EA046106B1 - USE OF AN mGluR5 ANTAGONIST FOR THE TREATMENT OF TOLERANCE TO OPIOID ANALGESICS - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to the use of an mGluR5 antagonist for the treatment of opioid analgesic tolerance associated with long-term use of opioid drugs for chronic pain.

BACKGROUND OF THE INVENTION

Pain management is a major healthcare challenge that requires a careful balance between pain relief and associated adverse events. In Europe, one fifth of the population suffers from chronic pain. In addition, the incidence of pain-associated diseases is increasing, and, furthermore, pain relief rates of more than 50% are observed in only one-third to two-thirds of the chronic pain patient population (Trends in Neurosciences, 2014, Vol. 37, No. 3, 146).

Opioid drugs, such as morphine, are potent analgesics used to treat chronic pain of moderate to severe intensity due to non-malignant or malignant (ie, cancer) sources. However, although medical guidelines recommend the use of opioid therapy for the management of patients with cancer-related pain, their use for the long-term treatment of non-malignant pain is controversial, in particular due to the numerous adverse events associated with these (eg, nausea, vomiting, itching, drowsiness, cognitive impairment or dry mouth), the development of tolerance to analgesics and, furthermore, the risks of overdose or the development of opioid use disorder. According to the CDC's 2016 opioid prescribing guidelines for chronic pain, more than 165,000 people died from drug-related overdoses between 1999 and 2014 in the United States. with taking opioid painkillers.

Tolerance to opioid analgesics is a well-known pharmacological phenomenon associated with opioid therapy, the underlying biological mechanism of action of which is still poorly understood (International Journal of Clinical Pharmacology and Therapeutics, 2004, Vol. 42, No. 4, 191). This phenomenon is characterized by a decrease in the effectiveness of the analgesic over time and, thus, the need to increase the dose of the opioid in order to maintain the analgesic effect. As the dose of an opioid drug increases, the potential for side effects (eg, respiratory depression, sedation, dizziness, pruritus, nausea, vomiting, constipation, immunological and hormonal dysfunction) and the risk of overdose also increases. According to the CDC report: 1) taking doses equal to 50 MME/day or greater increases the risk of overdose by at least twofold compared with the risk of taking a dose less than 20 MME/day; 2) In a nationally representative sample of Veterans Health Administration chronic pain patients treated with opioids between 2004 and 2209, patients who died of overdose were prescribed doses that averaged 98 MME/day. There is currently no treatment available to reverse opioid analgesic tolerance associated with long-term opioid use for chronic pain. Finding pharmacotherapies to treat opioid analgesic tolerance thus represents a pressing need in the medical field and a major clinical challenge. Treatment of morphine tolerance has been carried out, for example, with the use of ibudilast, minocycline, fluorocitrate, propentofylline, however, the use of these drugs has been associated with the development of significant adverse events. Accordingly, there is a need to identify new therapeutic agents that can be used to treat tolerance to opioid analgesics, in particular, drugs that have the ability to reverse established tolerance, more specifically, without increasing the incidence of adverse events.

Brief Description of the Present Invention

The present invention relates to the use of an mGluR5 antagonist, for example as defined herein, in the treatment of opioid analgesic tolerance associated with long-term use of opioids for chronic pain;

in the treatment of tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain, wherein the treatment eliminates tolerance to opioid analgesics;

in treatment aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioids for chronic pain;

in treatment aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain;

- 1 046106 in the treatment of chronic pain, aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain;

in the treatment of tolerance to opioid analgesics, aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain;

in treatment aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain, where the dose of the opioid drug [eg, daily dose of the opioid drug; e.g., a dose greater than 50 mg oral morphine/day, or an equianalgesic daily dose of another opioid (i.e., morphine milligram equivalents MME/day), e.g., greater than 60 mg oral morphine/day, or the equianalgesic daily dose of another opioid (eg, hydrocodone or oxycodone), up to 100 mg oral morphine/day, or the equianalgesic daily dose of another opioid (eg, hydrocodone or oxycodone) administered to the patient is reduced (eg, by 50% or more, e.g., 70% or more, e.g., 90% or more), and the analgesic effect of the opioid (ie, the effect previously achieved with a higher dose of the opioid) is maintained.

Brief description of graphic materials

In fig. Figure 1 shows: the effect of compound (III) on the latency period before licking the hind paw.

In fig. 2 shows: the effect of compound (I) on the latency to lick the hind paw.

In fig. Figure 3 shows: the effect of compound (II) on the latency period before licking the hind paw.

Detailed Description of the Invention

It has been found that mavoglurant may be an ideal candidate for the treatment of opioid analgesic tolerance associated with long-term use of opioids for chronic pain, and is characterized by therapeutic benefits such as one or more of the following:

i) it reverses opioid analgesic tolerance associated with long-term opioid use, e.g., compared to placebo: e.g., compared to placebo, it reduces opioid consumption [e.g., results in a reduction of 50% or more of baseline opioid consumption funds per day or per week, for example, a reduction of 70% or more, for example, a reduction of 90% or more; for example, as assessed using biomarkers of opioid metabolites or as assessed using self-reported opioid use information (eg, using a self-administered Opioid Diary based on a retrospective timeline; e.g., Sobell LC, et al., in The reliability of the timeline followback method applied to drug, cigarette, and cannabis use (Paper presented at the ^30th Annual Meeting of the Association for the Advancement of Behavioral Therapy, New York, New York, November 1996), with retention of analgesic effect;

ii) it reduces opioid use while maintaining analgesic effects and eliminates or reduces (e.g., one or more) withdrawal symptoms associated with opioid use disorder, e.g., compared with placebo, e.g., as assessed using the Clinical Opiate Withdrawal Scale (COWS; eg, Wesson DR, et al., in Journal of Psychoactive Drugs, 2003, Apr-Jun; 35(2): 253-9);

iii) it reduces opioid consumption while maintaining analgesic effects and eliminates or reduces (e.g., one or more) opioid-associated craving symptoms, e.g., compared to placebo, e.g., as assessed using a rating scale opioid craving (OCS; eg, McHugh RK et al., Drug and Alcohol Dependency, 2014, Dec 1; 145: 121-6);

iv) it reduces opioid consumption while maintaining analgesic effects and eliminates or reduces (e.g., one or more) opioid-associated side effects, e.g., compared with placebo, e.g., as assessed using an assessment tool opioid side effects (nOsE; eg, Smith H.S., et al., Med Clin North Am., 2007, 91(2):213-228);

v) it eliminates or reduces (e.g., a reduction of 10% or more; e.g., a reduction of 30% or more) the intensity, duration, or frequency of one or more of the adverse events associated with long-term use of opioids (e.g., respiratory depression, sedation, dizziness, itching, nausea, vomiting, constipation), for example, compared with placebo;

vi) it reduces the risk of opioid overdose associated with long-term use of opioids, for example, as assessed using the Sedation Rating Scale

- 2 046106 Pasero Opioid Induced Effect (POSS; e.g. in Pasero C, McCaffery M. Pain Assessment and Pharmacologic Management. St. Louis: Mosby/Elsevier; 2011. Section IV, Opioid Analgesics; p.277-622) , for example, compared to placebo;

vii) it improves overall functional status, for example, as assessed using the Clinical Global Impression of Illness Severity (CGI-S) and Improvement (CGI-I) Scale (Psychiatry, 2007, 4(7): 28-37), for example , compared to placebo;

viii) it is characterized by a favorable therapeutic profile, such as a favorable safety profile or a metabolic profile, for example, a favorable profile with respect to off-target effects, psychiatric adverse events, toxicity (for example, genotoxicity) or cardiovascular adverse events (for example, blood parameters). pressure, heart rate, electrocardiography).

Embodiments of the present invention are described herein below.

Embodiments (a).

Embodiment 1a. An mGluR5 antagonist for use in the treatment of opioid analgesic tolerance associated with long-term opioid use for chronic pain.

Embodiment 2a. An mGluR5 antagonist for use in the treatment of opioid analgesic tolerance associated with long-term opioid use for chronic pain, wherein the treatment reverses opioid analgesic tolerance.

Embodiment 3a. An mGluR5 antagonist for use in eliminating tolerance to opioid analgesics associated with long-term use of opioids for chronic pain.

Embodiment 4a. An mGluR5 antagonist for use in treatment aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain.

Embodiment 5a. An mGluR5 antagonist for use in the treatment of chronic pain, aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain.

Embodiment 6a. An mGluR5 antagonist for use in the treatment of opioid analgesic tolerance, aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain.

Embodiment 7a. An mGluR5 antagonist for use in reducing opioid use in chronic pain.

Embodiment 8a. An mGluR5 antagonist for use in reversing opioid analgesic tolerance associated with long-term use of opioids for chronic pain, where the dose of the opioid [e.g., daily dose of the opioid] administered to the patient is reduced (e.g., by 50% or more, e.g. 70% or greater, e.g., 90% or greater), and the analgesic effect of the opioid (i.e., previously achieved with a higher dose of the opioid) is maintained.

Embodiment 9a. An mGluR5 antagonist for use according to any of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient receiving a dose of an opioid agent that is greater than 50 mg oral morphine/day, or an equianalgesic daily dose of another opioid agent (i.e., the number of milligram equivalents of morphine MME/day), for example, a patient receiving an opioid dose of 60 mg to 100 mg oral morphine/day, or an equianalgesic daily dose of another opioid.

Embodiment 10a. An mGluR5 antagonist for use as in any of the preceding embodiments, wherein chronic pain is associated with injury (eg, wound, burn, or fracture) or disease (eg, diabetes, multiple sclerosis, arthritis, autoimmune disease, or infection).

Embodiment 11a. An mGluR5 antagonist for use as in any of the preceding embodiments, wherein the chronic pain is chronic pain of non-malignant origin.

Embodiment 12a. An mGluR5 antagonist for use in embodiment 11a, wherein the non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example, with or without prior spinal surgery.

Embodiment 13a. An mGluR5 antagonist for use according to any of the previous embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.

Embodiment 14a. An mGluR5 antagonist for use as in any of the preceding embodiments, wherein the chronic pain is chronic pain due to postoperative neuropathy.

- 3 046106

Embodiment 15a. An mGluR5 antagonist for use according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; particularly in a modified release form.

Embodiment 16a. An mGluR5 antagonist for use according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

Embodiment 17a. An mGluR5 antagonist for use according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in combination with one or more additional pharmaceutical active ingredients.

Embodiment 18a. An mGluR5 antagonist for use according to any of the previous 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.

Embodiment 19a. An mGluR5 antagonist for use in embodiment 18a, wherein the mGluR5 antagonist is compound (I) or a pharmaceutically acceptable salt thereof.

Embodiment 20a. An mGluR5 antagonist for use according to embodiment 19a, wherein the mGluR5 antagonist is administered in an amount of 50 mg/b.i.d. to 200 mg/b.i.d., in particular 50 mg/b.i.d., 100 mg/b.i.d. or 200 mg/b.i.d., for example 200 mg /b.i.d.

Embodiment 21a. An mGluR5 antagonist for use in embodiment 18a, wherein the mGluR5 antagonist is compound (II) or a pharmaceutically acceptable salt thereof.

Embodiment 22a. An mGluR5 antagonist for use in embodiment 21a, wherein the mGluR5 antagonist is administered in an amount ranging from 1 mg/day to 100 mg/day.

Embodiment 23a. An mGluR5 antagonist for use in embodiment 18a, wherein the mGluR5 antagonist is compound (III) or a pharmaceutically acceptable salt thereof.

Embodiment 24a. Combination containing an mGluR5 antagonist and an opioid agent.

Embodiment 25a. The combination of embodiment 24a, wherein the opioid agent is selected from the group consisting of alphamethylfentanyl, alfentanyl, buprenorphine, butorphanol, codeine, diacetylmorphine, dihydrocodeine, dihydroetorphine, dihydromorphine, ethylmorphine, etorphine, fentanyl, hydrocodone, hydromorphone, L-acetylmethadol, levorphanol, methadone , meperidine, morphine, nicomorphine, normethadone, noroxycodone, normorphine, norlevorphanol, oxycodone, oxymorphone, phenazocine, propoxyphene, remifentanil, tramadol, thebaine, tapentadol, levorphanol, sufentanil, pentazocine, carfentanil, ohmfentanil, nocaine, ketobemidone, allylprodine, prodine, dextropropoxyphene , dextromoramide, bezitramide, piritramide, dipipanone, loperamide, diphenoxylate, nalbuphine, levometorfa, dezocine, lefetamine and tildin; in particular, the opioid agent is selected from the group consisting of hydrocodone and oxycodone.

