Patent Application
20220175793
The invention relates to the use of an mGluR5 antagonist for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain.
Treatment of pain is a major healthcare challenge, which requires careful balance between pain control and associated adverse events. In Europe, one-fifth of the population suffers from chronic pain. In addition, diseases associated with pain are rising and furthermore, only one-third to two-thirds of the chronic pain patient population reports >50% pain relief (Trends in Neurosciences, 2014, Vol. 37, No. 3, 146).
Opioids, such as morphine, are potent analgesics used for the treatment of moderate to severe chronic pain of non-malignant or malignant (i.e. cancer) source. However, while medical guidelines recommend the use of opioid therapy for the management of cancer pain, the use thereof for the long-term treatment of non-malignant pain is questionable, in particular due to the many adverse events associated (e.g. nausea, vomiting, pruritus, somnolence, cognitive impairment or dry mouth), the development of analgesic tolerance, and moreover the risks of overdose or opioid use disorder. As stated in the 2016 CDC (Centers for Disease Control and Prevention US Department of Health and Human Services) Guidelines for prescribing opioids for chronic pain, from 1999 to 2014, in the United States, over 165,000 persons died from overdose related to opioid pain medication.
Opioid analgesic tolerance is a well-recognized pharmacological phenomenon associated to opioid therapy, whose underlying biological mechanism is still poorly understood (International Journal of Clinical Pharmacology and Therapeutics, 2004, Vol. 42, No. 4, 191). This phenomenon is characterized by reduced analgesic efficacy, over time, and thus need to increase the opioid dosing in order to maintain analgesic effect. As the dose of an opioid is increased, the potential for side effects is also increased (e.g. respiratory depression, sedation, dizziness, pruritus, nausea, vomiting, constipation, immunologic and hormonal dysfunction), as is the risk for overdose. As reported by the CDC: 1) dosages ≥50 MME/day increase the overdose risk by at least twice the risk at <20 MME/day; 2) in a national sample of Veterans Health Administration patients with chronic pain receiving opioids from 2004-2209, patients who died of overdose were prescribed an average of 98 MME/day. At present, there is no known treatment to reverse opioid analgesic tolerance associated with chronic opioid use in patients with chronic pain. Finding pharmacotherapies for the treatment of opioid analgesic tolerance is thus a high medical need and a major clinical challenge. Morphine tolerance has been treated, for example, with ibudilast, minocycline, fluorocitrate, propentofylline, however, the use of these drugs was associated with significant adverse events. Accordingly, there is a need to identify new therapeutic agents that can be used to treat opioid analgesic tolerance, in particular dugs that can reverse established tolerance, more particularly without increasing adverse effects.
The invention relates to the use of an mGluR5 antagonist, for example as defined herein:
Embodiments of the present invention are described herein below:
Embodiments (a):
Embodiment 1a: A mGluR5 antagonist for use in the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain.
Embodiment 2a: A mGluR5 antagonist for use in the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance.
Embodiment 3a: A mGluR5 antagonist for use in reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain.
Embodiment 4a: A mGluR5 antagonist for use in a treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.
Embodiment 5a: A mGluR5 antagonist for use in the treatment of chronic pain in order to reverse opioid analgesic tolerance associated with chronic opioid use.
Embodiment 6a: A mGluR5 antagonist for use in the treatment of opioid analgesic tolerance in order to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.
Embodiment 7a: A mGluR5 antagonist for use in reducing opioid consumption in chronic pain.
Embodiment 8a: A mGluR5 antagonist for use in reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the opioid dosage [e.g. daily opioid dose] being administered to the patient is decreased (e.g. by 50% or more, such as by 70% or more, e.g. by 90% or more) and the opioid analgesic effect (i.e. previously achieved by using the higher opioid dosage) is maintained.
Embodiment 9a: A mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient on an opioid dose of >50 mg oral morphine/day or daily equianalgesic dose of another opioid (i.e. morphine milligram equivalent MME/day), such as a patient on an opioid dose of from 60 to 100 mg oral morphine/day or daily equianalgesic dose of another opioid.
Embodiment 10a: A mGluR5 antagonist for use according to any one of the preceding embodiments, wherein chronic pain is associated to an injury (e.g. wound, burn or fracture) or a disease (e.g. diabetes, multiple sclerosis, arthritis, an autoimmune disease or an infection).
