid use among treatment-seeking prescription opioid dependent patients, Drug and Alcohol Dependency, 2014 Dec 1;145:121-6).

[0289] The Clinical Opiate Withdrawal Symptom Scale (COWS) consists of an 11-item scale that is administered by a physician and is used to assess the more common signs and symptoms of opiate withdrawal and to review these symptoms over a period of time (e.g., Wesson DR et al., Journal of Psychoactive Drugs, 2003 Apr-Jun;35(2):253-9). The additional score of the entire 11-item scale can help the physician assess the stage or severity of opiate withdrawal symptoms that the user is experiencing and also provide an indication of the degree of physical dependence on opiates.

[0290] The Numerical Opioid Side Effects (NOSE) assessment (e.g., in Smith HS et al., Med Clin North Am., 2007, 91(2):213-228) is a 10-item scale of common opiate-specific side effects. Each side effect is represented by an analog scale from 0 to 10, with zero indicating no side effect and 10 being the worst side effect an opiate user could imagine.

[0291] The Numerical Rating Scale (NRS, eg, in Childs JD et al., Spine, 2005;30:1331-4) assesses pain intensity on a scale from 0 (no pain) to 10 (worst imaginable pain).

[0292] The Columbia Suicide Severity Rating Scale (C-SSRS; for example in Posner K et al., Am. J. Psychiatry; 2011, 168: 1266-1277) is a rating scale for suicidal ideation and behavior used to assess suicide risk.

[0293] As used herein, the term "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, etc. and combinations thereof as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 22nd Edition Mack Printing Company, 2013, pp. 1049-1070). Except in the case where any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical composition is contemplated.

[0294] The terms "drug", "active substance", "active ingredient", "pharmaceutical active ingredient", "active agent" or "therapeutic agent" are understood to mean a compound, particularly a compound of the type specified herein, in free form or in pharmaceutically acceptable salt form.

[0295] The term "combination" or "pharmaceutical combination" refers to a fixed combination, a non-fixed combination, or a kit for combined administration in a unit dosage form (e.g., a capsule or tablet), wherein the compound of the invention and one or more combination partners (e.g., another drug specified herein, also referred to as an additional "pharmaceutically active ingredient", "therapeutic agent" or "co-agent") can be administered simultaneously and independently or separately at time intervals, especially when these time intervals allow the combination partners to show cooperation, such as synergistic effects. As used herein, the terms "co-administration" or "combined administration" and the like are intended to cover the administration of the selected combination partners to a single subject (e.g., a patient) in need, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or are administered simultaneously. The term "fixed combination" means that the active ingredients (e.g., a compound of the invention and one or more combination partners) are all administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" refers to that the active ingredients (e.g., a compound of the invention and one or more combination partners) are all administered to the patient as separate entities simultaneously or sequentially without specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the patient.

[0296] The compounds of the present invention can be administered separately with other agents by the same or different routes of administration, or administered together in the same pharmaceutical composition. In the combination therapy of the present invention, the compounds of the present invention and other therapeutic agents can be manufactured and / or formulated by the same or different manufacturers. In addition, the compounds of the present invention and other therapeutic agents can be formed into a combination therapy together in the following manner: (i) before the combination product is issued to the physician (e.g., in the case of a kit including the compounds of the present invention and other therapeutic agents); (ii) shortly before administration, by the physician himself (or under the guidance of a physician); (iii) by the patient himself, for example, during the sequential administration of the compounds of the present invention and other therapeutic agents.

[0297] In particular, as used herein (e.g. in any of the embodiments above, or in any of the claims below), reference to a combination with an additional active agent refers, for example, to a combination with at least one additional active agent selected from the group consisting of an antidepressant (e.g. a tricyclic antidepressant such as amitriptyline, nortriptyline, doxepin, desipramine, imipramine, protriptyline, trimipramine, clomipramine), a serotonin-norepinephrine HT reuptake inhibitors (e.g., duloxetine, venlafaxine, desvenlafaxine, milnacipran, levomilnacipran), serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, vilazodone, vortioxetine), anticonvulsants (e.g., gabapentin, pregabalin, carbamazepine, valproic acid, phenytoin, lamotrigine, tiagabine, lacosamide, topiramate, levetiracetam, oxcarbazepine, zonisamide), nonsteroidal anti-inflammatory drugs (NSAIDs; such as naproxen, ibuprofen, meloxicam, diclofenac, fenoprofen, flurbiprofen, diflunisal, etodolac, nabumetone, ketoprofen, piroxicam, sulindac, tolmetin, ketorolac, mefenamic acid, oxaprozin), proton pump inhibitors (e.g. omeprazole, pantoprazole, lansoprazole, dexlansoprazole, esomeprazole, rabeprazole), H2 receptor antagonists (e.g. famotidine, nizatidine, ranitidine, cimetidine), NMDA inhibitors agents (e.g., ketamine, amantadine, memantine), NO-NSAIDs, COX-2 selective inhibitors, cannabinoid agonists, nitric oxide donors, beta adrenergic agonists, alpha-2 agonists, selective prostanoid receptor antagonists, local anesthetics (e.g., capsaicin, lidocaine), purinergic P2 receptor antagonists, neuronal nicotinic receptor agonists, calcium channel antagonists, sodium channel blockers (e.g., mexiletine, flecainide), superoxide dismutase mimetics, p38 MAP kinase inhibitors, TRPV1 agonists, glycine receptor antagonists, corticosteroids, and acetaminophen; or a pharmaceutically acceptable salt thereof.