Embodiment 26a. The combination of Embodiment 24a or Embodiment 25a, comprising at least one additional active ingredient selected from the group consisting of an antidepressant (e.g., a tricyclic antidepressant such as amitriptyline, nortriptyline, doxepin, desipramine, imipramine, protriptyline, trimipramine, clomipramine) , serotonin and norepinephrine reuptake inhibitor (eg, duloxetine, venlafaxine, desvenlafaxine, milnacipran, levomilnacipran), serotonin reuptake inhibitor (eg, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, vilazodone, vortioxetine), anticonvulsant (eg, gabapentin, pregabalin, carbamazepine, valproic acid, phenytoin, lamotrigine, tiagabine, lacosamide, topiramate, levetiracetam, oxcarbazepine, zonisamide), non-steroidal anti-inflammatory drug (NSAID; such as naproxen, ibuprofen, meloxicam, diclofenac, fenoprofen, flurbiprofen, diflunisal, etodolac , nabomethumon, ketoprofen, pyroxics, Sulindak, Tolmetin, ketorolac, mephenamic acid, oxaprosine), proton pump inhibitor (for example, omeprazole, pantoprazole, lansoprazole, dexlaxoprazole, esomeprazole, rabepperpperpepprazole), antagonist H2 REGURE (for example, Famotidin, Nizatidin, Nizatidin, Nizatidin, Nizatidin, Nizatidin, Nizatidin, Nizatidine, Nizatidine, Nizatidin, Nizatidine, Nizatidine, Nizatidine, Nizatidine, Nizatidin, Nizatidin, Nizatidin, Nizatidin. Dina, Tsimetidin ), NMDA inhibitor (eg, ketamine, amantadine, mematine), NO-NSAID, selective COX-2 inhibitor, cannabinoid receptor agonist, nitric oxide donor, beta-adrenergic receptor agonist, alpha-2 receptor agonist, selective prostanoid receptor antagonist, local anesthetic (eg, capsaicin, lidocaine), purinergic P2 receptor antagonist, neural nicotinic receptor agonist, calcium channel antagonist, sodium channel blocker (eg, mexiletine, flecainide), superoxide dismutase mimetic, p38 MAP kinase inhibitor, TRPV1 agonist, glycine antagonist receptor, corticosteroid and acetaminophen.

Embodiment 27a. The combination according to any of the previous 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.

Embodiment 28a. The combination of embodiment 27a, wherein the mGluR5 antagonist

- 4 046106 represents compound (I) or a pharmaceutically acceptable salt thereof.

Embodiment 29a. The combination of embodiment 27a, wherein the mGluR5 antagonist is compound (II) or a pharmaceutically acceptable salt thereof.

Embodiment 30a. The combination of embodiment 27a, wherein the mGluR5 antagonist is compound (III) or a pharmaceutically acceptable salt thereof.

Embodiments (b).

Embodiment 1b. A pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use in the treatment of tolerance to opioid analgesics associated with long-term use of opioids for chronic pain.

Embodiment 2b. A pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use in the treatment of tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain, wherein the treatment eliminates tolerance to opioid analgesics.

Embodiment 3b. A pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use in eliminating tolerance to opioid analgesics associated with long-term use of opioids for chronic pain.

Embodiment 4b. A pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use in treatment aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain.

Embodiment 5b. A pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use in the treatment of chronic pain aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioids.

Embodiment 6b. A pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use in the treatment of tolerance to opioid analgesics, aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain.

Embodiment 7b. A pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use in reducing the consumption of opioids for chronic pain.

Embodiment 8b. A pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use in eliminating tolerance to opioid analgesics associated with long-term use of opioids for chronic pain, wherein the dose of the opioid [e.g., daily dose of the opioid] administered patient is reduced (e.g., 50% or more, e.g., 70% or more, e.g., 90% or more), and the analgesic effect of the opioid (i.e., previously achieved with a higher dose of the opioid) is maintained .

Embodiment 9b. A pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use according to any of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient receiving a dose of an opioid agent that is greater than 50 mg oral morphine/day, or an equianalgesic daily dose dose of another opioid agent (i.e., morphine milligram equivalents MME/day), for example, to a patient receiving an opioid dose of 60 mg to 100 mg oral morphine/day, or an equianalgesic daily dose of another opioid agent.

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

Embodiment 11b. A pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use according to any of the previous embodiments, wherein the chronic pain is chronic pain of non-malignant origin.

Embodiment 12b. A pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use in embodiment 11b, wherein chronic pain of non-malignant origin is

- 5 046106 is chronic back pain, such as chronic low back pain, for example, with or without previous spinal surgery.

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

Embodiment 14b. A pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use according to any of the previous embodiments, wherein the chronic pain is chronic pain due to postoperative neuropathy.

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

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

Embodiment 17b. A pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use according to any of the previous 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.

Embodiment 18b. A pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use in embodiment 17b, wherein the mGluR5 antagonist is compound (I) or a pharmaceutically acceptable salt thereof.

Embodiment 19b. A pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for use in embodiment 18b, wherein the mGluR5 antagonist is administered in an amount of between 50 mg/b.i.d. up to 200 mg/b.i.d., in particular 50 mg/b.i.d., 100 mg/b.i.d. or 200 mg/b.i.d., e.g. 200 mg/b.i.d.

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

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

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

Embodiments (c).

Embodiment 1c. A pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient, for use in the treatment of opioid analgesic tolerance associated with long-term use of opioids for chronic pain.

Embodiment 2c. A pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient, for use in the treatment of opioid analgesic tolerance associated with long-term use of opioid drugs for chronic pain, wherein the treatment eliminates tolerance to opioid analgesics.

Embodiment 3c. A pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient, for use in eliminating tolerance to opioid analgesics associated with long-term use of opioids for chronic pain.

Embodiment 4c. A pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for use in treatment aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain.

Embodiment 5c. Pharmaceutical combination containing an mGluR5 antagonist and

- 6 046106 at least one additional pharmaceutical active ingredient, for use in the treatment of chronic pain aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioids.

Embodiment 6c. A pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient, for use in the treatment of tolerance to opioid analgesics, aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain.

Embodiment 7c. A pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for use in reducing the consumption of opioids for chronic pain.

Embodiment 8c. A pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient, for use in reversing opioid analgesic tolerance associated with long-term use of opioids for chronic pain, wherein the dose of the opioid [e.g., daily dose of the opioid] administered patient is reduced (e.g., 50% or more, e.g., 70% or more, e.g., 90% or more), and the analgesic effect of the opioid (i.e., previously achieved with a higher dose of the opioid) is maintained .

Embodiment 9c. A pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient, for use according to any of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient receiving a dose of an opioid agent that is greater than 50 mg oral morphine/day, or an equianalgesic daily dose dose of another opioid agent (i.e., morphine milligram equivalents MME/day), for example, to a patient receiving an opioid dose of 60 mg to 100 mg oral morphine/day, or an equianalgesic daily dose of another opioid agent.

Embodiment 10c. A pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient, for use as in any of the preceding embodiments, wherein chronic pain is associated with injury (e.g., wound, burn, or fracture) or disease (e.g., diabetes, multiple sclerosis, arthritis, autoimmune disease or infection).

Embodiment 11c. A pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient, for use according to any of the previous embodiments, wherein the chronic pain is chronic pain of non-malignant origin.

Embodiment 12c. A pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient, for use in embodiment 11b, wherein the chronic pain of non-malignant origin is chronic back pain, such as chronic low back pain, for example with prior surgery with or without the spine.

Embodiment 13c. A pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for use according to any of the previous embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.

Embodiment 14c. A pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient, for use according to any of the previous embodiments, wherein the chronic pain is chronic pain due to postoperative neuropathy.

Embodiment 15c. A pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for use according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; particularly in a modified release form.

Embodiment 16c. A pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for use according to any of the previous 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.

Embodiment 17c. A pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient, for use in embodiment 16c, wherein the mGluR5 antagonist is compound (I) or a pharmaceutically acceptable salt thereof.

Embodiment 18c. Pharmaceutical combination containing an mGluR5 antagonist and

- 7 046106 at least one additional pharmaceutical active ingredient, for use in embodiment 17c, wherein the mGluR5 antagonist is administered in an amount of from 50 mg/b.i.d. up to 200 mg/b.i.d., in particular 50 mg/b.i.d., 100 mg/b.i.d. or 200 mg/b.i.d., e.g. 200 mg/b.i.d.

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

Embodiment 20c. A pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient, for use in embodiment 19c, wherein the mGluR5 antagonist is administered in an amount ranging from 1 mg/day to 100 mg/day.

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

Embodiments (d).

Embodiment 1d. A method of treating opioid analgesic tolerance associated with long-term use of opioid drugs for chronic pain in a subject in need thereof, comprising administering to said subject an effective amount of an mGluR5 antagonist.

Embodiment 2d. A method of treating opioid analgesic tolerance associated with long-term use of opioid medications for chronic pain, wherein the treatment reverses opioid analgesic tolerance in a subject in need thereof, comprising administering to said subject an effective amount of an mGluR5 antagonist.

Embodiment 3d. A method of treatment for eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain in a subject in need thereof, comprising administering to said subject an effective amount of an mGluR5 antagonist.

Embodiment 4d. A method of treatment aimed at reducing the risk of opioid analgesic overdose associated with long-term use of opioid drugs for chronic pain in a subject in need thereof, comprising administering to said subject an effective amount of an mGluR5 antagonist.

Embodiment 5d. A method of treating chronic pain aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs in a subject in need thereof, comprising administering to said subject an effective amount of an mGluR5 antagonist.

Embodiment 6d. A method of treating opioid analgesic tolerance aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain in a subject in need thereof, comprising administering to said subject an effective amount of an mGluR5 antagonist.

Embodiment 7d. A method of treatment for reducing the consumption of opioids for chronic pain in a subject in need thereof, comprising administering to said subject an effective amount of an mGluR5 antagonist.

Embodiment 8d. A method of treatment for eliminating tolerance to opioid analgesics associated with long-term use of opioid agents for chronic pain in a subject in need thereof, comprising administering to said subject an effective amount of an mGluR5 antagonist, whereby a dose of the opioid agent [e.g., a daily dose of the opioid agent] that administered to a patient is reduced (eg, by 50% or more, e.g., 70% or more, e.g., 90% or more), and the analgesic effect of the opioid (i.e., previously achieved with a higher dose of the opioid) is saved.

Embodiment 9d. The method of any of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient receiving a dose of an opioid agent that is greater than 50 mg oral morphine/day, or an equianalgesic daily dose of another opioid agent (i.e., the number of morphine milligram equivalents MME/day ), for example, a patient receiving a dose of 60 mg to 100 mg oral morphine/day of an opioid, or an equianalgesic daily dose of another opioid.

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

Embodiment 11d. The method according to any of the previous embodiments, wherein the chronic pain is chronic pain of non-malignant origin.

Embodiment 12d. The method of embodiment 11d, wherein chronic pain

- 8 046106 of non-malignant origin is chronic back pain, such as chronic low back pain, for example, with or without previous spinal surgery.

Embodiment 13d. The method according to any of the previous embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.

Embodiment 14d. The method according to any of the previous embodiments, wherein the chronic pain is chronic pain due to postoperative neuropathy.

Embodiment 15d. The method according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in an immediate release form or in a modified release form; particularly in a modified release form.

Embodiment 16d. The method according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in the form of a pharmaceutical composition further containing at least one pharmaceutically acceptable excipient.

Embodiment 17d. The method according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in combination with one or more additional pharmaceutical active ingredients.

Embodiment 18d. The method according to any of the previous 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.

Embodiment 19d. The method of embodiment 18d, wherein the mGluR5 antagonist is compound (I) or a pharmaceutically acceptable salt thereof.

Embodiment 20d. The method according to embodiment 19d, wherein the mGluR5 antagonist is administered in an amount of 50 mg/b.i.d. to 200 mg/b.i.d., in particular 50 mg/b.i.d., 100 mg/b.i.d. or 200 mg/b.i.d., for example 200 mg/b.i.d.

Embodiment 21d. The method of embodiment 18d, wherein the mGluR5 antagonist is compound (II) or a pharmaceutically acceptable salt thereof.

Embodiment 22d. The method of embodiment 21d, wherein the mGluR5 antagonist is administered in an amount ranging from 1 mg/day to 100 mg/day.

Embodiment 23d. The method of embodiment 18d, wherein the mGluR5 antagonist is compound (III) or a pharmaceutically acceptable salt thereof.

Embodiments (e).

Embodiment 1e. A method of treating opioid analgesic tolerance associated with long-term use of opioid drugs for chronic pain in a subject in need thereof, comprising administering to said subject a pharmaceutical composition containing an effective amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient.

Embodiment 2e. A method of treating opioid analgesic tolerance associated with long-term use of opioid drugs for chronic pain, wherein the treatment eliminates opioid analgesic tolerance in a subject in need thereof, comprising administering to said subject a pharmaceutical composition containing an effective amount of an mGluR5 antagonist and at least one pharmaceutical acceptable excipient.

Embodiment 3e. A method of treatment for eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain in a subject in need thereof, comprising administering to said subject a pharmaceutical composition containing an effective amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient.

Embodiment 4e. A method of treatment aimed at reducing the risk of opioid overdose associated with long-term use of opioid drugs for chronic pain in a subject in need thereof, comprising administering to said subject a pharmaceutical composition containing an effective amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient.