Embodiment 11a: A mGluR5 antagonist for use according to any one of the preceding embodiments, wherein chronic pain is non-malignant chronic pain.
Embodiment 12a: A mGluR5 antagonist for use according to embodiment 11a, wherein non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example with or without previous spine surgery.
Embodiment 13a: A mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.
Embodiment 14a: A mGluR5 antagonist for use according to any one of the preceding embodiments, wherein chronic pain is chronic post-surgical neuropathic pain.
Embodiment 15a: A mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in an immediate-release form or a modified-release form; in particular a modified-release form.
Embodiment 16a: A mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.
Embodiment 17a: A mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in combination with one or more further pharmaceutical active ingredient.
Embodiment 18a: A mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each instance a pharmaceutically acceptable salt thereof.
Embodiment 19a: A mGluR5 antagonist for use according to embodiment 18a, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.
Embodiment 20a: The mGluR5 antagonist for use according to embodiment 19a, wherein the mGluR5 antagonist is administered in an amount of 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., such as 200 mg/b.i.d.
Embodiment 21a: A mGluR5 antagonist for use according to embodiment 18a, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.
Embodiment 22a: The mGluR5 antagonist for use according to embodiment 21a, wherein the mGluR5 antagonist is administered in an amount of from 1 mg/day to 100 mg/day.
Embodiment 23a: A mGluR5 antagonist for use according to embodiment 18a, wherein the mGluR5 antagonist is Compound (III) or a pharmaceutically acceptable salt thereof.
Embodiment 24a: A combination comprising a mGluR5 antagonist and an opioid.
Embodiment 25a: A combination according to embodiment 24a, wherein the opioid is selected from the group consisting of 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, oxymorphone, phenazocine, propoxyphene, remifentanil, tramadol, thebaine, tapentadol, levorphanol, sufentanil, pentazocine, carfentanyl, ohmfentanyl, nocaine, ketobemidone, allylprodine, prodine, dextropropoxyphene, dextromoramide, benzitramide, piritramide, dipipanone, loperamide, diphenoxylate, nalbuphine, levomethorpha, dezocine, lefetamine and tildine; in particular the opioid is selected from the group consisting of hydrocodone and oxycodone.
Embodiment 26a: A combination according to embodiments 24a or 25a comprising at least one further 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), a serotonin norepinephrine reuptake inhibitor (e.g. duloxetine, venlafaxine, desvenlafaxine, milnacipran, levomilnacipran), a serotonine reuptake inhibitor (e.g. fluoxetine, setraline, paroxetine, fluvoxamine, citalopram, escitalopram, vilazodone, vortioxetine), an anticonvulsant (e.g. gabapentin, pregabalin, carbamazepine, valproic acid, phenytoin, lamotrigine, tiagabine, lacosamide, topiramate, levetiracetam, oxacarbazepine, zonisamide), a non-steroidal anti-inflammatory drug (NSAID; such as naproxen, ibuprofen, meloxicam, diclofenac, fenoprofen, flurbiprofen, diflunisal, etodolac, nabumetone, ketoprofen, piroxicam, sulindac, tolmetin, ketorolac, mefenamic, oxaprozin), a proton pump inhibitor (e.g. omeprazole, pantoprazole, lansoprazole, dexlansoprazole, esomeprazole, rabeprazole), a H2 receptor antagonist (e.g. famotidine, nizatidine, ranitidine, cimetidine), an NMDA inhibitor (e.g. ketamine, amantadine, mematine), NO-NSAID, a COX-2 selective inhibitor, a cannabinoid agonist, a nitric oxide donor, a beta adrenergic agonist, an alpha-2 agonist, a selective prostanoid receptor antagonist, a local anesthetic (e.g. capsaicin, lidocaine), a purinergic P2 receptor antagonist, a neuronal nicotinic receptor agonist, a calcium channel antagonist, a sodium channel blocker (e.g. mexiletine, flecainide), a superoxide dismutase mimetic, a p38 MAP kinase inhibitor, a TRPVI agonist, a glycine receptor antagonist, a corticosteroid, and acetaminophen.