[0298] The term "immediate release form" refers to a pharmaceutical composition designed to release the active substance immediately after administration in vivo.

[0299] The term "modified release form" refers to a pharmaceutical composition that does not release the active substance immediately, but rather provides a sustained, delayed, continuous, gradual, extended or pulsatile release and thus specifically alters the drug plasma level compared to an immediate release form. The term "modified release form" encompasses forms described as: controlled release forms, sustained release forms, extended release forms, and long-acting forms; in particular, sustained release forms.

[0300] As used herein, the terms "a", "an", "the" and similar terms used in the context of the present invention (especially in the context of the claims) should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0301] The use of any and all examples, or exemplary language (eg, "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.

[0302] As used herein, as used above and below, the compound of the present invention (alternatively referred to as Compound (I)) is a mGluR5 antagonist (-)-(3aR, 4S, 7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester, also known as (-)-(3aR, 4S, 7aR)-4-hydroxy-4-[2-(3-methylphenyl)ethynyl]perhydroindole-1-carboxylic acid methyl ester (also known as mavogulan) having the following formula:

[0303]

[0304] , which can be prepared, for example, as described in WO 2003 / 047581 (e.g., in Example 1) or as described in WO 2010 / 018154. WO 2003 / 047581 (which is incorporated herein by reference) also describes its in vitro biological data according to page 7. As used herein, "Mavogulan" refers to the free form. In particular, Mavogulan is in free form. Unless otherwise indicated herein, as used herein, as used in the context of the present invention (especially in the context of any of the above or below embodiments and claims), the term "Mavogulan or its salt, such as a pharmaceutically acceptable salt thereof" should therefore be interpreted as covering its free form and its pharmaceutically acceptable salt.

[0305] In one embodiment, compound (I) is also intended to represent an isotopically labeled form. An isotopically labeled compound has the structure depicted by the above formula, except that one or more atoms are replaced by atoms 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., compounds having the formula:

[0306]

[0307] Each of 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 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 is 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.

[0308] As used herein, as used above and below, the compound of the present invention (alternatively referred to as Compound (II)) is an mGluR5 antagonist referred to as 9-cyclopropyl-10-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one having the following formula:

[0309]

[0310] , which can be prepared, for example, as described in WO 2014 / 030128 (e.g., in Example 96-2), which is incorporated herein by reference and also describes its in vitro biological data according to page 203. Unless otherwise indicated herein, as used in the context of the present invention (especially in the context of any of the above or below embodiments and claims), the term "compound (II)" should be interpreted as covering its free form and its pharmaceutically acceptable salts.

[0311] In one embodiment, compound (II) is also intended to represent an isotopically labeled form. An isotopically labeled compound has the structure depicted by the above formula, except that one or more atoms are replaced by atoms 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., compounds having the following formula:

[0312]

[0313] Each of 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 , R 18 , R 19 , R 20 and R 21is 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. The isotopically labeled form of compound (II) is, for example:

[0314]

[0315] As used herein, as used above and below, the compound of the present invention (alternatively referred to as Compound (III)) is an mGluR5 antagonist known as 2-methyl-6-(phenylethynyl)pyridine (also known as MPEP) having the following formula:

[0316]

[0317] , whose CAS number is 96206-92-7 and which is commercially available. Unless otherwise specified herein, as used in the context of the present invention (especially in the context of any one of the above or below embodiments and claims), the term "compound (III)" should be interpreted as covering its free form and its pharmaceutically acceptable salt.