Embodiment 5e. A method of treating chronic pain aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioids in a subject in need thereof, comprising administering to said subject a pharmaceutical composition containing an effective amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient.

Embodiment 6e. A method of treating opioid analgesic tolerance aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain in a subject in need thereof, comprising administering to said subject a pharmaceutical composition containing an effective

- 9 046106 an amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient.

Embodiment 7e. A method of treatment for reducing the consumption of opioids for chronic pain in a subject in need thereof, comprising administering to said subject a pharmaceutical composition containing an effective amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient.

Embodiment 8e. A method of treatment for eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain in a subject in need thereof, comprising administering to said subject a pharmaceutical composition containing an effective amount of an mGluR5 antagonist and at least one pharmaceutically acceptable excipient, whereby the dose of opioid agent [e.g., daily dose of opioid agent] administered to the patient is reduced (e.g., 50% or more, e.g., 70% or more, e.g., 90% or more), and the analgesic effect of the opioid agent (t i.e. previously achieved using a higher dose of the opioid) is maintained.

Embodiment 9e. The method of any of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient receiving a dose of an opioid agent that is greater than 50 mg oral morphine/day, or an equianalgesic daily dose of another opioid agent (i.e., the number of morphine milligram equivalents MME/day ), for example, a patient receiving a dose of 60 mg to 100 mg oral morphine/day of an opioid, or an equianalgesic daily dose of another opioid.

Embodiment 10e The method as in any of the preceding embodiments, wherein the chronic pain is associated with an injury (eg, a wound, burn, or fracture) or a disease (eg, diabetes, multiple sclerosis, arthritis, an autoimmune disease, or infection).

Embodiment 11e. The method according to any of the previous embodiments, wherein the chronic pain is chronic pain of non-malignant origin.

Embodiment 12e. The method of embodiment 11e, wherein the non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example, with or without prior spinal surgery.

Embodiment 13e. An mGluR5 antagonist for use according to any of the previous embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.

Embodiment 14e. The method according to any of the previous embodiments, wherein the chronic pain is chronic pain due to postoperative neuropathy.

Embodiment 15e. The method according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in an immediate release form or in a modified release form; particularly in a modified release form.

Embodiment 16e. The method according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in combination with one or more additional pharmaceutical active ingredients.

Embodiment 17e. The method according to any of the previous 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.

Embodiment 18e. The method of embodiment 17e, wherein the mGluR5 antagonist is compound (I) or a pharmaceutically acceptable salt thereof.

Embodiment 19e. The method of embodiment 18e, wherein the mGluR5 antagonist is administered in an amount of 50 mg/b.i.d. to 200 mg/b.i.d., in particular 50 mg/b.i.d., 100 mg/b.i.d. or 200 mg/b.i.d., for example 200 mg/b.i.d.

Embodiment 20e. The method of embodiment 17e, wherein the mGluR5 antagonist is compound (II) or a pharmaceutically acceptable salt thereof.

Embodiment 21e. The method of embodiment 20e, wherein the mGluR5 antagonist is administered in an amount ranging from 1 mg/day to 100 mg/day.

Embodiment 22e. The method of embodiment 17e, wherein the mGluR5 antagonist is compound (III) or a pharmaceutically acceptable salt thereof.

Embodiments (f).

Embodiment 1f. A method of treating opioid analgesic tolerance associated with long-term use of opioid drugs for chronic pain in a subject in need thereof, comprising administering to said subject a pharmaceutical combination containing an effective amount of an mGluR5 antagonist and at least one additional pharmaceutical active ingredient.

Embodiment 2f. Method for treating tolerance to opioid analgesics,

- 10 046106 associated with long-term use of opioid drugs for chronic pain, wherein the treatment reverses tolerance to opioid analgesics, in a subject in need thereof, comprising administering to said subject a pharmaceutical combination containing an effective amount of an mGluR5 antagonist and at least one additional pharmaceutical active ingredient .

Embodiment 3f. A method of treatment for eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain in a subject in need thereof, comprising administering to said subject a pharmaceutical combination containing an effective amount of an mGluR5 antagonist and at least one additional pharmaceutical active ingredient.

Embodiment 4f. A method aimed at reducing the risk of opioid overdose associated with long-term use of opioid drugs for chronic pain in a subject in need thereof, comprising administering to said subject a pharmaceutical combination containing an effective amount of an mGluR5 antagonist and at least one additional pharmaceutical active ingredient.

Embodiment 5f. A method of treating chronic pain aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs in a subject in need thereof, comprising administering to said subject a pharmaceutical combination containing an effective amount of an mGluR5 antagonist and at least one additional pharmaceutical active ingredient.

Embodiment 6f. A method of treating opioid analgesic tolerance aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain in a subject in need thereof, comprising administering to said subject a pharmaceutical combination containing an effective amount of an mGluR5 antagonist and at least one additional pharmaceutical active ingredient.

Embodiment 7f. A method of treatment for reducing the consumption of opioids for chronic pain in a subject in need thereof, comprising administering to said subject a pharmaceutical combination containing an effective amount of an mGluR5 antagonist and at least one additional pharmaceutical active ingredient.

Embodiment 8f. A method of treatment for eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain in a subject in need thereof, comprising administering to said subject a pharmaceutical combination containing an effective amount of an mGluR5 antagonist and at least one additional pharmaceutical active ingredient, whereby the dose of opioid agent [e.g., daily dose of opioid agent] administered to the patient is reduced (e.g., 50% or more, e.g., 70% or more, e.g., 90% or more), and the analgesic effect of the opioid agent (t i.e. previously achieved using a higher dose of the opioid) is maintained.

Embodiment 9f. The method of any of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient receiving a dose of an opioid agent that is greater than 50 mg oral morphine/day, or an equianalgesic daily dose of another opioid agent (i.e., the number of morphine milligram equivalents MME/day ), for example, a patient receiving a dose of 60 mg to 100 mg oral morphine/day of an opioid, or an equianalgesic daily dose of another opioid.

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

Embodiment 11f. The method according to any of the previous embodiments, wherein the chronic pain is chronic pain of non-malignant origin.

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

Embodiment 13f. An mGluR5 antagonist for use according to any of the previous embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.

Embodiment 14f. The method according to any of the previous embodiments, wherein the chronic pain is chronic pain due to postoperative neuropathy.

Embodiment 15f. The method according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in an immediate release form or in a modified release form; particularly in a modified release form.

- 11 046106

Embodiment 16f. The method according to any of the previous 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.

Embodiment 17f. The method of embodiment 16f, wherein the mGluR5 antagonist is compound (I) or a pharmaceutically acceptable salt thereof.

Embodiment 18f. Method according to embodiment 17f, wherein the mGluR5 antagonist is administered in an amount ranging from 50 mg/b.i.d. to 200 mg/b.i.d., in particular 50 mg/b.i.d., 100 mg/b.i.d. or 200 mg/b.i.d., for example 200 mg/b.i.d.

Embodiment 19f. The method of embodiment 16f, wherein the mGluR5 antagonist is compound (II) or a pharmaceutically acceptable salt thereof.

Embodiment 20f. The method of embodiment 19f, wherein the mGluR5 antagonist is administered in an amount ranging from 1 mg/day to 100 mg/day.

Embodiment 21f. The method of embodiment 16f, wherein the mGluR5 antagonist is compound (III) or a pharmaceutically acceptable salt thereof.

Embodiments (g).

Embodiment 1g. Use of an mGluR5 antagonist for the manufacture of a medicinal product for the treatment of opioid analgesic tolerance associated with long-term use of opioid drugs for chronic pain.

Embodiment 2g. Use of an mGluR5 antagonist to formulate a medicinal product for the treatment of opioid analgesic tolerance associated with long-term opioid use for chronic pain, wherein the treatment reverses opioid analgesic tolerance.

Embodiment 3g. Use of an mGluR5 antagonist for the manufacture of a medicinal product for treatment aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain.

Embodiment 4g. Use of an mGluR5 antagonist to formulate a medicinal product for treatment aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain.

Embodiment 5g. Use of an mGluR5 antagonist for the manufacture of a medicinal product for the treatment of chronic pain aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioids.

Embodiment 6g. Use of an mGluR5 antagonist for the manufacture of a medicinal product for the treatment of tolerance to opioid analgesics, aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain.

Embodiment 7g. Use of an mGluR5 antagonist for the manufacture of a medicinal product for treatment aimed at reducing opioid use in chronic pain.

Embodiment 8g. The use of an mGluR5 antagonist for the manufacture of a medicinal product for treatment aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain, where the dose of the opioid drug [e.g., the daily dose of the opioid drug] administered to the patient is reduced (for example, by 50% or more, e.g., 70% or more, e.g., 90% or more), and the analgesic effect of the opioid (i.e., previously achieved with a higher dose of the opioid) is maintained.

Embodiment 9g. Use of an mGluR5 antagonist for the manufacture of a medicinal product according to any of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient receiving a dose of an opioid agent that is greater than 50 mg of oral morphine/day, or an equianalgesic daily dose of another opioid agent (i.e., number of milligrams) -morphine equivalents MME/day), for example, a patient receiving an opioid dose of 60 mg to 100 mg oral morphine/day, or an equianalgesic daily dose of another opioid.

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

Embodiment 11g. Use of an mGluR5 antagonist for the manufacture of a medicament according to any of the previous embodiments, wherein the chronic pain is non-malignant chronic pain.

Embodiment 12g. Use of an mGluR5 antagonist for the manufacture of a medicament according to embodiment 11g, wherein the chronic pain of non-malignant origin is chronic back pain, such as chronic low back pain,

- 12 046106 for example, with or without previous spinal surgery.

Embodiment 13g. Use of an mGluR5 antagonist for the manufacture of a medicament according to any of the previous embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.

Embodiment 14g. Use of an mGluR5 antagonist for the manufacture of a medicament according to any of the previous embodiments, wherein the chronic pain is chronic pain due to post-operative neuropathy.

Embodiment 15g. Use of an mGluR5 antagonist for the manufacture of a medicament according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; particularly in a modified release form.

Embodiment 16g. Use of an mGluR5 antagonist for the manufacture of a medicinal product according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in the form of a pharmaceutical composition further containing at least one pharmaceutically acceptable excipient.

Embodiment 17g. Use of an mGluR5 antagonist for the manufacture of a medicament according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in combination with one or more additional pharmaceutical active ingredients.

Embodiment 18g. Use of an mGluR5 antagonist for the manufacture of a medicinal product according to any of the previous 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.

Embodiment 19g. Use of an mGluR5 antagonist for the manufacture of a medicament according to Embodiment 18g, wherein the mGluR5 antagonist is compound (I) or a pharmaceutically acceptable salt thereof.

Embodiment 20g. Use of an mGluR5 antagonist for the manufacture of a medicinal product according to embodiment 19g, wherein the mGluR5 antagonist is administered in an amount of 50 mg/b.i.d. to 200 mg/b.i.d., in particular 50 mg/b.i.d., 100 mg/b.i.d. or 200 mg/b.i.d., for example , 200 mg/b.i.d.

Embodiment 21g. Use of an mGluR5 antagonist for the manufacture of a medicament according to Embodiment 18g, wherein the mGluR5 antagonist is compound (II) or a pharmaceutically acceptable salt thereof.

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

Embodiment 23g. Use of an mGluR5 antagonist for the manufacture of a medicament according to Embodiment 18g, wherein the mGluR5 antagonist is compound (III) or a pharmaceutically acceptable salt thereof.

Embodiments (h).

Embodiment 1h. The use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product for the treatment of tolerance to opioid analgesics associated with long-term use of opioids for chronic pain.

Embodiment 2h. The use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product for the treatment of tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain, wherein the treatment eliminates tolerance to opioid analgesics.

Embodiment 3h. The use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product for treatment aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioids for chronic pain.

Embodiment 4h. The use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product for treatment aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain.

Embodiment 5h. Application of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product for the treatment of chronic pain, aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioids.

- 13 046106 funds.

Embodiment 6h. The use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product for the treatment of tolerance to opioid analgesics, aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain.

Embodiment 7h. The use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product for treatment aimed at reducing the consumption of opioids for chronic pain.

Embodiment 8h. The use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product for treatment aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain, where the dose of the opioid drug [for example, daily dose of opioid] administered to the patient is reduced (e.g., 50% or more, e.g., 70% or more, e.g., 90% or more), and the analgesic effect of the opioid (i.e., previously achieved with higher dose of opioid) is maintained.

Embodiment 9h. Use of a pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product according to any of the previous embodiments, wherein the mGluR5 antagonist is administered to a patient receiving a dose of an opioid agent of more than 50 mg of oral morphine/day, or an equianalgesic daily dose of another opioid drug (i.e., the number of morphine milligram equivalents MME/day), for example, a patient receiving a dose of an opioid drug ranging from 60 mg to 100 mg oral morphine/day, or an equianalgesic daily dose of another opioid drug.