Embodiment 27a: A combination according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each instance a pharmaceutically acceptable salt thereof.
Embodiment 28a: A combination according to embodiment 27a, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.
Embodiment 29a: A combination according to embodiment 27a, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.
Embodiment 30a: A combination according to embodiment 27a, wherein the mGluR5 antagonist is Compound (III) or a pharmaceutically acceptable salt thereof.
Embodiments (b):
Embodiment 1b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain.
Embodiment 2b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance.
Embodiment 3b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain.
Embodiment 4b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in a treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.
Embodiment 5b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in the treatment of chronic pain in order to reverse opioid analgesic tolerance associated with chronic opioid use.
Embodiment 6b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in the treatment of opioid analgesic tolerance in order to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.
Embodiment 7b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in reducing opioid consumption in chronic pain.
Embodiment 8b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use in reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the opioid dosage [e.g. daily opioid dose] being administered to the patient is decreased (e.g. by 50% or more, such as by 70% or more, e.g. by 90% or more) and the opioid analgesic effect (i.e. previously achieved by using the higher opioid dosage) is maintained.
Embodiment 9b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient on an opioid dose of >50 mg oral morphine/day or daily equianalgesic dose of another opioid (i.e. morphine milligram equivalent MME/day), such as a patient on an opioid dose of from 60 to 100 mg oral morphine/day or daily equianalgesic dose of another opioid.
Embodiment 10b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to any one of the preceding embodiments, wherein chronic pain is associated to an injury (e.g. wound, burn or fracture) or a disease (e.g. diabetes, multiple sclerosis, arthritis, an autoimmune disease or an infection).
Embodiment 11b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to any one of the preceding embodiments, wherein chronic pain is non-malignant chronic pain.
Embodiment 12b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to embodiment 11b, wherein non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example with or without previous spine surgery.
Embodiment 13b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.
Embodiment 14b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to any one of the preceding embodiments, wherein chronic pain is chronic post-surgical neuropathic pain.
Embodiment 15b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in an immediate-release form or a modified-release form; in particular a modified-release form.
Embodiment 16b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in combination with one or more further pharmaceutical active ingredient.
Embodiment 17b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each instance a pharmaceutically acceptable salt thereof.
Embodiment 18b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to embodiment 17b, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.
Embodiment 19b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to embodiment 18b, wherein the mGluR5 antagonist is administered in an amount of 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., such as 200 mg/b.i.d.
Embodiment 20b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to embodiment 17b, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.
Embodiment 21b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to embodiment 20b, wherein the mGluR5 antagonist is administered in an amount of from 1 mg/day to 100 mg/day.
Embodiment 22b: A pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for use according to embodiment 17b, wherein the mGluR5 antagonist is Compound (III) or a pharmaceutically acceptable salt thereof.
Embodiments (c):
Embodiment 1c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use in the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain.
Embodiment 2c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use in the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance.
Embodiment 3c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use in reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain.
Embodiment 4c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use in a treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.
Embodiment 5c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use in the treatment of chronic pain in order to reverse opioid analgesic tolerance associated with chronic opioid use.
Embodiment 6c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use in the treatment of opioid analgesic tolerance in order to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.
Embodiment 7c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use in reducing opioid consumption in chronic pain.
Embodiment 8c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use in reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the opioid dosage [e.g. daily opioid dose] being administered to the patient is decreased (e.g. by 50% or more, such as by 70% or more, e.g. by 90% or more) and the opioid analgesic effect (i.e. previously achieved by using the higher opioid dosage) is maintained.
Embodiment 9c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient on an opioid dose of >50 mg oral morphine/day or daily equianalgesic dose of another opioid (i.e. morphine milligram equivalent MME/day), such as a patient on an opioid dose of from 60 to 100 mg oral morphine/day or daily equianalgesic dose of another opioid.
Embodiment 10c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use according to any one of the preceding embodiments, wherein chronic pain is associated to an injury (e.g. wound, burn or fracture) or a disease (e.g. diabetes, multiple sclerosis, arthritis, an autoimmune disease or an infection).
Embodiment 11c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use according to any one of the preceding embodiments, wherein chronic pain is non-malignant chronic pain.
Embodiment 12c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use according to embodiment 11b, wherein non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example with or without previous spine surgery.