[0318] In one embodiment, compound (III) is also intended to represent an isotopically labeled form. An isotopically labeled compound has the structure depicted by the above formula, except that one or more atoms are replaced by atoms 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., compounds having the following formula:

[0319]

[0320] Each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 is 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.

[0321] Incorporation of certain isotopes, especially deuterium (i.e. 2H or D) can provide certain therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improvements in therapeutic index or tolerability. It should be understood that deuterium is considered a substituent of the compounds of the invention in this context. The concentration of deuterium can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of the invention is indicated as deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation on 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 a similar manner as described for deuterium.

[0322] Other examples of isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen (except deuterium), carbon, nitrogen, oxygen and fluorine, such as 3 H. 11 C. 13 C. 14 C. 15 N. 18 F. Thus, it is to be understood that the present invention includes the incorporation of one or more of any of the foregoing isotopes (including, for example, radioactive isotopes such as 3 H and 14 C)) or compounds in which non-radioactive isotopes such as 2 H and 13 C). Such isotope-labeled compounds can be used for metabolic studies (using 14 C) reaction kinetics studies (e.g. 2 H or 3 H), 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 radiotherapy for patients. In particular, 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described for the preparation of the compounds of the invention by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used.

[0323] As used herein, the term "free form" or "free forms" refers to a compound in a non-salt form, such as a base free form or an acid free form of the corresponding compound, e.g., a compound specified herein [e.g., Compound (I), Compound (II), Compound (III), or another pharmaceutically active ingredient, e.g., as defined herein].

[0324] As used herein, the term "salt" or "salt form" refers to an acid addition salt or a base addition salt of the corresponding compound, e.g., a compound specified herein [e.g., Compound (I), Compound (II), Compound (III), or another pharmaceutically active ingredient, e.g., as defined herein]. "Salts" specifically include "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compound, and which are typically not biologically or otherwise undesirable.

[0325] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0326] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0327] 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.

[0328] Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.

[0329] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns 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 ammonium, potassium, sodium, calcium, and magnesium salts.

[0330] 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. Certain organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0331] Pharmaceutically acceptable salts can be synthesized by alkaline or acidic moieties by conventional chemical methods. Usually, such salts can be prepared in the following manner: react the free acid form of the compound with a suitable alkali (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, etc.) of a stoichiometric amount, or by reacting the free alkali form of the compound with a suitable acid of a stoichiometric amount. Typically, such reactions are carried out in water or in an organic solvent or in a mixture of the two. Usually, where feasible, it is desirable to use a non-aqueous medium, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Lists of further suitable salts can be found, for example, in the following documents: “Remington's Pharmaceutical Sciences”, 22nd edition, Mack Printing Company (2013); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, 2011, 2nd edition).

[0332] The compounds specified herein [e.g. Compound (I), Compound (II), Compound (III) or another pharmaceutically active ingredient, e.g. as defined herein] can be administered by conventional routes, in particular orally, such as in the form of tablets or capsules, which can be manufactured according to pharmaceutical techniques as known in the art (e.g., in "Remington Essentials of Pharmaceutics", 2013, 1st edition, edited by Linda Felton, published by Pharmaceutical Press in 2012, ISBN 978 0 85711 105 0; in particular Chapter 30), wherein pharmaceutical excipients are, for example, as described in "Handbook of Pharmaceutical Excipients", 2012, 7th edition, edited by Raymond C. Rowe, Paul J. Sheskey, Walter G. Cook and Marian E. Fenton, ISBN 9780 85711 027 5". In particular, WO 2014 / 199316 describes formulations comprising mavogulan, in particular a modified release form thereof, and is incorporated herein by reference (more particularly the examples, preferred embodiments and claims therein).

[0333] The pharmaceutical composition, or combination of the present invention may be in a unit dosage form (e.g., tablet or capsule) containing a compound specified herein (e.g., mavogulan) in an amount ranging from 1 mg to 300 mg, in particular from 1 mg to 200 mg, such as from 1 mg to 100 mg, the amount referring to the amount of the free form of the compound, and if a salt thereof is used, the amount will be adjusted accordingly. In particular, mavogulan is in free form.

[0334] For the above-mentioned uses / treatment methods, the appropriate dosage may vary according to a variety of factors such as age, body weight, sex, route of administration or salt used. In patients weighing, for example, from 50 to 70 kg, the specified daily dosage is 200 mg / bid of mavogulan, or from 1 mg / day to 100 mg / day of compound (II), which daily dosage refers to the amount of the free form, and if a salt thereof is used, the amount will be adjusted accordingly.