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

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

Embodiment 12h. Use of a pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicament according to embodiment 11h, wherein the chronic pain of non-malignant origin is chronic back pain, such as chronic low back pain, e.g. previous spinal surgery or without it.

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

Embodiment 14h. Use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicament according to any of the previous embodiments, wherein the chronic pain is chronic pain due to postoperative neuropathy.

Embodiment 15h. Use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; particularly in a modified release form.

Embodiment 16h. Use of a pharmaceutical composition comprising an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in combination with one or more additional pharmaceutical active ingredients.

Embodiment 17h. The use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for

- 14 046106 manufacturing a medicinal product according to any of the previous 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.

Embodiment 18h. Use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product according to embodiment 17h, wherein the mGluR5 antagonist is compound (I) or a pharmaceutically acceptable salt thereof.

Embodiment 19h. Use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product according to embodiment 18h, wherein the mGluR5 antagonist is administered in an amount ranging from 50 mg/b.i.d to 200 mg/b.i.d, in particular 50 mg /b.i.d., 100 mg/b.i.d. or 200 mg/b.i.d., e.g. 200 mg/b.i.d.

Embodiment 20h. Use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product according to embodiment 17h, wherein the mGluR5 antagonist is compound (II) or a pharmaceutically acceptable salt thereof.

Embodiment 21h. Use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product according to embodiment 20h, wherein the mGluR5 antagonist is administered in an amount ranging from 1 mg/day to 100 mg/day.

Embodiment 22h. Use of a pharmaceutical composition containing an mGluR5 antagonist and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product according to embodiment 17h, wherein the mGluR5 antagonist is compound (III) or a pharmaceutically acceptable salt thereof.

Embodiments (j).

Embodiment 1j. The use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product for the treatment of tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain.

Embodiment 2j. The use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product for the treatment of tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain, wherein the treatment eliminates tolerance to opioid analgesics.

Embodiment 3j. The use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product for treatment aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioids for chronic pain.

Embodiment 4j. The use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product for treatment aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain.

Embodiment 5j. The use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product for the treatment of chronic pain aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioids.

Embodiment 6j. The use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product for the treatment of tolerance to opioid analgesics, aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain.

Embodiment 7j. The use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product for treatment aimed at reducing the consumption of opioids for chronic pain.

Embodiment 8j. The use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product for treatment aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for

- 15 046106 chronic pain, where the dose of the opioid agent [for example, the daily dose of the opioid drug] administered to the patient is reduced (for example, by 50% or more, for example, by 70% or more, for example, by 90% or more), and the analgesic effect of the opioid (i.e., previously achieved with a higher dose of the opioid) is maintained.

Embodiment 9j. Use of a pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product according to any of the previous embodiments, wherein the mGluR5 antagonist is administered to a patient receiving a dose of an opioid agent of more than 50 mg of oral morphine/day, or an equianalgesic daily dose of another opioid drug (i.e., the number of morphine milligram equivalents MME/day), for example, a patient receiving a dose of an opioid drug ranging from 60 mg to 100 mg oral morphine/day, or an equianalgesic daily dose of another opioid drug.

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

Embodiment 11j. Use of a pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicament according to any of the previous embodiments, wherein the chronic pain is chronic pain of non-malignant origin.

Embodiment 12j. Use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product according to embodiment 11j, wherein the chronic pain of non-malignant origin is chronic back pain, such as chronic low back pain, e.g. previous spinal surgery or without it.

Embodiment 13j. Use of a pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicament according to any of the previous embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.

Embodiment 14j. Use of a pharmaceutical combination comprising an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicament according to any of the previous embodiments, wherein the chronic pain is chronic pain due to post-operative neuropathy.

Embodiment 15j. Use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product according to any of the previous embodiments, wherein the mGluR5 antagonist is administered in an immediate release form or a modified release form; particularly in a modified release form.

Embodiment 16j. Use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product according to any of the previous 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.

Embodiment 17j. Use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product according to embodiment 16j, wherein the mGluR5 antagonist is compound (I) or a pharmaceutically acceptable salt thereof.

Embodiment 18j. Use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product according to embodiment 17j, wherein the mGluR5 antagonist is administered in an amount ranging from 50 mg/b.i.d to 200 mg/b.i.d, in particular 50 mg /b.i.d., 100 mg/b.i.d. or 200 mg/b.i.d., e.g. 200 mg/b.i.d.

Embodiment 19j. Use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product according to embodiment 16j, wherein the mGluR5 antagonist is a compound (II) or a pharmaceutically acceptable salt thereof.

Embodiment 20j. Use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product according to embodiment 19j, wherein the mGluR5 antagonist is administered into

- 16 046106 in an amount ranging from 1 mg/day to 100 mg/day.

Embodiment 21j. Use of a pharmaceutical combination containing an mGluR5 antagonist and at least one additional pharmaceutical active ingredient for the manufacture of a medicinal product according to embodiment 16j, wherein the mGluR5 antagonist is a compound (III) or a pharmaceutically acceptable salt thereof.

General terms.

The term opioid drug or opioid analgesic as used herein refers to both natural (opiate) and synthetic (opioid) forms, as well as natural or synthetic mixed opioid receptor agonists/antagonists, and includes, without limitation, alphamethylfentanyl, alfentanil, buprenorphine, butorphanol, codeine, diacetylmorphine, dihydrocodeine, dihydroetorphine, dihydromorphine, ethylmorphine, etorphine, fentanyl, hydrocodone, hydromorphone, L-acetylmethadol, levorphanol, methadone, meperidine, morphine, nicomorphine, normethadone, noroxycodone, normorphine, norlevorphanol, oxycodone, oxymorph he, phenazocine, propoxyphene, remifentanil, tramadol, thebaine, tapentadol, levorphanol, sufentanil, pentazocine, carfentanil, ohmfentanil, nocaine, ketobemidone, allylprodine, prodine, dextropropoxyphene, dextromoramide, bezitramide, piritramide, dipipanone, loperamide, diphenoxylate, nalbuphine, levo etorfa, dezocin, lefetamine and tildin. In one embodiment, the opioid agent is selected from the group consisting of morphine, hydrocodone, oxycodone and codeine; in particular, the opioid agent is selected from the group consisting of hydrocodone and oxycodone. In one embodiment, the opioid agent is hydrocodone. In another embodiment, the opioid agent is oxycodone.

The term long-term use of opioids or long-term use of an opioid as used herein refers to treatment/therapy using opioids (eg, daily) lasting more than 6 months, where the opioid is, for example, as defined herein. In one embodiment, long-term opioid use refers to long-term use of alphamethylfentanyl, long-term use of alfentanil, long-term use of buprenorphine, long-term use of butorphanol, long-term use of codeine, long-term use of diacetylmorphine, long-term use of dihydrocodeine, long-term use of dihydroetorphine, long-term use of dihydromorphine, long-term use of Iu ethylmorphine, long-term use of etorphine, long-term use of fentanyl, long-term use of hydrocodone, long-term use of hydromorphone, long-term use of L-acetylmethadol, long-term use of levorphanol, long-term use of methadone, long-term use of meperidine, long-term use of morphine, long-term use of nicomorphine, long-term use of normethadone, long-term use of noroxycodone, long-term use of normorphine, long-term use of norlevorphanol, long-term use of oxycodone, long-term use of oxymorphone, long-term use of phenazocine, long-term use of propoxyphene, long-term use of remifentanil, long-term use of tramadol, long-term use of thebaine, long-term use of tapentadol, long-term use of levorphan ola, long-term use of sufentanil, long-term use pentazocine, long-term use of carfentanil, long-term use of ohmfentanil, long-term use of nocaine, long-term use of ketobemidone, long-term use of allylprodine, long-term use of prodine, long-term use of dextropropoxyphene, long-term use of dextromoramide, long-term use of bezitramide, long-term use of pyritramide, long-term use of dipipanone, long-term use of loperamide, long-term use of diphenoxylate, long-term use of nalbuphine, long-term use of levometorfa, long-term use of dezocine, long-term use of lefetamine and long-term use of tildin; wherein the term long-term in each case refers to use (eg, daily) lasting more than 6 months. In another embodiment, long-term opioid use refers to long-term use of morphine, long-term use of hydrocodone, long-term use of oxycodone, or long-term use of codeine, in one embodiment long-term use of hydrocodone, in another embodiment long-term use of oxycodone; wherein the term long-term in each case refers to use (eg, daily) lasting more than 6 months.

The term long-term use of opioids for chronic pain as used herein means long-term use of opioids, as defined herein, by a patient with chronic pain. The term long-term opioid user refers to a patient with chronic pain receiving opioid medications (eg, daily), as defined herein, for more than 6 months.

The term opioid-assisted treatment or opioid-assisted therapy as used herein refers to treatment aimed at treating

- 17 046106 chronic pain with the use of an opioid, for example, as defined herein [see, for example, Interagency Guidelines for Prescribing Opioid Drugs for Pain, ^3rd Edition, published June 2015, or Guidelines for Prescribing Opioid Drugs for Pain chronic pain from the Centers for Disease Control and Prevention (CDC), published in 2016, or in The Journal of Pain, 2009, 10(2), 113-130; the entire contents of which are incorporated herein by reference].

The term tolerance as used herein should be understood, for example, in accordance with the definition provided by the National Institute on Drug Abuse (NIDA), namely as a condition in which the patient's body no longer responds to a drug and requires higher dose (eg, higher daily dose). Tolerance, therefore, is a phenomenon in the body that develops over time in which one or more of the effects of a drug are reduced with repeated use at the same dose, and a higher dose is required to achieve results (for example, there is a need to increase the dosage to maintain analgesic effect).

The term opioid tolerance or opioid analgesic tolerance as used herein refers to long-term use of an opioid that results in a gradual increase in dose (eg, increased daily dose) of the opioid to maintain analgesic effect. Assessment of the presence of tolerance can be carried out, for example, according to the PEG rating scale [i.e. assessment of pain intensity (P), enjoyment of life (E), general activity (G); the PEG score demonstrated sensitivity to change and differences between patients with and without pain improvement; for example, in http://mytopcare.org/wp-content/uploads/2013/06/PEG-Pain-Screening-Tool1.pdf, Krebs EE, et. al. in J.Gen. Intern. Med, 2009, 24, 733-8]. In one embodiment, the opioid analgesic tolerance is selected from the group consisting of the analgesic tolerance alphamethylfentanyl, the analgesic tolerance alfentanil, the analgesic tolerance buprenorphine, the analgesic tolerance butorphanol, the analgesic tolerance codeine, the analgesic tolerance diacetylmorphine, the analgesic tolerance dihydrocodeine tolerance to the analgesic dihydroetorphine, tolerance to the analgesic dihydromorphine, tolerance to the analgesic ethylmorphine, tolerance to the analgesic etorphine, tolerance to the analgesic fentanyl, tolerance to the analgesic hydrocodone, tolerance to the analgesic hydromorphone, tolerance to the analgesic L-acetylmethadol, tolerance to an algesic levorphanol, tolerance to the analgesic methadone , tolerance to the analgesic meperidine, tolerance to the analgesic morphine, tolerance to the analgesic nicomorphine, tolerance to the analgesic normethadone, tolerance to the analgesic noroxycodone, tolerance to the analgesic normorphine, tolerance to the analgesic norlevorphanol, tolerance to the analgesic oxycodone, tolerance tolerance to the analgesic oxymorphone, tolerance to the analgesic phenazocine , tolerance to the analgesic propoxyphene, tolerance to the analgesic remifentanil, tolerance to the analgesic tramadol, tolerance to the analgesic thebaine, tolerance to the analgesic tapentadol, tolerance to the analgesic levorphanol, tolerance to the analgesic sufentanil, tolerance to the analgesic pentazocine, tolerance tolerance to the analgesic carfentanil, tolerance to the analgesic ohmphentanil , tolerance to the analgesic nocaine, tolerance to the analgesic ketobemidon, tolerance to the analgesic allylprodine, tolerance to the analgesic prodine, tolerance to the analgesic dextropropoxyphene, tolerance to the analgesic dextromoramide, tolerance to the analgesic benzitramide, tolerance to the analgesic piritram du, tolerance to the analgesic dipipanone, tolerance to the analgesic loperamide , tolerance to the analgesic diphenoxylate, tolerance to the analgesic nalbuphine, tolerance to the analgesic levometorphe, tolerance to the analgesic dezocine, tolerance to the analgesic lefetamine and tolerance to the analgesic tildin. In another embodiment, the opioid analgesic tolerance 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 tolerance to the analgesic hydrocodone and tolerance to the analgesic oxycodone; in one embodiment, tolerance to the analgesic hydrocodone; in another embodiment, tolerance to the analgesic oxycodone.