Embodiment 13c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.
Embodiment 14c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use according to any one of the preceding embodiments, wherein chronic pain is chronic post-surgical neuropathic pain.
Embodiment 15c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in an immediate-release form or a modified-release form; in particular a modified-release form.
Embodiment 16c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each instance a pharmaceutically acceptable salt thereof.
Embodiment 17c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use according to embodiment 16c, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.
Embodiment 18c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use according to embodiment 17c, wherein the mGluR5 antagonist is administered in an amount of 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., such as 200 mg/b.i.d.
Embodiment 19c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use according to embodiment 16c, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.
Embodiment 20c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use according to embodiment 19c, wherein the mGluR5 antagonist is administered in an amount of from 1 mg/day to 100 mg/day.
Embodiment 21c: A pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for use according to embodiment 16c, wherein the mGluR5 antagonist is Compound (III) or a pharmaceutically acceptable salt thereof.
Embodiments (d):
Embodiment 1d: A method for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject an effective amount of a mGluR5 antagonist.
Embodiment 2d: A method for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance, in a subject in need thereof, comprising administering to said subject an effective amount of a mGluR5 antagonist.
Embodiment 3d: A method of treatment for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject an effective amount of a mGluR5 antagonist.
Embodiment 4d: A method of treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject an effective amount of a mGluR5 antagonist.
Embodiment 5d: A method of treatment of chronic pain in order to reverse opioid analgesic tolerance associated with chronic opioid use, in a subject in need thereof, comprising administering to said subject an effective amount of a mGluR5 antagonist.
Embodiment 6d: A method of treatment of opioid analgesic tolerance in order to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject an effective amount of a mGluR5 antagonist.
Embodiment 7d: A method of treatment for reducing opioid consumption in chronic pain, in a subject in need thereof, comprising administering to said subject an effective amount of a mGluR5 antagonist.
Embodiment 8d: A method of treatment for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject an effective amount of a mGluR5 antagonist, whereby the opioid dosage [e.g. daily opioid dose] being administered to the patient is decreased (e.g. by 50% or more, such as by 70% or more, e.g. by 90% or more) and the opioid analgesic effect (i.e. previously achieved by using the higher opioid dosage) is maintained.
Embodiment 9d: A method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient on an opioid dose of >50 mg oral morphine/day or daily equianalgesic dose of another opioid (i.e. morphine milligram equivalent MME/day), such as a patient on an opioid dose of from 60 to 100 mg oral morphine/day or daily equianalgesic dose of another opioid.
Embodiment 10d: A method according to any one of the preceding embodiments, wherein chronic pain is associated to an injury (e.g. wound, burn or fracture) or a disease (e.g. diabetes, multiple sclerosis, arthritis, an autoimmune disease or an infection).
Embodiment 11d: A method according to any one of the preceding embodiments, wherein chronic pain is non-malignant chronic pain.
Embodiment 12d: A method according to embodiment 11d, wherein non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example with or without previous spine surgery.
Embodiment 13d: A method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.
Embodiment 14d: A method according to any one of the preceding embodiments, wherein chronic pain is chronic post-surgical neuropathic pain.
Embodiment 15d: A method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in an immediate-release form or a modified-release form; in particular a modified-release form.
Embodiment 16d: A method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.
Embodiment 17d: A method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in combination with one or more further pharmaceutical active ingredient.
Embodiment 18d: A method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each instance a pharmaceutically acceptable salt thereof.
Embodiment 19d: A method according to embodiment 18d, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.
Embodiment 20d: A method according to embodiment 19d, wherein the mGluR5 antagonist is administered in an amount of 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., such as 200 mg/b.i.d.
Embodiment 21d: A method according to embodiment 18d, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.
Embodiment 22d: A method according to embodiment 21d, wherein the mGluR5 antagonist is administered in an amount of from 1 mg/day to 100 mg/day.
Embodiment 23d: A method according to embodiment 18d, wherein the mGluR5 antagonist is Compound (III) or a pharmaceutically acceptable salt thereof.
Embodiments (e):
Embodiment 1e: A method for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject a pharmaceutical composition comprising an effective amount of a mGluR5 antagonist and at least one pharmaceutically acceptable excipient.