[0335] abbreviation

[0336] ℃ = degrees Celsius

[0337] bid=bid=bid=twice a day

[0338] cm = centimeters

[0339] DSM 5 = Diagnostic and Statistical Manual of Mental Disorders, 5th edition

[0340] ip = intraperitoneal

[0341] Kg = kilogram

[0342] mg = milligrams

[0343] po = oral

[0344] PEG = Evaluation of pain intensity (P), enjoyment of life (E), general activities (G) NRS = Numerical rating scale

[0345] TLFB-Opioids = Timeline Tracking Opioid Self-Report Diary COWS = Clinical Opioid Truncated Symptom Scale

[0346] OCS = Opioid Craving Scale

[0347] NOSE = Digital Opioid Side Effects

[0348] DSM-5 = DMS-V = Diagnostic and Statistical Manual of Mental Disorders, 5th edition

[0349] QTcF = QT interval corrected by Fridericia's formula

[0350] QTcB = QT interval corrected by Bazett's formula

[0351] ECG = electrocardiogram

[0352] C-SSRS = Columbia-Suicidality Severity Rating Scale

[0353] AST = aspartate aminotransferase

[0354] ALT = alanine aminotransferase

[0355] GGT = gamma-glutamyl transferase

[0356] ULN = Upper limit of normal

[0357] OUD = opioid use disorder

[0358] hCG = human chorionic gonadotropin

[0359] FDA = Food and Drug Administration

[0360] QT = time from the beginning of the Q wave to the end of the T wave

[0361] T wave = positive deflection after each QRS complex

[0362] ST wave = time from the beginning of the S wave to the end of the T wave

[0363] Examples

[0364] The following examples are used to illustrate the present invention without limiting its scope. As used in the context of these examples, the term "compound (I)" (i.e., mavogulan) refers to the free form. As used in the context of these examples, the term "compound (II)" {i.e., 9-cyclopropyl-10-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepine [7,1-a]isoquinolin-5(4H)-one} refers to the free form. As used in the context of these examples, the term "compound (III)" (i.e., MPEP) refers to the free form.

[0365] Example 1: Opiate Tolerance Test in Mice (Hot Plate)

[0366] The method for detecting tolerance to analgesic activity follows the method described by Fernandes et al. (Naunyn-Schmiedeberg's Arch. Pharmacol. [Naunyn-Schmiedeberg Pharmacological Archives], 297, 53-60, 1977).

[0367] Mice were placed on a hot metal plate (Bioseb: Model PE34) kept at 54°C, surrounded by a Plexiglas cylinder (height: 13 cm; diameter: 19 cm). The latency to the first paw lick was measured (maximum: 30 seconds). Morphine (32 mg / kg i.p.) or vehicle was administered twice daily for 6 days (at approximately 9:00 and 15:00), and then administered with morphine 8 mg / kg ip (or saline) 30 minutes before testing on the 7th day to assess morphine tolerance.

[0368] The test substances were evaluated at 3 doses each (1, 3 and 10 mg / kg for compound (I) and 0.3, 1 and 3 mg / kg for compound (II)), acutely administered po in morphine-tolerant mice 60 minutes before testing on day 7. Appropriate control groups were included in the experiment to evaluate the potential effects of the test substances on morphine tolerance. Compound (III) was evaluated at 1 dose (10 mg / kg), administered under the same experimental conditions and used as a comparative substance.

[0369] Ten mice were studied in each group. The test was performed blindly. Data were analyzed by comparing the treatment groups with appropriate controls using an unpaired Student's t-test.

[0370] result:

[0371] Compound (III) (10 mg / kg) administered po 60 min before testing on day 7 significantly increased paw licking latency in animals that received vehicle po and morphine (32 mg / kg) ip twice daily from day 1 to day 6 (+32%, p<0.05) compared to animals that received morphine from day 1 to day 6 ( Figure 1 ).

[0372] Compound (I) (1 mg / kg) administered po 60 min prior to testing on day 7 significantly increased paw licking latency in animals receiving vehicle po and morphine (32 mg / kg) ip twice daily from day 1 to day 6 (+44%, p<0.01) compared to animals receiving morphine from day 1 to day 6. It had no significant effect at 3 or 10 mg / kg ( Figure 2 ).