The term reversing opioid analgesic tolerance associated with long-term opioid use for chronic pain, reversing opioid analgesic tolerance associated with long-term opioid use for chronic pain or reversing opioid analgesic tolerance associated with long-term opioid use for chronic pain, used as used herein, refers to the reversal of existing (ie, established) tolerance to opioid analgesics, as defined herein, in a chronic pain patient who is a long-term opioid user, as defined herein. In particular,

- 18 046106 this refers to the ability of an active ingredient, such as an mGluR5 antagonist, for example as defined herein, to reduce the dose of an opioid [for example, a daily dose of an opioid, for example, greater than 50 mg oral morphine/day, or equianalgesic daily dose of another opioid (i.e., number of morphine milligram equivalents MME/day)] administered to a patient with chronic pain [eg, result in a reduction of 50% or more of baseline opioid intake per day or per week, for example, a reduction of 70% or more, for example, a reduction of 90% or more; e.g., as assessed using biomarkers of opioid metabolites or as assessed using patient-reported opioid use (eg, using a self-administered Opioid Diary based on a retrospective timeline)] and maintain analgesic effect (i.e. maintain the analgesic effect previously achieved with a higher dose, for example a higher daily dose, of the indicated opioid). Assessing reductions in opioid use can be achieved, for example, using biomarkers of opioid metabolites or using patient-reported opioid use.

The term PEG rating scale used in this document refers to the three-part PEG rating scale (i.e., as defined, for example, in http://mytopcare.org/wpcontent/uploads/2013/06/PEG-Pain-Screening- Tool1.pdf, Krebs EE, et al. in J. Gen. Intern. Med, 2009, 24, 7338, incorporated herein by reference). This scale is a clinical interview consisting of 3 components, during which i) an assessment of the average intensity of pain (P) on a scale from 1 to 10, ii) an assessment of the impact on enjoyment of life (E) on a scale from 1 to 10 and iii) assessing the effect on overall activity on a scale of 1 to 10. This scale demonstrates sensitivity to change and helps detect differences between subjects with and without improvement in pain.

In particular, the term for use in reversing tolerance to opioid analgesics associated with long-term use of opioids for chronic pain, as used herein, is intended to be used for use in treatment aimed at reversing tolerance to opioid analgesics associated with long-term use of opioids for chronic pain. pain or for use in a treatment method aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain.

The term equianalgesic dose of another opioid as used herein refers to the number of morphine milligram equivalents MME/day as calculated, for example, according to the US Department of Health and Human Services Centers for Disease Control and Prevention guidance (for example, see https: //www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf; the entire contents of which are incorporated herein by reference), whereby the morphine equivalent dose is calculated using the following conversion factors._________________

OPIOID MEDICATION (doses in mg/day unless otherwise stated) CONVERSION RATIO Codeine 0.15 Fentanyl for transdermal use (in mcg/hour) 2.4 Hydrocodone 1 Hydromorphone 4 Methadone 1-20 mg/day 4 21-40 mg/day 8 41-60 mg/day 10 >61-80 mg/day 12 Oxycodone 1.5 Oxymorphone 3 Morphine 1

Thus, 50 MME/day corresponds to, for example, 50 mg hydrocodone, 33 mg oxycodone or 12 mg methadone per day; and 90 MME/day corresponds to, for example, 90 mg hydrocodone, 60 mg oxycodone, or approximately 20 mg methadone per day.

The term MME refers to the dose equivalent to that of morphine, in milligrams.

The term reduce the risk of opioid overdose associated with long-term use of opioid drugs for chronic pain as used herein means reducing the risk of overdose associated with long-term use of opioid drugs in a patient with chronic pain. Assessing the risk of overdose can be

- 19 046106 carried out, for example, according to the Pasero Opioid Sedation Scale (POSS; for example, in Pasero C, McCaffery M. Pain Assessment and Pharmacologic Management. St. Louis: Mosby/Elsevier; 2011. Section IV, Opioid Analgesics; p.277-622), for example, compared with placebo.

The term reduce opioid intake for chronic pain, reduce opioid intake for chronic pain, or reduce opioid intake for chronic pain, as used herein, as used herein, refers to reducing the intake of opioid medications in a patient with chronic pain. In one embodiment, the term also refers to a dose reduction of an opioid agent (eg, a decrease in the daily dose of an opioid agent) administered to a chronic pain patient who is a long-term opioid user, as defined herein. In another embodiment, the term also implies a reduction in opioid use disorder status (eg, moderate to mild according to DMS-V diagnostic criteria for opioid use disorder). In particular, reducing the consumption of opioids in a patient with chronic pain is accompanied by preservation of the analgesic effect.

Specifically, reducing the use of opioids for chronic pain or reducing the use of opioids in a patient with chronic pain refers to a reduction in the dose of the opioid that is 50% of the original dose of the opioid, e.g., a reduction in the dose of the opioid that is 50% of the original dose an opioid drug, with an initial dose of an opioid drug ranging from 60 mg to 100 mg oral morphine/day or an equianalgesic daily dose of another opioid drug; e.g., a dose reduction of an opioid that is 50% of the initial opioid dose over 5 weeks, e.g., a 50% reduction in opioid dose over a 5-week period compared to the initial opioid dose, with the initial opioid dose drug is 60 mg to 100 mg oral morphine/day or an equianalgesic daily dose of another opioid drug.

In particular, the term opioid dose as used herein refers to the daily dose of the opioid. The term daily dose of an opioid as used herein refers to oral morphine mg/day or an equianalgesic daily dose of another opioid (ie, morphine milligram equivalents MME/day). In one embodiment, the daily dose of the opioid agent is, for example, greater than 50 mg of oral morphine/day or the equianalgesic daily dose of another opioid agent (i.e., the number of morphine milligram equivalents MME/day), for example, from 60 mg of morphine for up to 100 mg oral morphine/day or equianalgesic daily dose of another opioid (eg, hydrocodone or oxycodone).

Specifically, the daily dose of an opioid administered to a patient with chronic pain is reduced by 50% or more, for example, reduced by 70% or more, such as by 90% or more. In another embodiment, the daily dose of an opioid administered to a patient with chronic pain is reduced by 50% over 5 weeks, e.g., the dose reduction of the opioid is 50% over 5 weeks compared to the initial dose of the opioid, wherein the initial dose of an opioid is 60 mg to 100 mg oral morphine/day or an equianalgesic daily dose of another opioid. Opioid tapering is assessed, for example, using biomarkers of opioid metabolites or as assessed using patient-reported opioid use (eg, using a self-administered Opioid Diary based on a retrospective timeline)].

In particular, the term for use in reducing the use of opioids for chronic pain as used herein means for use in a treatment aimed at reducing the use of opioids in chronic pain or for use in a method of treatment aimed at reducing the use of opioids in chronic pain. pain.

In particular, the term for use in reducing the consumption of opioids for chronic pain as used herein is meant for use in a treatment for reducing the consumption of opioids for chronic pain or for use in a method of treatment for reducing the consumption of opioids for chronic pain.

The term chronic pain as used herein means, as defined, for example, in the 2017 American Chronic Pain Association (ACPA) Guide to the Management of Chronic Pain, continuous or recurrent pain lasting beyond the normal duration of an acute illness. or injury or

- 20 046106 for more than 6 months, and which adversely affects the well-being of the individual. Typically, based on pathophysiology (functional changes associated with or resulting from disease or injury), chronic pain is classified as nociceptive (mediated by long-term tissue damage), neuropathic (resulting from injury to the brain, spinal cord, or peripheral nerves), or a mixture of both. The term chronic pain as used herein may imply an action performed by a patient with chronic pain or belonging to a patient with chronic pain.

The term non-malignant chronic pain as used herein refers to chronic pain not associated with cancer, which includes, for example, postherpetic 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 pain due to postoperative neuropathy. In another embodiment, non-malignant chronic pain refers to back pain, such as chronic low back pain. The term low back pain or chronic low back pain as used herein refers to pain that persists for 12 weeks or more even after treatment of the original injury or underlying cause of acute low back pain (for example, see , for example, the American Spinal Society (NASS) Evidence-Based Guidelines for the Diagnosis and Treatment of Low Back Pain, published in 2016; or the Guidelines for the Evaluation and Management of Patients with Low Back Pain: Review of the Evidence, R Chou, L. Hoyt Huffman, American Pain Society).

The term chronic pain of malignant origin as used in this document refers to chronic pain due to cancer (eg, types of chronic pain syndromes as described in Appendix E of the Interagency Guidelines for Prescribing Opioid Treatments for Pain, ^3rd edition, published June 2015 , the entire contents of which are incorporated herein by reference).

As used herein, the terms treat, treat, or cure any disease or disorder refer in one embodiment to reducing the severity of the disease or disorder (i.e., slowing, stopping, or reducing the progression of a disease or at least one of its clinical symptoms). In another embodiment, the terms treat, treat, or cure refer to alleviating or decreasing the severity of at least one physical parameter, including those that may not be felt by the patient. In yet another embodiment, the terms treat, treat, or cure refer to modulating a disease or disorder either physically (eg, stabilizing an overt symptom), physiologically (eg, stabilizing a physical parameter), or both. In one embodiment, the term treatment method as used herein refers to a method of treating.

The term elderly patient as used in this document refers to a patient who is sixty-five years of age or older.

As used herein, bid, b.i.d or b.i.d. refers to twice daily dosing (eg, 200 mg b.i.d=400 mg/day), eg, morning and evening dosing (eg, approximately 12 hours apart).

The term patient as used herein refers to a subject who is affected by a disease and will benefit from treatment. The term chronic pain patient or chronic pain patient as used herein refers to a subject with chronic pain (ie, who has been diagnosed with chronic pain as defined herein). In one embodiment, the term patient refers to a subject who has been diagnosed with chronic pain, as defined herein, who is a long-term user of opioid drugs and is dependent on the use of opioid drugs (i.e., who develops withdrawal symptoms when cessation of opioid use but who does not meet DSM-V criteria for opioid use disorder). In another embodiment, the term patient refers to a subject who has been diagnosed with chronic pain, as defined herein, who meets DSM-V criteria for mild to moderate opioid use disorder.

As used herein, the term subject refers to a mammalian organism, preferably a human (male or female).

As used herein, a subject requires treatment if such subject (patient) will benefit from such treatment with a biological,

- 21 046106 from a medical point of view or from a quality of life point of view.

The term "therapeutically effective amount of a compound of the present invention" refers to the amount of a compound of the present invention that will produce a biological or medical response in a subject, such as a reduction in the intensity of symptoms, alleviation of a condition, etc.

The term opioid use disorder or OUD as used in this document refers to the DSM-5 criteria for opioid use disorder (i.e., the Diagnostic and Statistical Manual of Mental Disorders. ^5th publication, 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., there are 2 to 3 symptoms, defined relatively DSM-5 criteria), moderate (i.e., 4 to 5 symptoms defined relative to DSM-5 criteria are present), and severe (i.e., 6 or more symptoms defined relative to DSM-5 criteria are present). Thus, as used herein, the term opioid use disorder is defined as a problematic pattern of opioid use resulting in clinically significant impairment or distress, as defined by at least two of the following, occurring over a 12-month period.

1) Opioid medications are often taken in larger quantities or for a longer period than intended.

2) There is a persistent desire or unsuccessful attempts to reduce or control opioid use.

3) A large amount of time is spent on activities necessary to obtain opioid medications, use opioid medications, or recover from their effects.

4) Craving, or strong desire, or urge to use opioid drugs.

5) Occasional opioid use results in inability to perform basic responsibilities at work, school, or home.

6) Continued use of opioid drugs despite persistent or recurrent social or interpersonal problems caused or aggravated by the effects of opioid drugs.

7) Important social, occupational, or recreational activities are missed or limited due to opioid use.

8) Periodic use of opioids in situations in which they are physically dangerous.

9) Opioid drug use continues despite knowledge of the presence of an ongoing or recurrent physical or psychological problem that may have been caused or aggravated by opioid drugs.

10) Tolerance, as defined by one of the following: a) the need for significantly increased amounts of opioid drugs to achieve intoxication or the desired effect; b) significantly reduced effect with prolonged use of the same amount of opioid drugs.

11) Withdrawal syndrome as defined by any of the following.

a) Presence of a characteristic opioid withdrawal syndrome (applies to criteria A and B of the DSM-5 opioid withdrawal syndrome criteria list).

b) An opioid (or closely related substance) is taken to relieve or avoid withdrawal symptoms.

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 for the purpose of treating a specific condition (i.e., disease, disorder or condition, or at least one of their clinical symptoms) affecting the subject.

The Opioid Craving Scale (OCS), a modification of the Cocaine Craving Scale, is a short, 3-item questionnaire used to assess cravings during opioid use. The 3-item scale includes a visual analogue scale from 1 to 10 and is used to determine the degree to which an opioid user is craving an opiate; the severity of the desire of the person using opioid drugs to take an opiate in the previous day; and whether the person using opioid drugs has a desire to take opioid drugs at the same time during the current day. Based on responses on a scale of 1 to 10 for the three components, each one-point increase was associated with a 17% increase in the likelihood of opioid use in the following week (eg, McHugh RK et al., in Assessing craving and its relationship to subsequent opioid prescription use among treatment-seeking prescription opioid dependent patients, Drug and Alcohol Dependency, 2014, Dec 1; 145: 121-6).