Embodiment 2e: A method for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance, in a subject in need thereof, comprising administering to said subject a pharmaceutical composition comprising an effective amount of a mGluR5 antagonist and at least one pharmaceutically acceptable excipient.
Embodiment 3e: A method of treatment for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject a pharmaceutical composition comprising an effective amount of a mGluR5 antagonist and at least one pharmaceutically acceptable excipient.
Embodiment 4e: A method of treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject a pharmaceutical composition comprising an effective amount of a mGluR5 antagonist and at least one pharmaceutically acceptable excipient.
Embodiment 5e: A method of treatment of chronic pain in order to reverse opioid analgesic tolerance associated with chronic opioid use, in a subject in need thereof, comprising administering to said subject a pharmaceutical composition comprising an effective amount of a mGluR5 antagonist and at least one pharmaceutically acceptable excipient.
Embodiment 6e: A method of treatment of opioid analgesic tolerance in order to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject a pharmaceutical composition comprising an effective amount of a mGluR5 antagonist and at least one pharmaceutically acceptable excipient.
Embodiment 7e: A method of treatment for reducing opioid consumption in chronic pain, in a subject in need thereof, comprising administering to said subject a pharmaceutical composition comprising an effective amount of a mGluR5 antagonist and at least one pharmaceutically acceptable excipient.
Embodiment 8e: A method of treatment for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject a pharmaceutical composition comprising an effective amount of a mGluR5 antagonist and at least one pharmaceutically acceptable excipient, whereby the opioid dosage [e.g. daily opioid dose] being administered to the patient is decreased (e.g. by 50% or more, such as by 70% or more, e.g. by 90% or more) and the opioid analgesic effect (i.e. previously achieved by using the higher opioid dosage) is maintained.
Embodiment 9e: A method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient on an opioid dose of >50 mg oral morphine/day or daily equianalgesic dose of another opioid (i.e. morphine milligram equivalent MME/day), such as a patient on an opioid dose of from 60 to 100 mg oral morphine/day or daily equianalgesic dose of another opioid.
Embodiment 10e: A method according to any one of the preceding embodiments, wherein chronic pain is associated to an injury (e.g. wound, burn or fracture) or a disease (e.g. diabetes, multiple sclerosis, arthritis, an autoimmune disease or an infection).
Embodiment 11e: A method according to any one of the preceding embodiments, wherein chronic pain is non-malignant chronic pain.
Embodiment 12e: A method according to embodiment 11e, wherein non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example with or without previous spine surgery.
Embodiment 13e: A mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.
Embodiment 14e: A method according to any one of the preceding embodiments, wherein chronic pain is chronic post-surgical neuropathic pain.
Embodiment 15e: A method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in an immediate-release form or a modified-release form; in particular a modified-release form.
Embodiment 16e: A method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in combination with one or more further pharmaceutical active ingredient.
Embodiment 17e: A method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each instance a pharmaceutically acceptable salt thereof.
Embodiment 18e: A method according to embodiment 17e, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.
Embodiment 19e: A method according to embodiment 18e, wherein the mGluR5 antagonist is administered in an amount of 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., such as 200 mg/b.i.d.
Embodiment 20e: A method according to embodiment 17e, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.
Embodiment 21e: A method according to embodiment 20e, wherein the mGluR5 antagonist is administered in an amount of from 1 mg/day to 100 mg/day.
Embodiment 22e: A method according to embodiment 17e, wherein the mGluR5 antagonist is Compound (III) or a pharmaceutically acceptable salt thereof.
Embodiments (f):
Embodiment 1f: A method for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject a pharmaceutical combination comprising an effective amount of a mGluR5 antagonist and at least one further pharmaceutical active ingredient.
Embodiment 2f: A method for treating opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance, in a subject in need thereof, comprising administering to said subject a pharmaceutical combination comprising an effective amount of a mGluR5 antagonist and at least one further pharmaceutical active ingredient.
Embodiment 3f: A method of treatment for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject a pharmaceutical combination comprising an effective amount of a mGluR5 antagonist and at least one further pharmaceutical active ingredient.