[0373] Compound (II) (3 mg / kg) administered po 60 minutes before testing on day 7 significantly increased paw licking latency in animals receiving vehicle po and morphine (32 mg / kg) ip twice daily from day 1 to day 6 (+38%, p<0.05) compared to animals receiving morphine from day 1 to day 6. It had the same trend at 1 mg / kg (+37%, p=0.0555), but had no effect at 0.3 mg / kg ( Figure 3 ).

[0374] in conclusion:

[0375] These results indicate that po administration of Compound (I) (1 mg / kg), Compound (II) (3 mg / kg) and Compound (III) (10 mg / kg) acutely and significantly reduced the expression of morphine tolerance. Example 2: Clinical Testing [Compound (I)]

[0376]

[0377]

[0378] Study Design

[0379] This study is a randomized, subject and investigator blinded, placebo-controlled, parallel group study to evaluate the efficacy of compound (I) in reducing opioid intake (hydrocodone, oxycodone) in subjects who have used opioids for less than two years in 80 patients with chronic low back pain and postoperative pain. This study includes outpatient visits to the subjects' usual pain clinic and consists of 3 periods: screening and baseline period; treatment period; followed by a treatment follow-up period. The total duration of the subjects may be up to 122 days (approximately 4 months, including screening and baseline periods), depending on the selected opioid reduction percentage.

[0380] Screening / Baseline Period

[0381] The Screening / Baseline Period lasted 14 days and consisted of:

[0382] 1. Obtain informed consent

[0383] 2. Initial diagnostic criteria for opioid tolerance using DSM-V criteria.

[0384] 3. Hematology / biochemistry laboratory safety assessment, including pregnancy testing for premenopausal female subjects

[0385] 4. Medical history, physical examination and vital signs, current medications, and period of treatment for suicidal tendencies

[0386] Subjects who meet all eligibility criteria will be randomly assigned to the compound (I) group or the placebo matching group at a ratio of 1: 1. Study drug treatment should start on day 1, and the total treatment lasts for approximately 93 days, during which the subject will consult with his / her research physician to reduce his / her opioid dose by at least 10% of his / her starting dose every week. Subjects will be titrated by 50 mg, 100 mg and 200 mg bid every 4 days (see Table 1) to reach a total daily dose of 400 mg on day 12. During this titration phase, the safety of the subject will be monitored as the dose of the study drug increases, which will include visits on days 1, 5 and 9 to ensure that the subject has reached a maintenance dose of 400 mg / day without tolerance issues.

[0387] PK samples will be collected pre-dose and 4±1 hours post-dose on Days 13, 55, and 69, respectively, and a pre-dose PK sample will be collected on Day 83. On the day of PK sampling, subjects will take the Compound (I) dose on-site, as pre-dose sampling is required prior to dosing.

[0388] Table 1. Titration schedule for compound (I)

[0389]

[0390] After titration to 400mg / days, the subject will continue to use 400mg compound (I) (200mgb.id) or placebo daily dose from the 13th day to the 82nd day. During this time, the subject will consult with his research physician to reduce his opioid consumption by at least 10% per week until they reach at least 50% of the daily opioid consumption of their starting opioid MME dosage. Subjects who cannot reduce can remain at the current opioid dosage they achieved during the previous week's study. Subjects can reduce their opioid consumption to more than 50% under the guidance of their research physician. Subjects can also aim to reduce their opioid intake by utilizing alternative treatment methods. However, according to this scheme, marijuana is not allowed to treat pain.

[0391] The starting day of compound (I) taper is day 83, and the taper of compound (I) is completed on day 90. Assuming that opioids are conservatively reduced by 10% per week, opioid reduction can be throughout the entire maintenance period of compound (I) administration, or the subject can remain on the opioid dose achieved during the opioid reduction period during the entire remaining compound (I) maintenance period and taper period. The scheme is flexible to allow physicians and patients to choose to reduce the opioid consumption that best suits the subject's treatment and medical history. However, compound (I) treatment is not flexible and should follow the assessment schedule of upward titration, maintenance and taper. Subjects will gradually taper their study drugs (compound (I) or placebo) until they reach their last dose of compound (I) or placebo (Table 2). Subjects will continue to use the opioid dose they have achieved during the reduction process.

[0392] Table 2. Gradual reduction schedule of compound (I)

[0393]

[0394] Treatment follow-up period

[0395] Subjects will return to the clinic for an End of Treatment Completion Visit on Day 97. Subjects must have tapered off study medication prior to the End of Treatment Completion Visit.