The Clinical Opiate Withdrawal Scale (COWS) consists of an 11-item scale,

- 22 046106 which is completed by a physician and is used to assess more commonly encountered signs and symptoms of opiate withdrawal and to reassess these symptoms over a period of time (eg, Wesson DR, et al., in Journal of Psychoactive Drugs, 2003, Apr-Jun ; 35(2): 253-9). The total score for the entire 11-item scale can help clinicians assess the stage or severity of opiate withdrawal experienced by an opiate user, as well as provide insight into the degree of physical dependence on the opiate.

The Opioid Side Effects Evaluation (NOSE) tool (eg, in Smith H.S., et al., Med Clin North Am., 2007, 91(2):213-228) is a 10-item scale assessing commonly encountered side effects. specific for the use of opiates. Each side effect is presented on an analog scale from 0 to 10, with zero indicating no side effect and 10 indicating a side effect as severe as the opiate user could imagine.

The Numeric Rating Scale (NRS; eg, Childs J.D., et al., Spine, 2005; 30:1331-4) allows pain intensity to be rated on a scale from 0 (no pain) to 10 (worst pain imaginable). ).

The Columbia Suicidality Rating Scale (C-SSRS; eg, Posner K et al., Am. J. Psychiatry; 2011, 168:1266–1277) is a suicidal ideation and behavior scale to assess risk for suicide.

As used herein, the term pharmaceutically acceptable excipient includes all possible solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungals), isotonicity agents, absorption retardants, salts, preservatives, drug stabilizers agents, binders, auxiliaries, disintegrating agents, lubricants, sweeteners, flavoring agents, coloring agents, etc. and combinations thereof, which will be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 22 ^nd Ed. Mack Printing Company, 2013, pp. 1049-1070). Unless any conventional carrier is incompatible with the active ingredient, its use is contemplated in therapeutic or pharmaceutical compositions.

The terms drug, active substance, active ingredient, pharmaceutically active ingredient, active agent or therapeutic agent are to be understood to mean a compound in free form or in pharmaceutically acceptable salt form, particularly a compound of the type set forth herein.

The term combination or pharmaceutical combination refers to either a fixed combination in the form of a single unit dosage form (for example, a capsule or tablet), or a non-fixed combination, or a set of parts for combined administration, in which a compound of the present invention and one or more partners combinations (e.g., another drug as defined herein, also referred to as an additional pharmaceutical active ingredient, therapeutic agent, or co-administered agent) may be administered independently at the same time or separately within time intervals, particularly when the given time intervals intervals allow the combination partners to exhibit a combined, eg synergistic, effect. The terms co-administration or combination administration or the like as used herein are intended to encompass the administration of a selected combination partner to a single subject in need thereof (eg, a patient) and are intended to include treatment regimens in which the agents are not necessarily administered in the same manner. the same way of administration or at the same time. The term fixed combination means that the active ingredients, eg, a compound of the present invention and one or more combination partners, are administered to a patient simultaneously in the form of a single entity or dose. The term "unfixed combination" means that the active ingredients, for example, a compound of the present invention and one or more combination partners, are administered to a patient as separate entities, either simultaneously or sequentially without specific time restrictions, where such administration provides therapeutically effective levels of the two compounds in the patient's body.

The compound of the present invention can be administered separately through the same or different route of administration or together in the same pharmaceutical composition as other agents. In the combination therapies of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, a compound of the present invention and another therapeutic agent may be combined into a combination therapy: (i) before the combination product reaches physicians (eg, in the case of a kit containing a compound of the present invention and another therapeutic agent); (ii) by the physicians themselves (or under the supervision of a physician) shortly before administration; (iii) by the patients themselves, for example during

- 23 046106 sequential administration of a compound of the present invention and another therapeutic agent.

In particular, reference to a combination with an additional active agent as used herein (for example, in any of the embodiments set forth above herein or in any of the claims set forth below herein) refers to, for example, to combination with at least one additional active agent, for example selected from the group consisting of an antidepressant (for example, a tricyclic antidepressant such as amitriptyline, nortriptyline, doxepin, desipramine, imipramine, protriptyline, trimipramine, clomipramine), a serotonin reuptake inhibitor, and norepinephrine (eg, duloxetine, venlafaxine, desvenlafaxine, milnacipran, levomilnacipran), serotonin reuptake inhibitor (eg, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, vilazodone, vortioxetine), anticonvulsant (eg, gabapentin, pregabalin, carbamazine) Epina, valproic acid, phenytoin, lamotrigine, tiagabine, lacosamide, topiramate, levetiracetam, oxcarbazepine, zonisamide), non-steroidal anti-inflammatory drug (NSAID; such as naproxen, ibuprofen, meloxicam, diclofenac, fenoprofen, flurbiprofen, diflunisal, etodolac, nabumetone, ketoprofen, piroxicam, sulindac, tolmetin, ketorolac, mefenamic acid, oxaprozin), proton pump inhibitor (eg, omeprazole, pantoprazole, lansoprazole, dexlansoprazole, esomeprazole, rabeprazole), I-receptor antagonist (eg, famotidine, nizatidine, ranitidine, cimetidine), NMDA inhibitor (eg, ketamine, amantadine, mematine), NO-NSAID, selective COX-2 inhibitor, cannabinoid receptor agonist, nitric oxide donor , beta-adrenergic receptor agonist, alpha-2 receptor agonist, selective prostanoid receptor antagonist, local anesthetic (eg, capsaicin, lidocaine), purinergic P2 receptor antagonist, neural nicotinic receptor agonist, calcium channel antagonist, sodium channel blocker (eg, mexiletine, flecainide), superoxide dismutase mimetic, p38 MAP kinase inhibitor, TRPVl agonist, glycine receptor antagonist, corticosteroid and acetaminophen; or pharmaceutically acceptable salts thereof.

The term immediate release form refers to a pharmaceutical composition intended to release the active substance directly upon administration in vivo.

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 therefore alters plasma drug levels compared to the immediate-release form. The term modified release form includes forms that are described as a controlled release form, an extended release form, an extended release form, and an extended release form; particularly the sustained release form.

As used herein, the singular form and similar terms used in the context of the present invention (in particular, in the context of the claims) should be construed to cover both the singular form and the plural form, unless otherwise specified herein. or it is clearly consistent with the context.

The use of all possible examples or introductory words before examples (eg, such) provided herein is intended solely to better explain the present invention and does not limit the scope of the present invention as otherwise claimed.

The compound of the present invention as used herein, alternatively referred to as compound (I), as used herein above and below, is the mGluR5 antagonist methyl ester (-)-(3aR,4S,7aR)-4-hydroxy- 4-m-Tolylethynyl-octahydroindole-1-carboxylic acid, also called (-)-(3aR,4S,7aR)-4-hydroxy4-[2-(3-methylphenyl)ethynyl]perhydroindole-1-carboxylic acid methyl ester , also known as mavoglurant, formulas:

- 24 046106 which can be obtained, for example, as described in WO 2003/047581, for example in example 1, or as described in WO 2010/018154. WO2003/047581, which is incorporated herein by reference, also describes its in-vitro biological data as on page 7. The mavoglurant used herein is free form. In particular, mavoglurant is in free form. As used herein, the term mavoglurant or a salt thereof, such as a pharmaceutically acceptable salt thereof, as used in the context of the present invention (especially in the context of any of the embodiments above or below and the claims) is therefore to be understood to cover both the free form , and a pharmaceutically acceptable salt thereof, unless otherwise stated herein.

In one embodiment, it is also contemplated that compound (I) is in isotopically labeled forms. Isotopically labeled compounds have the structure depicted by the formula above, except that one or more atoms are replaced by an atom of the chosen atomic mass or mass number. Isotopes that may be included in the compound of the present invention include, for example, isotopes of hydrogen, namely the compound of the formula

^{where each of} R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and R ₂₃ independently selected from H or deuterium; provided that at least one deuterium atom is present in the compound. In other embodiments, multiple deuterium atoms are present in the compound.

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

which can, for example, be prepared as described in WO2014/030128, for example in Example 96-2, which is incorporated herein by reference, and which also describes its in-vitro biological data, as on page 203. Used in In the context of the present invention (especially in the context of any of the embodiments given above or below and the claims), the term compound (II) should be understood to cover both the free form and its pharmaceutically acceptable salt, unless otherwise specified herein.

In one embodiment, it is also contemplated that compound (II) is in isotopically labeled forms. Isotopically labeled compounds have the structure shown with

- 25 046106 using the formula above, except that one or more atoms are replaced by an atom of the selected atomic mass or mass number. Isotopes that may be included in the compound of the present invention include, for example, isotopes of hydrogen, namely the compound of the formula

^{where each of} R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, ^R16 , R17, R18, R19, R20 ^and R21 is independently selected from H or deuterium; provided that at least one deuterium atom is present in the compound. In other embodiments, multiple deuterium atoms are present in the compound. Isotopically labeled forms of compound (II) are, for example:

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

whose CAS number is 96206-92-7 and is commercially available. As used in the context of the present invention (especially in the context of any of the embodiments given above or below and the claims), the term compound (III) should be understood to cover both the free form and its pharmaceutically acceptable salt, unless otherwise specified herein other.

In one embodiment, it is also contemplated that compound (III) is represented by

- 26 046106 isotope-labeled forms. Isotopically labeled compounds have the structure depicted by the formula above, except that one or more atoms are replaced by an atom of the chosen atomic mass or mass number. Isotopes that may be included in the compound of the present invention include, for example, isotopes of hydrogen, namely the compound of the formula

wherein each of R1, R2, R3, _R4 , R5, _R6 , R7, _R8 , _R9 , _R10 and R11 is independently selected from H or deuterium; provided that at least one deuterium atom is present in the compound. In other embodiments, multiple deuterium atoms are present in the compound.

Inclusion of certain isotopes, particularly deuterium (i.e., 2H or D), may provide certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life, or reduced dosage requirement, or improved therapeutic index or tolerability. It is intended that deuterium in this context be considered as a substituent in the compound of the present invention. Deuterium concentration can be determined by the isotope enrichment coefficient. As used herein, the term isotope enrichment factor means the ratio of the abundance of an isotope to the natural abundance of that isotope. If the substituent in a compound of the present invention is specified as deuterium, then such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (incorporation of 52.5% deuterium for each designated deuterium atom), at least 4000 (incorporation of 60 % deuterium), at least 4500 (67.5% deuterium injection), at least 5000 (75% deuterium injection), at least 5500 (82.5% deuterium injection), at least 6000 (90% deuterium injection ), at least 6333.3 (95% deuterium injection), at least 6466.7 (97% deuterium injection), at least 6600 (99% deuterium injection) or at least 6633.3 (99.5 injection % deuterium). It is understood that the term isotope enrichment factor can be applied to any isotope in the same manner as described for deuterium.

Other examples of isotopes that may be included in the compound of the present invention include non-deuterium isotopes of hydrogen, carbon, nitrogen, oxygen and fluorine isotopes such as ³ H, 11 C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, respectively. Therefore, it should be understood that the present invention includes compounds that include one or more of any of the above isotopes, including, for example, radioactive isotopes such as ³ H and ¹⁴ C, or compounds that contain non-radioactive isotopes such as such as 2H and ^13C . Such isotope-labeled compounds are useful in metabolic studies (using ^14C ), reaction kinetic studies (for example, using ^2H or ^3H ), detection or imaging techniques such as positron emission tomography (PET ) or single photon emission computed tomography (SPECT), including tests of drug or substrate distribution in tissues, or in radiotherapy patients. In particular, ^{the 18} F or labeled compound may be particularly useful for PET or SPECT studies. Isotope-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those describing the preparation of a compound of the present invention using a suitable isotope-labeled reagent in place of the unlabeled reagent previously used.

As used herein, the terms free form or free forms refer to a compound in a form other than a salt form, such as the basic free form or the acidic free form of the corresponding compound, for example, the compounds described herein [eg, compound (I), compound (II ), compound (III) or an additional pharmaceutical active ingredient, for example, as defined herein].

As used herein, the terms salt, salts or salt form refer to the acid addition salt or base addition salt of the corresponding compound, for example the compounds specified herein [for example, compound (I), compound (II), compound (III) or additional pharmaceutical active ingredient, for example as defined herein

- 27 046106 document]. Salts include, in particular, pharmaceutically acceptable salts. The term pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds and that are generally not biologically or otherwise undesirable.

Pharmaceutically acceptable acid addition salts can be formed using inorganic acids and organic acids.

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

Organic acids from which salts can be prepared 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.

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

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table of elements. In certain embodiments, salts are prepared using sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; in particular, suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

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, and the like. Specific organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

Pharmaceutically acceptable salts can be synthesized from the basic or acidic moiety using conventional chemical methods. Typically, such salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate and the like salt of Na, Ca, Mg or K) or by reacting the free base form of the compound with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or a mixture of both. In general, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile when practical. Listings of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, ^22nd edition, Mack Publishing Company (2013); and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use of Stahl and Wermuth (Wiley-VCH, Weinheim, 2011, ^2nd edition).