Embodiment 4f: A method of treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject a pharmaceutical combination comprising an effective amount of a mGluR5 antagonist and at least one further pharmaceutical active ingredient.
Embodiment 5f: A method of treatment of chronic pain in order to reverse opioid analgesic tolerance associated with chronic opioid use, in a subject in need thereof, comprising administering to said subject a pharmaceutical combination comprising an effective amount of a mGluR5 antagonist and at least one further pharmaceutical active ingredient.
Embodiment 6f: A method of treatment of opioid analgesic tolerance in order to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject a pharmaceutical combination comprising an effective amount of a mGluR5 antagonist and at least one further pharmaceutical active ingredient.
Embodiment 7f: A method of treatment for reducing opioid consumption in chronic pain, in a subject in need thereof, comprising administering to said subject a pharmaceutical combination comprising an effective amount of a mGluR5 antagonist and at least one further pharmaceutical active ingredient.
Embodiment 8f: A method of treatment for reversing opioid analgesic tolerance associated with chronic opioid use in chronic pain, in a subject in need thereof, comprising administering to said subject a pharmaceutical combination comprising an effective amount of a mGluR5 antagonist and at least one further pharmaceutical active ingredient, whereby the opioid dosage [e.g. daily opioid dose] being administered to the patient is decreased (e.g. by 50% or more, such as by 70% or more, e.g. by 90% or more) and the opioid analgesic effect (i.e. previously achieved by using the higher opioid dosage) is maintained.
Embodiment 9f: A method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient on an opioid dose of >50 mg oral morphine/day or daily equianalgesic dose of another opioid (i.e. morphine milligram equivalent MME/day), such as a patient on an opioid dose of from 60 to 100 mg oral morphine/day or daily equianalgesic dose of another opioid.
Embodiment 10f: A method according to any one of the preceding embodiments, wherein chronic pain is associated to an injury (e.g. wound, burn or fracture) or a disease (e.g. diabetes, multiple sclerosis, arthritis, an autoimmune disease or an infection).
Embodiment 11f: A method according to any one of the preceding embodiments, wherein chronic pain is non-malignant chronic pain.
Embodiment 12f: A method according to embodiment 11f, wherein non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example with or without previous spine surgery.
Embodiment 13f: A mGluR5 antagonist for use according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.
Embodiment 14f: A method according to any one of the preceding embodiments, wherein chronic pain is chronic post-surgical neuropathic pain.
Embodiment 15f: A method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in an immediate-release form or a modified-release form; in particular a modified-release form.
Embodiment 16f: A method according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each instance a pharmaceutically acceptable salt thereof.
Embodiment 17f: A method according to embodiment 16f, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.
Embodiment 18f: A method according to embodiment 17f, wherein the mGluR5 antagonist is administered in an amount of 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., such as 200 mg/b.i.d.
Embodiment 19f: A method according to embodiment 16f, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.
Embodiment 20f: A method according to embodiment 19f, wherein the mGluR5 antagonist is administered in an amount of from 1 mg/day to 100 mg/day.
Embodiment 21f: A method according to embodiment 16f, wherein the mGluR5 antagonist is Compound (III) or a pharmaceutically acceptable salt thereof.
Embodiments (g):
Embodiment 1g: Use of a mGluR5 antagonist for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain.
Embodiment 2g: Use of a mGluR5 antagonist for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance.
Embodiment 3g: Use of a mGluR5 antagonist for the manufacture of a medicament for a treatment to reverse opioid analgesic tolerance associated with chronic opioid use in chronic pain.
Embodiment 4g: Use of a mGluR5 antagonist for the manufacture of a medicament for a treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.
Embodiment 5g: Use of a mGluR5 antagonist for the manufacture of a medicament for the treatment of chronic pain in order to reverse opioid analgesic tolerance associated with chronic opioid use.
Embodiment 6g: Use of a mGluR5 antagonist for the manufacture of a medicament for the treatment of opioid analgesic tolerance in order to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.
Embodiment 7g: Use of a mGluR5 antagonist for the manufacture of a medicament for a treatment to reduce opioid consumption in chronic pain.