[0396] Administration in combination with mandatory opioid reduction during the study period

[0397] Because patients may be taking different doses of different opioids (hydrocodone and oxycodone), these medications should be converted to morphine equivalent doses (MEDs), and opioid reduction should be performed using the MEDs. Because opioid reduction plans should be individualized to minimize opioid withdrawal symptoms while maximizing pain management, they should be performed by the investigator according to the criteria outlined in the Oxford University Hospitals Guidance for Opioid Reduction in Primary Care (v1.1 December 2017), as a reference, see Table 3.

[0398] Table 3. Exemplary reduction schedule assuming at least 10% opioid reduction per week at a starting dose of 100 MME

[0399]

[0400]

[0401] Subjects were not mandated to reduce their opioid intake to zero MME. The study physician and subject should determine the stopping point for opioid reduction.

[0402] group

[0403] A total of approximately 80 patients between the ages of 18 and 65 years, inclusive, with a diagnosis of opioid use disorder were recruited into the study.

[0404] The investigator must ensure that all subjects considered for the study meet the following eligibility criteria. No additional criteria should be applied by the investigator so that the study population will be representative of all eligible subjects.

[0405] Subject selection is established by checking all eligibility criteria at Screening and again at Baseline to ensure that subjects remain eligible for entry into the study. Relevant records of the eligibility criteria (e.g., checklist) must be stored with the source files at the research site.

[0406] Deviation from any of the entry criteria excluded the subject from recruitment into this study.

[0407] Inclusion criteria

[0408] Subjects eligible for inclusion in this study must meet all of the following criteria:

[0409] 1. Healthy male and female subjects aged 18 to 65 years (inclusive) who can provide written informed consent.

[0410] 2. Ability to communicate well with the researcher to understand and comply with the study requirements.

[0411] 3. Future subjects should take opioids according to a fixed dosing schedule (e.g., bid).

[0412] 4. Documented evidence of increased opioid dose without pain relief or increased pain intensity while taking the same amount of medication within at least 4 weeks prior to screening.

[0413] 5. Subjects must be in good health as determined by medical history and physical examination at screening.

[0414] 6. Subjects with chronic low back pain or chronic post-operative neuropathic pain taking between 60 and 100 mg morphine equivalent doses for more than 6 months following a traumatic or surgical event (such as, for example, a motor vehicle accident, a fall, a sports injury, a knee or hip replacement). Subjects with mild to moderate osteoarthritis may be enrolled.

[0415] 7. At Screening, vital signs (systolic and diastolic blood pressure, pulse rate, and respiratory rate) will be assessed in the sitting position and again (when necessary) in the standing position. Vital signs should be within normal limits determined by the Principal Investigator.

[0416] 8. Patients have mild to moderate DSM-5 criteria for a diagnosis of opioid use disorder.

[0417] Exclusion criteria

[0418] Subjects meeting any of the following criteria were not eligible for inclusion in this study.

[0419] 1. The subject cannot foresee any major problems with transportation arrangements or available time to travel to the study site, or have any plans to move to a location within the next few months that would make continued participation in the study impractical.

[0420] 2. Subjects should not be involved in any unresolved legal issues that may jeopardize the continuation or completion of the study.

[0421] 3. History of immunodeficiency disease according to medical records

[0422] 4. History of chronic infection with hepatitis B (HBV) or hepatitis C (HCV) according to medical history.

[0423] 5. The subject's history of ECG abnormalities or current diagnosis indicates that there are significant safety risks for the subject to participate in this study, such as:

[0424] Concomitant clinically significant arrhythmias, such as sustained ventricular tachycardia, and clinically significant second- or third-degree AV block without a pacemaker

[0425] A known family history of long QT syndrome or torsades de pointes

[0426] Resting heart rate (physical examination or 12-lead ECG) < 60 bpm

[0427] Resting QTcF ≥450ms (males) or ≥460ms (females) before treatment [at screening]

[0428] • Note that if QTcB (Bazett) is the only available calibrated value generated by the ECG machine, the Investigator must calculate QTcF at Screening and / or Baseline (as applicable) according to the instructions in the Site Operations Manual.

[0429] Note that sinus tachycardia, left axis deviation, and nonspecific ST or T wave changes are not excluded.

[0430] Use of agents known to prolong the QT interval, unless they can be permanently discontinued during the study

[0431] 6. Please mark “yes” on item 4 or 5 of the suicidal ideation section of the C-SSRS if suicidal ideation has occurred within the past 6 months, or “yes” on any item in the suicidal behavior section (except “non-suicidal self-injurious behavior” which is also included in the items in the suicidal behavior section) if this behavior has occurred within the past 2 years.