The compounds specified herein [e.g., compound (I), compound (II), compound (III), or an additional pharmaceutical active ingredient, e.g., as defined herein] can be administered via a conventional route of administration, particularly orally, such as , for example, in the form of tablets or capsules, which can be manufactured in accordance with pharmaceutical techniques that are known in the art (for example, in Remington Essentials of Pharmaceutics, 2013, 1 ^st Edition, edited by Linda Felton, published by Pharmaceutical Press 2012, ISBN 978 0 85711 105 0; in particular Chapter 30), wherein the pharmaceutical excipients, for example, are as described in the Handbook of Pharmaceutical Excipients, 2012, ^7th Edition, edited by Raymond C. Rowe, Paul J. Sheskey, Walter G. Cook and Marian E. Fenton, ISBN 978 0 85711 027 5. In particular, WO2014/199316 describes formulations containing mavoglurant, in particular modified release formulations thereof, and is incorporated herein by reference, more specifically, examples, preferred embodiments and claims thereof.

The pharmaceutical composition or combination of the present invention may be in unit dosage form (eg tablets or capsules) containing an amount in the range of 1 mg to 300 mg, in particular 1 mg to 200 mg, for example 1 mg to 100 mg of a compound referred to herein (eg, mavoglurant), which means the amount of the free form of the compound and, if a salt is used, the amount will be adjusted accordingly. In particular, mavoglurant is in free form.

For the above routes/methods of treatment, the appropriate dose may vary depending on a variety of factors such as, for example, age, body weight, gender, route of administration or salt used. For example, for patients with a body weight of 50-70 kg, the indicated daily dose is, for example, 200 mg/b.i.d. mavoglurant, or from 1 mg/day to 100 mg/day of compound (II), which means the amount of the free form, and if its salt is used, the amount will be adjusted accordingly.

- 28 046106

Abbreviations.

°C=degrees Celsius.

bid=b.i.d=b.i.d. = twice (twice) a day.

cm=centimeter.

DSM 5=Diagnostic and Statistical Manual of Mental Disorders, 5th edition.

i.p. = intraperitoneal.

kg=kilogram.

mg=milligram.

P.O.=intra, orally.

PEG=o^h^ pain intensity (P), enjoyment of life (E), general activity (G).

MK5=Digital rating scale.

TLFB-Opioid=Self-administered opioid diary based on retrospective timeline.

COWS=Clinical Opiate Withdrawal Scale.

OCS=Opioid Craving Scale.

NOSE=Opioid Side Effects Assessment Tool.

DSM-5=DMS-V=Diagnostic and Statistical Manual of Mental Disorders, ^5th edition.

QTcF=QT interval corrected by Frederick's formula.

QTcB=QT interval corrected by Bazett's formula.

ECG=electrocardiogram.

C-SSRS=Columbia University Suicidality Rating Scale.

AST=aspartate aminotransferase.

ALT=alanine aminotransferase.

GGT=gamma glutamyl transferase.

Ub^upper limit of normal.

OUD=opioid use disorder.

hCG=human chorionic gonadotropin.

FDA=Food and Drug Administration.

QT=time between the start of the Q wave and the end of the T wave.

T wave = positive displacement after each QRS complex.

ST wave=time between the start of the S wave and the end of the T wave.

Examples

The following examples serve to illustrate the present invention without limiting its scope. The term compound (I) (ie mavoglurant) as used in the context of these examples refers to the free form. The term compound (II) {i.e. 9-cyclopropyl-10-fluoro-2-(4(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinoline-5(4H) -on} used in the context of these examples is free form. The term compound (III) (ie MPEP) as used in the context of these examples refers to the free form.

Example 1: Opiate Tolerance Test (Hot Plate) in Mice.

The method by which tolerance to analgesic action is determined corresponds to the method described by Fernandes et al. (Naunyn-Schmiedeberg's Arch. Pharmacol., 297, 53-60, 1977).

Mice were placed on a hot metal plate maintained at 54°C, surrounded by a plexiglass cylinder (height: 13 cm; diameter: 19 cm) (Bioseb: model PE34). The latency to the first lick of the hind paw was measured (maximum value: 30 seconds). Morphine (32 mg/kg i.p.) or vehicle was administered twice daily for 6 days (at approximately 9:00 am and 3:00 pm) followed by morphine 8 mg/kg i.p. (or saline) 30 minutes before the Day 7 test to assess morphine tolerance.

Each test substance was evaluated using 3 doses (1, 3 and 10 mg/kg for compound (I) and 0.3, 1 and 3 mg/kg for compound (II) administered once p.o. to morphine-tolerant mice for 60 minutes prior to testing on Day 7. Appropriate control groups were included to evaluate the potential effect of test substances on morphine tolerance.Compound (III) was assessed using 1 dose (10 mg/kg) administered under the same experimental conditions and was used as a reference substance.

10 mice per group were studied. Testing was carried out in a blind mode. Data were analyzed by comparing treatment groups with matched control groups using an unpaired Student's t test.

Results.

Compound (III) (10 mg/kg), administered p.o. 60 minutes before the test on day 7 in animals receiving carrier medium p.o. and morphine (32 mg/kg) i.p. twice daily from day 1 to day 6, largely

- 29 046106 degree, the latency period to lick the hind paw increased compared to animals receiving morphine from day 1 to day 6 (+32%, p <0.05) (Figure 1).

Compound (I) (1 mg/kg) administered p.o. 60 minutes before the test on day 7 in animals receiving carrier medium p.o. and morphine (32 mg/kg) i.p. twice daily from day 1 to day 6, the latency to hind paw licking was significantly increased compared to animals receiving morphine from day 1 to day 6 (+44%, p < 0.01). It had no significant effect at 3 mg/kg or 10 mg/kg (Figure 2).

Compound (II) (3 mg/kg), administered p.o. 60 minutes before the test on day 7 in animals receiving carrier medium p.o. and morphine (32 mg/kg) i.p. twice daily from day 1 to day 6, the latency to hind paw licking was significantly increased compared to animals receiving morphine from day 1 to day 6 (+38%, p < 0.05). It had a similar trend at 1 mg/kg (+37%, p=0.0555), but had no effect at 0.3 mg/kg (Figure 3).

Conclusion.

These results indicate that compound (I) (1 mg/kg), compound (II) (3 mg/kg) and compound (III) (10 mg/kg) when administered once p.o. significantly reduce the manifestation of tolerance to morphine.

Example 2 Clinical Study [Compound (I)].

Goal(s) Endpoint(s) Main goal(s) End point(s) for main goal(s) • To evaluate the effectiveness of Compound (I) in patients with chronic back pain and postoperative pain in achieving a clinically significant reduction in opioid consumption. • Proportion of patients with a 50% reduction in consumption using the self-administered Opioid Flow Diary based on a retrospective timeline (TLFB). Secondary goal(s) End point(s) for secondary goal(s) • Suicidality. • Columbia Suicidal Severity Rating Scale (C-SSRS). • Change in pain status. • Change in disease status for opioid use disorder. • Adverse outcomes of opioid use disorder. • Pathological attraction associated with the use of opioid drugs. • Withdrawal symptoms associated with opioid use disorder. • To evaluate the effectiveness of compound (I) in patients with chronic back pain and postoperative pain in achieving a reduction in opioid consumption. • Changes in pain, activity and pleasure. • Numeric Rating Scale (NRS). • DSM-5 diagnostic criteria for opioid use disorder. • The Opioid Adverse Event Evaluation (NOSE) tool. • Opioid Craving Scale (OCS). • Clinical Opiate Withdrawal Scale (COWS). • Proportion of patients with a 20% reduction in consumption or a 70% reduction in consumption using the Self-Complete Opioid Diary based on a retrospective timeline. • Pain, activity and pleasure rating scale (PEG)

Research plan.

This study is a randomized, subject- and investigator-blind, placebo-controlled, parallel group study to evaluate the effectiveness of Compound (I) in 80 patients with chronic back pain and postoperative pain in reducing the consumption of opioids (hydrocodone, oxycodone) in subjects who used opioids for less than two years. The study includes outpatient visits to the subject's usual pain clinic and consists of 3 periods. Screening period with baseline determination; treatment period followed by a post-treatment observation period. The total duration for a subject may be no more than 122 days (approximately 4 months, including the screening period and baseline determination) depending on the selected percentage of opioid dose reduction.

Screening/baseline period.

The screening/baseline period lasts for 14 days and consists of the following.

- 30 046106

1. Obtaining informed consent.

2. Definition of initial diagnostic criteria for opioid tolerance using DSM-V criteria.

3. Safety assessments using CBC/blood chemistry laboratory parameters, including pregnancy testing, in premenopausal female subjects.

4. Anamnesis, medical examination and determination of vital signs, a list of medications taken and the risk of suicide.

Treatment period.

Subjects meeting the eligibility criteria will be randomly assigned to either the compound (I) group or the corresponding placebo group in a 1:1 ratio. Treatment with the study drug should begin on Day 1, with a total treatment period of approximately 93 days, during which subjects will reduce the dose of the opioid by at least 10% of the initial dose per week in consultation with the physician in charge. for conducting the research. Subjects will be dose titrated between 50 mg, 100 mg, and 200 mg bid every 4 days (see Table 1) to achieve a total daily dose of 400 mg by day 12. Subjects will be monitored for safety during this dose titration phase as the dose of study drug is increased, which will include visits on Days 1, 5, and 9 to ensure that subjects achieve the maintenance dose of 400 mg per day without issues related to tolerance.

Samples for PK analysis will be collected predose and 4 ± 1 h postdose on days 13, 55, and 69, respectively, and a sample will be collected for PK analysis predose on day 83. On the day of sample collection for PK analysis, subjects will administer a dose of Compound (I) at the study site, as pre-dose sampling must occur prior to dosing.

Table 1

Dosage schedule for compound (I)

Research day Dose of treatment Total daily dose of treatment 1-4 50 mg compound (I) placebo bid or 100 mg of compound (I) or placebo per day 5-8 100 mg compound (I) placebo bid or 200 mg of compound (I) or placebo per day 9-12 200 mg compound (I) placebo bid or 400 mg of compound (I) or placebo per day After implementation selection of a dose that is not more than 400 mg per day, subjects will

continue taking a daily dose of 400 mg of Compound (I) (200 mg b.i.d) or placebo from Day 13 to Day 82. During this period, subjects will reduce their opioid use by at least 10% per week in consultation with the treating physician study until they achieve a daily opioid intake of at least 50% of their baseline opioid dose in the MME. Subjects who are unable to taper may continue to take the current dose of opioid they achieved during the previous study week. Under the guidance of the study physician, subjects can reduce their opioid use by more than 50%. Subjects may also seek to reduce their opioid use through the use of alternative therapies. However, the use of marijuana for pain relief is not permitted under this protocol.

The day the dose reduction of compound (I) begins is day 83, and the dose reduction of compound (I) is completed on day 90. The dose reduction of the opioid agent can continue during the maintenance dosing period of compound (I), which implies a conservative dose reduction of the opioid agent by 10% per week, or subjects may continue to receive the dose of opioid they achieved during the opioid taper period for the remainder of the maintenance period and the dose taper period of Compound (I). The protocol is flexible in allowing the physician and patients to select the level of opioid reduction that best matches the subject's treatment and medical history. However, the treatment regimen using Compound (I) is not flexible and must follow an evaluation schedule for a dose escalation period, a maintenance period, and a dose reduction period. Subjects will decrease their dose of study drug (compound (I) or placebo) until they reach the last dose of compound (I) or placebo (Table 2). Subjects will continue to take the dose of opioid they achieved during the taper process.

- 31 046106

table 2

Research day

Dose reduction schedule for compound (I)

Dose of treatment

83-86

87-90

100 mg compound (I) or placebo b.i.d mg compound (I) or placebo b.i.d

Post-study follow-up

Total daily dose of treatment

200 mg compound (I) or placebo per day

100 mg compound (I) or placebo per day

Follow-up at the end of the treatment period.

Subjects will return to the clinic on day 97 for a final follow-up visit at the end of the treatment period. Subjects will be required to taper their dose of study medication prior to the final follow-up visit at the end of the treatment period.

Dosing in combination with a forced tapering of the opioid during the study.

Given that patients may be taking different opioid medications (hydrocodone and oxycodone) at different doses, doses of these medications should be converted to morphine equivalent dose (MED) and opioid dose reductions should be made using the MED. While opioid tapering plans are individualized to minimize symptoms of opioid withdrawal while maximizing analgesic effect, at the discretion of the investigator, dose reductions will be made in accordance with the criteria outlined in the Primary Opioid Tapering Guidelines. Oxford University Health Care (version 1.1, December 2017), for reference see table. 3.