Embodiment 8g: Use of a mGluR5 antagonist for the manufacture of a medicament for a treatment to reverse opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the opioid dosage [e.g. daily opioid dose] being administered to the patient is decreased (e.g. by 50% or more, such as by 70% or more, e.g. by 90% or more) and the opioid analgesic effect (i.e. previously achieved by using the higher opioid dosage) is maintained.
Embodiment 9g: Use of a mGluR5 antagonist for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient on an opioid dose of >50 mg oral morphine/day or daily equianalgesic dose of another opioid (i.e. morphine milligram equivalent MME/day), such as a patient on an opioid dose of from 60 to 100 mg oral morphine/day or daily equianalgesic dose of another opioid.
Embodiment 10g: Use of a mGluR5 antagonist for the manufacture of a medicament according to any one of the preceding embodiments, wherein chronic pain is associated to an injury (e.g. wound, burn or fracture) or a disease (e.g. diabetes, multiple sclerosis, arthritis, an autoimmune disease or an infection).
Embodiment 11g: Use of a mGluR5 antagonist for the manufacture of a medicament according to any one of the preceding embodiments, wherein chronic pain is non-malignant chronic pain.
Embodiment 12g: Use of a mGluR5 antagonist for the manufacture of a medicament according to embodiment 11g, wherein non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example with or without previous spine surgery.
Embodiment 13g: Use of a mGluR5 antagonist for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.
Embodiment 14g: Use of a mGluR5 antagonist for the manufacture of a medicament according to any one of the preceding embodiments, wherein chronic pain is chronic post-surgical neuropathic pain.
Embodiment 15g: Use of a mGluR5 antagonist for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in an immediate-release form or a modified-release form; in particular a modified-release form.
Embodiment 16g: Use of a mGluR5 antagonist for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.
Embodiment 17g: Use of a mGluR5 antagonist for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in combination with one or more further pharmaceutical active ingredient.
Embodiment 18g: Use of a mGluR5 antagonist for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each instance a pharmaceutically acceptable salt thereof.
Embodiment 19g: Use of a 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 a mGluR5 antagonist for the manufacture of a medicament according to embodiment 19g, wherein the mGluR5 antagonist is administered in an amount of 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., such as 200 mg/b.i.d.
Embodiment 21g: Use of a 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 a mGluR5 antagonist for the manufacture of a medicament according to embodiment 21g, wherein the mGluR5 antagonist is administered in an amount of from 1 mg/day to 100 mg/day.
Embodiment 23g: Use of a 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: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain.
Embodiment 2h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance.
Embodiment 3h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament for a treatment to reverse opioid analgesic tolerance associated with chronic opioid use in chronic pain.
Embodiment 4h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament for a treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.
Embodiment 5h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament for the treatment of chronic pain in order to reverse opioid analgesic tolerance associated with chronic opioid use.
Embodiment 6h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament for the treatment of opioid analgesic tolerance in order to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.
Embodiment 7h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament for a treatment to reduce opioid consumption in chronic pain.
Embodiment 8h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament for a treatment to reverse opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the opioid dosage [e.g. daily opioid dose] being administered to the patient is decreased (e.g. by 50% or more, such as by 70% or more, e.g. by 90% or more) and the opioid analgesic effect (i.e. previously achieved by using the higher opioid dosage) is maintained.
Embodiment 9h: Use of a pharmaceutical composition comprising, and at least one pharmaceutically acceptable excipient, a mGluR5 antagonist for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient on an opioid dose of >50 mg oral morphine/day or daily equianalgesic dose of another opioid (i.e. morphine milligram equivalent MME/day), such as a patient on an opioid dose of from 60 to 100 mg oral morphine/day or daily equianalgesic dose of another opioid.
Embodiment 10h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according to any one of the preceding embodiments, wherein chronic pain is associated to an injury (e.g. wound, burn or fracture) or a disease (e.g. diabetes, multiple sclerosis, arthritis, an autoimmune disease or an infection).
Embodiment 11h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according to any one of the preceding embodiments, wherein chronic pain is non-malignant chronic pain.
Embodiment 12h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according to embodiment 11h, wherein non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example with or without previous spine surgery.
Embodiment 13h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.
Embodiment 14h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according to any one of the preceding embodiments, wherein chronic pain is chronic post-surgical neuropathic pain.
Embodiment 15h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in an immediate-release form or a modified-release form; in particular a modified-release form.