[0432] 7. A current diagnosis of a substance use disorder (according to DSM-5) for alcohol or other stimulants (other than opioids prescribed by a physician).

[0433] 8. Any surgical or medical condition that could significantly alter the absorption, distribution, metabolism, or excretion of the drug, or that could endanger the subject while participating in the study. The Investigator should make this determination taking into account the subject's medical history and / or clinical or laboratory evidence of any of the following: Clinical laboratory values ​​(including AST, ALT, total bilirubin, or creatinine) that, in the opinion of the Principal Investigator, are considered clinically unacceptable for the OUD population at Screening.

[0434] Serum bilirubin should not exceed 1.5x ULN

[0435] ALT, AST, GGT should not exceed 3x ULN.

[0436] NOTE: In the event that the safety laboratory assessment at screening is outside the range specified above, the assessment may be repeated once prior to randomization. If the repeated value remains outside the specified range, the subject will be excluded from the study.

[0437] 9. History of hypersensitivity to any study treatment or excipient, or to drugs of similar chemical class.

[0438] 10. Any disease, condition, or history of medication that, in the opinion of the principal investigator or designated personnel, may confound the study results or present additional risks when administering the investigational agent to the subject, or may prevent the successful completion of the study.

[0439] 11. Current and / or previous treatment with concomitant medications that are strong or moderate inducers / inhibitors of CYP3A4 (e.g., clarithromycin, ketoconazole, ritonavir, rifampicin, etc.)

[0440] NOTE: Concomitant medications that are strong or moderate inducers / inhibitors of CYP3A4 should be discontinued for at least five (5) half-lives prior to the first dose.

[0441] 12. Requires treatment with any psychoactive medication, including any anti-epileptic medication (except medication used for the short-term treatment of insomnia).

[0442] NOTE: SSRIs are permitted if adequate stable dosing has been achieved for at least one (1) month prior to dosing.

[0443] 13. History of malignancy of any organ system (except localized basal cell carcinoma of the skin or in situ cervical carcinoma) treated or untreated within the past 5 years (regardless of whether there is evidence of local recurrence or metastasis).

[0444] 14. Known history or presence of cardiovascular or cerebrovascular disease such as angina pectoris, myocardial infarction, stroke, transient ischemic attack, peripheral vascular disease, etc.

[0445] 15. Concomitant use of agents known to prolong the QT interval, unless these agents can be permanently discontinued during this study.

[0446] 16. History of porphyria.

[0447] 17. Women of childbearing potential, defined as all women who are physiologically capable of becoming pregnant, unless they use highly effective contraceptive methods during dosing and within 30 days / weeks after stopping the study drug. Highly effective contraceptive methods include:

[0448] • Complete abstinence from heterosexual intercourse (when this is consistent with the subject's preferences and daily lifestyle). Periodic abstinence (e.g., calendar, ovulation, temperature, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

[0449] Female sterilization (bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks prior to taking the study drug. In the case of oophorectomy only, only if the female's reproductive status has been confirmed by subsequent hormone level assessment.

[0450] Male sterilization (at least 6 months before screening). For female subjects in the study, the vasectomized male partner should be the subject's only partner.

[0451] Barrier methods: condoms or occlusive caps (diaphragms or cervical / vault caps) with spermicidal foam / gel / cream / vaginal suppositories; insertion of an intrauterine device (IUD) or birth control system (IUS).

[0452] · NOTE: Injectable or implantable or oral or transdermal hormonal contraceptives are not considered effective methods of contraception if taken with study medication.

[0453] Women are considered postmenopausal and of no reproductive potential if they have had 12 months of natural (spontaneous) amenorrhea and have an appropriate clinical profile (eg, appropriate age, history of vasoconstrictive symptoms).

[0454] 18. Pregnant or lactating (lactating) women, where pregnancy is defined as the state of a woman after conception until termination of pregnancy, as confirmed by a positive hCG laboratory test.

[0455] 19. Use of other investigational drugs at the time of recruitment, or within 5 half-lives of recruitment, or within 30 days (whichever is longer), or longer if required by local regulations.

[0456] Treatment Group

[0457] Subjects will be assigned at baseline in a 1:1 ratio to one of the following 2 treatment groups.

[0458] Compound (I) group: Up-titration bid schedule, followed by a fixed dose bid method and ending with a tapering bid schedule. For up-titration and tapering schedules, see the study design section (Tables 1 and 2).