Table 3

An illustrative dose reduction schedule that involves reducing the opioid dose by at least 10% per week from a starting dose of 100 MME_, _i.e. Daily equivalent dose

Days of the study period Total daily dose of compound (I) morphine (10% reduction)

1-4 100 mg per day 100 5-8 200 mg per day 100 9-12 400 mg per day 100 13-19 rev. 400 mg per day 90-80 20-26 400 mg per day 80-70 27-33 rev. 400 mg per day 70-60 34-40 400 mg per day 60-50 41-47 vol. 400 mg per day 50-45 48-54 400 mg per day 45-40 55-61 rev. 400 mg per day 40-35 62-68 400 mg per day 35-30 69-75 rev. 400 mg per day 30-25 76-82 400 mg per day Last dose of opioid achieved 83-86 vol. 200 mg per day Last dose of opioid achieved 87-90 100 mg per day Last dose of opioid achieved 97 Post-study follow-up

Subjects are not required to reduce their opioid intake to zero MME. The study physician and subject should determine the stopping point for opioid dose reduction.

Population.

The study will enroll a total of approximately 80 patients aged 18 to 65 years (inclusive) with a diagnosed opioid use disorder.

The investigator must ensure that all subjects considered for participation in the study meet the following eligibility criteria. No additional criteria should be used by the researcher to ensure that the subject being studied

- 32 046106 population was representative of all subjects eligible for the study.

Subject selection is accomplished by checking all eligibility criteria at screening and assessment again at baseline to ensure that the subject remains eligible for inclusion in the study. An appropriate record (eg, checklist) of all eligibility criteria should be kept with primary documentation at the study site.

Deviation from any inclusion criterion excludes the subject from inclusion in the study.

Inclusion criteria.

Subjects eligible for inclusion in this study must meet all of the following criteria.

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

2. Ability to communicate freely with the researcher, understand and comply with the requirements of the study.

3. Prospective subjects must take opioid medications according to a fixed dosing schedule (eg, bid).

4. Documented increase in opioid dose without decreasing pain intensity or increase in pain intensity while taking the same amount of medication at least 4 weeks before screening.

5. Subjects must be in good health as determined by medical record and physical examination at screening.

6. Subjects with chronic low back pain or chronic pain due to postoperative neuropathy present for more than 6 months after injury or surgery, such as, for example, a motor vehicle accident, fall, sports injury, knee or hip replacement , all of whom take a dose equivalent to 60-100 mg of morphine. Subjects with mild to moderate severity of osteoarthritis may be included.

7. During screening, vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate) will be assessed while sitting, and again (if necessary) while standing. Vital signs must be within normal limits as determined by the study director.

8. Patients with mild to moderate opioid use disorder according to DSM-5 diagnostic criteria.

Exclusion criteria.

Subjects meeting any of the following criteria are not eligible for inclusion in this study.

1. The subject may not have any significant problems with travel arrangements or available time to travel to the study site, or have any plans to move within the next few months to a location that would make it impossible to continue to participate in the study.

2. Subjects should not be involved in any unresolved legal issues that could jeopardize the continuation or lead to termination of the study.

3. History of immunodeficiency diseases according to the medical record.

4. History of chronic hepatitis B (HBV) or hepatitis C (HCV) according to the medical record.

5. Presence at the time of the study or a history of diagnosed ECG abnormalities indicating a significant safety risk for subjects participating in the study, such as the following.

Concomitant clinically significant forms of cardiac arrhythmia, such as sustained ventricular tachycardia and clinically significant second or third degree AV block without a pacemaker.

A history of hereditary long QT syndrome or a family history of torsade de pointes (TdP).

Resting heart rate (physical examination or 12-lead ECG) <60 bpm.

Resting QTcF >450 ms (men) or >460 ms (women) before treatment [at screening].

Note: If QTcB (Bazett's formula) is the only available adjustment by the ECG machine, the investigator should calculate QTcF at screening and/or baseline (as appropriate) according to the instructions in the site procedures manual.

Note: Sinus tachycardia, left axis deviation, and nonspecific ST or T wave changes are not exclusive.

Use of drugs known to prolong the QT interval unless they can be discontinued for the duration of the study.

- 33 046106

6. Answer yes to item 4 or item 5 in the C-SSRS suicidal ideation section if the ideation occurred within the previous 6 months, or yes to any item in the suicidal behavior section except non-suicidal self-injurious behavior (items are also included in the suicidal behavior section), if such behavior occurred within the last 2 years.

7. Having a diagnosed substance use disorder (DSM-5) for alcohol or other stimulants other than opioids as prescribed by your healthcare provider.

8. Any surgical or medical condition that may significantly alter the absorption, distribution, metabolism or excretion of drugs or which may place the subject at risk if participating in the study. The investigator should determine this by reviewing the subject's medical history and/or clinical or laboratory findings that support any of the following.

Clinical laboratory values (including AST, ALT, total bilirubin, or creatinine) considered clinically inappropriate for the OUD population by the study director at screening.

Serum bilirubin should not exceed 1.5 x ULN.

ALT, AST, GGT should not exceed 3 x ULN.

Note: If the screening laboratory safety assessment is outside the range specified above, the assessment may be repeated once before randomization. If the repeated value remains outside the specified ranges, the subject is excluded from the study.

9. A history of hypersensitivity to any investigational treatment, or to excipients, or to drugs of similar chemical classes.

10. A history of any disease, condition, or drug use that, in the opinion of the study director or designee, may distort the results of the study or create an additional risk when administering investigational drugs to the subject or interfere with the successful completion of the study.

11. Current and/or previous treatment with concomitant medications that are strong or moderate inducers/inhibitors of CYP3A4 (for example, clarithromycin, ketoconazole, ritonavir, rifampin, etc.).

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

12. Treatment with any psychoactive drugs is required, including any anticonvulsant drugs (except for drugs used for the short-term treatment of insomnia).

Note: SSRIs are permitted if they are at an appropriate steady-state dose for at least one (1) month prior to dosing.

13. A history of malignancy of any organ system (other than focal basal cell carcinoma of the skin or cervical carcinoma in situ), which has or has not been treated within the last 5 years, regardless of the presence of evidence of local recurrence or metastasis.

14. History or presence of cardiovascular or cerebrovascular disease such as angina, myocardial infarction, stroke, transient ischemic attack, peripheral vascular disease.

15. Concomitant use of drugs known to prolong the QT interval unless they can be discontinued for the duration of the study.

16. History of porphyria.

17. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant if they are not using a highly effective method of contraception during dosing and for 30 days/weeks after discontinuation of study drug. Highly effective methods of contraception include the following.

Complete abstinence from heterosexual sexual intercourse (if consistent with the subject's preferred and usual lifestyle). Intermittent abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and coitus interruptus are not acceptable methods of contraception.

Female sterilization (surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before study drug administration. In the case of oophorectomy only, only if the woman's reproductive status has been confirmed by subsequent assessment of hormone levels.

Male sterilization (at least 6 months before screening). For female subjects in the study, the vasectomized male partner must be the only partner

- 34 046106 of this subject.

Barrier method of contraception: condom or occlusive cap (diaphragm or cervical/vaginal caps) with spermicidal foam/gel/film/cream/vaginal suppositories; installation of an intrauterine device (IUD) or intrauterine system (IUS).

Note: Hormonal contraceptives that are administered by injection or implantation, or administered orally or transdermally, may not be considered effective forms of contraception when co-administered with a study drug.

Women are considered postmenopausal and nonfertile if they have had natural (spontaneous) amenorrhea for 12 months with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms).

18. Pregnant or breastfeeding (lactating) women, where pregnancy is defined as a woman’s condition after conception and lasting until the end of the gestational period, confirmed by a positive laboratory test for hCG.

19. Use of other investigational medicinal products at the time of enrollment or within 5 half-lives of enrollment or within 30 days, whichever is longer; or longer if required by local regulations.

Treatment groups.

Subjects will be allocated to one of 2 treatment groups in a 1:1 ratio at baseline.

Group receiving compound (I): dose escalation regimen b.i.d. followed by a fixed dose b.i.d. and ending with a dose reduction regimen b.i.d. See Study Design for dose escalation and dose reduction design (Tables 1 and 2).

Placebo group: matched placebo.

Efficiency.

Clinical efficacy measures (PEG, NRS and TLFB-Opioid) will be determined. In addition, assessment of areas recommended by the FDA's Draft Opioid Tapering Guidelines will also be assessed using COWS, OCS and NOSE, and the DSM-5 Opioid Use Disorder Severity Assessment.

Analysis of the primary endpoint(s).

The purpose of the study is to evaluate the effectiveness of compound (I) in reducing opioid consumption in patients with chronic low back pain and postoperative pain taking a dose equivalent to 60-100 mg of morphine per day. This assessment will be carried out by measuring daily intake using TLFB. A subject demonstrating a reduction in average weekly intake from baseline to the last week of treatment of at least 50% will be considered a treatment responder. PEG assessments at baseline, weeks 4, 8, and the end of the study will provide information about treatment response over time.

Determination of the primary endpoint(s).

The primary endpoint of the study is a binary endpoint (subject responding to treatment/subject not responding to treatment). Response was defined as a reduction of at least 50% in mean intake from baseline (the week before the baseline visit and the week including the baseline visit) to the last week of the maintenance dose treatment period (i.e., 200 mg). bid, days 76-82) if the subject completes the protocol treatment maintenance period or on any of the last 7 days of the treatment period if the subject stops treatment before day 82.

Statistical model, hypothesis and method of analysis.

The number of subjects responding to treatment in each treatment group is assumed to be a random variable following the binomial distribution Bn(n, pi) where ni is the number of subjects in treatment group i and pi is the true baseline proportion of subjects responding to treatment treatment I (i=1 for compound (I), i=2 for placebo).

Based on the uninformative beta(1/3,1/3) prior probability distributions for treatment response rates pi and p ₂ , the posterior probability of the difference between treatment response rates will be used to calculate Prob (p1-p ₂ >0/ data) and Prob (р1- _р2 >0.2/data).

Sample size calculation.

Primary endpoint(s).

The sample size is estimated based on the probability of success, i.e. that the true difference between the response rates for compound (I) and placebo is >0 with a confidence interval of at least 90% and is >20% with a confidence interval of at least 50% at the interim analysis or at the final analysis.

Efficacy criteria are formulated in terms of posterior probability statements regarding the difference between true treatment response rates Δ=ρ1-ρ2, where p1 denotes the true treatment response rate for patients treated with compound (I) and p2 denotes

-

Claims (15)

tin response rate for patients receiving placebo. Posterior probability distributions for both treatment groups are calculated using the standard binomial probability distribution model and the conjugate uninformative beta prior probability distribution Beta(a, a), where a=1/3 for both p1 and p2. Performance criteria for decision making. The decision rule used in conducting the final analysis for an effectiveness claim consists of the following two statements, which must be true simultaneously. 1. The posterior probability for Δ > 0 is more than 90%. 2. The posterior probability for Δ > 0.20 is more than 50%. CLAIM 1. The use of mavoglurant or a pharmaceutically acceptable salt thereof for the treatment of opioid analgesic tolerance associated with long-term use of opioid drugs for chronic pain. 2. The use of mavoglurant or a pharmaceutically acceptable salt thereof for the treatment of opioid analgesic tolerance associated with long-term use of opioid drugs for chronic pain, wherein the treatment reverses the opioid analgesic tolerance. 3. The use of mavoglurant or a pharmaceutically acceptable salt thereof for treatment aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain. 4. The use of mavoglurant or a pharmaceutically acceptable salt thereof for treatment aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain. 5. The use of mavoglurant or a pharmaceutically acceptable salt thereof for the treatment of chronic pain aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioids. 6. The use of mavoglurant or a pharmaceutically acceptable salt thereof for the treatment of tolerance to opioid analgesics, aimed at reducing the risk of opioid overdose associated with long-term use of opioids for chronic pain. 7. Use of mavoglurant or a pharmaceutically acceptable salt thereof for treatment aimed at reducing the use of opioids for chronic pain. 8. The use of mavoglurant or a pharmaceutically acceptable salt thereof for treatment aimed at eliminating tolerance to opioid analgesics associated with long-term use of opioid drugs for chronic pain, where the dose of the opioid drug administered to the patient is reduced and the analgesic effect of the opioid drug is maintained. 9. The use of mavoglurant or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein mavoglurant or a pharmaceutically acceptable salt thereof is administered to a patient receiving a dose of an opioid agent that is greater than 50 mg oral morphine/day, or an equianalgesic daily dose of another opioid agent, e.g. , a patient receiving an opioid dose of 60 mg to 100 mg oral morphine/day, or an equianalgesic daily dose of another opioid. 10. Use of mavoglurant or a pharmaceutically acceptable salt thereof according to any of the preceding claims, where chronic pain is associated with injury or disease. 11. The use of mavoglurant or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein the chronic pain is chronic pain of non-malignant origin. 12. The use of mavoglurant or a pharmaceutically acceptable salt thereof according to claim 11, wherein the non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example, with or without previous spinal surgery. 13. Use of mavoglurant or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein mavoglurant or a pharmaceutically acceptable salt thereof is administered to an elderly patient. 14. The use of mavoglurant or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein the chronic pain is chronic pain due to postoperative neuropathy. 15. The use of mavoglurant or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein mavoglurant or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition further containing at least one pharmaceutically acceptable excipient. -