[0459] Placebo group: matching placebo

[0460] effect

[0461] Clinical efficacy measures will be collected (PEG, NRS, and TLFB-opioids). In addition, areas proposed in the draft FDA guidance regarding opioid reduction will also be assessed through COWS, OCS, and NOSE, as well as DSM-5 defined opioid use disorder severity.

[0462] Analysis of the Primary End Point

[0463] The purpose of this study is to evaluate the efficacy of compound (I) in reducing opioid consumption in patients with chronic low back pain and postoperative pain who take between 60 and 100 mg of morphine equivalents per day. This will be evaluated by measuring daily consumption using TLFB. Subjects who show a reduction of at least 50% in average weekly consumption between baseline and the last week of treatment will be considered responders. PEG assessments at baseline, at weeks 4, 8, and at the end of the study will provide evidence of treatment response over time.

[0464] Definition of the primary end point

[0465] The primary endpoint of this study is a binary endpoint (responder / non-responder). Response is defined as at least a 50% reduction in mean weekly consumption between baseline (previous week and including baseline visit) and the last week of treatment at the maintenance dose (i.e., 200 mg bid, days 76 to 82) (if the subject completes the maintenance treatment period according to the protocol) or any last 7 days of treatment (if the subject stops treatment before day 82).

[0466] Statistical Models, Assumptions, and Analytical Methods

[0467] Assume that the number of responders in each treatment group follows a binomial distribution Bin(n i ,p i ) random variable, where n i is the number of subjects in treatment group i, and p i is the true potential proportion of subjects in Treatment I who are responders (i=1 for Compound (I) and i=2 for placebo).

[0468] Assuming non-informative β(1 / 3,1 / 3) prior values ​​for responder rates p1 and p2, the posterior probability of the difference in responder rates was used to calculate the probability (p1-p2>0 / data) and the probability (p1-p2>0.2 / data).

[0469] Sample size calculation

[0470] Primary End Point

[0471] Sample size was estimated based on the probability of "success", i.e., the true difference between Compound (I) responder rate and placebo responder rate being >0 with at least 90% confidence and >20% with at least 50% confidence at either the interim analysis or the final analysis.

[0472] The efficacy criteria are formulated according to the posterior probability statement about the difference in true responder rate Δ=p1-p2, where p1 represents the true responder rate of patients treated with Compound (I) and p2 represents the true responder rate of patients treated with placebo. The posterior probability distributions of the two groups are calculated using a standard binomial probability model with a conjugate non-informative beta distribution prior β(a,a), where a=1 / 3 for both p1 and p2.

[0473] Efficacy criteria

[0474] The decision rule used to make a claim about efficacy at the final analysis consists of the following two statements that must be true simultaneously:

[0475] 1. The posterior probability of Δ>0 is greater than 90%;

[0476] 2. The posterior probability of Δ>0.20 is greater than 50%.

Claims

1. Use of mavogulan for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain.

2. Use of mavogulan for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the treatment reverses opioid analgesic tolerance.

3. Use of mavogulan for the manufacture of a medicament for treatment to reverse opioid analgesic tolerance associated with chronic opioid use in chronic pain.

4. Use of mavogulan for the manufacture of a medicament for treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

5. Use of mavogulan for the manufacture of a medicament for the treatment of chronic pain to reverse opioid analgesic tolerance associated with chronic opioid use.

6. Use of mavogulan for the manufacture of a medicament for treating opioid analgesic tolerance to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.

7. Use of mavogulan for the manufacture of a medicament for treatment to reduce opioid consumption in chronic pain.

8. Use of mavogulan for the manufacture of a medicament for use in the treatment of reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the dose of opioid administered to the patient is reduced and the opioid analgesic effect is maintained.

9. The use according to any one of claims 1 to 8, wherein Mavogulan is administered to a patient receiving an opioid dose of >50 mg oral morphine / day or a daily equivalent analgesic dose of another opioid.

10. The use according to any one of claims 1 to 8, wherein the chronic pain is associated with an injury or disease.

11. The use according to any one of claims 1 to 8, wherein the chronic pain is non-malignant chronic pain.

12. The use according to claim 11, wherein the non-malignant chronic pain is chronic back pain.

13. The use according to any one of claims 1 to 8, wherein Mavogulan is administered to elderly patients.

14. The use according to any one of claims 1 to 8, wherein the chronic pain is chronic post-operative neuropathic pain.

15. The use according to any one of claims 1 to 8, wherein Mavogulan is administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

16. The use according to any one of claims 1 to 8, wherein Mavogulan is administered in combination with one or more additional pharmaceutically active ingredients.

17. A combination comprising mavogulan and an opioid.

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