Embodiment 16h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in combination with one or more further pharmaceutical active ingredient.
Embodiment 17h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each instance a pharmaceutically acceptable salt thereof.
Embodiment 18h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according to embodiment 17h, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.
Embodiment 19h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according to embodiment 18h, wherein the mGluR5 antagonist is administered in an amount of 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., such as 200 mg/b.i.d.
Embodiment 20h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according to embodiment 17h, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.
Embodiment 21h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according to embodiment 20h, wherein the mGluR5 antagonist is administered in an amount of from 1 mg/day to 100 mg/day.
Embodiment 22h: Use of a pharmaceutical composition comprising a mGluR5 antagonist, and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according embodiment 17h, wherein the mGluR5 antagonist is Compound (III) or a pharmaceutically acceptable salt thereof.
Embodiments (j):
Embodiment 1j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain.
Embodiment 2j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament for the treatment of opioid analgesic tolerance associated with chronic opioid use in chronic pain, the treatment reversing opioid analgesic tolerance.
Embodiment 3j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament for a treatment to reverse opioid analgesic tolerance associated with chronic opioid use in chronic pain.
Embodiment 4j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament for a treatment to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.
Embodiment 5j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament for the treatment of chronic pain in order to reverse opioid analgesic tolerance associated with chronic opioid use.
Embodiment 6j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament for the treatment of opioid analgesic tolerance in order to reduce the risk of opioid-related overdose associated with chronic opioid use in chronic pain.
Embodiment 7j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament for a treatment to reduce opioid consumption in chronic pain.
Embodiment 8j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament for a treatment to reverse opioid analgesic tolerance associated with chronic opioid use in chronic pain, wherein the opioid dosage [e.g. daily opioid dose] being administered to the patient is decreased (e.g. by 50% or more, such as by 70% or more, e.g. by 90% or more) and the opioid analgesic effect (i.e. previously achieved by using the higher opioid dosage) is maintained.
Embodiment 9j: Use of a pharmaceutical combination comprising, and at least one further pharmaceutical active ingredient, a mGluR5 antagonist for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to a patient on an opioid dose of >50 mg oral morphine/day or daily equianalgesic dose of another opioid (i.e. morphine milligram equivalent MME/day), such as a patient on an opioid dose of from 60 to 100 mg oral morphine/day or daily equianalgesic dose of another opioid.
Embodiment 10j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament according to any one of the preceding embodiments, wherein chronic pain is associated to an injury (e.g. wound, burn or fracture) or a disease (e.g. diabetes, multiple sclerosis, arthritis, an autoimmune disease or an infection).
Embodiment 11j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament according to any one of the preceding embodiments, wherein chronic pain is non-malignant chronic pain.
Embodiment 12j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament according to embodiment 11j, wherein non-malignant chronic pain is chronic back pain, such as chronic low back pain, for example with or without previous spine surgery.
Embodiment 13j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered to an elderly patient.
Embodiment 14j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament according to any one of the preceding embodiments, wherein chronic pain is chronic post-surgical neuropathic pain.
Embodiment 15j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is administered in an immediate-release form or a modified-release form; in particular a modified-release form.
Embodiment 16j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament according to any one of the preceding embodiments, wherein the mGluR5 antagonist is selected from the group consisting of Compound (I), Compound (II), and Compound (III); or in each instance a pharmaceutically acceptable salt thereof.
Embodiment 17j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament according to embodiment 16j, wherein the mGluR5 antagonist is Compound (I) or a pharmaceutically acceptable salt thereof.
Embodiment 18j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament according to embodiment 17j, wherein the mGluR5 antagonist is administered in an amount of 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., such as 200 mg/b.i.d.
Embodiment 19j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament according to embodiment 16j, wherein the mGluR5 antagonist is Compound (II) or a pharmaceutically acceptable salt thereof.
Embodiment 20j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament according to embodiment 19j, wherein the mGluR5 antagonist is administered in an amount of from 1 mg/day to 100 mg/day.
Embodiment 21j: Use of a pharmaceutical combination comprising a mGluR5 antagonist, and at least one further pharmaceutical active ingredient, for the manufacture of a medicament according to embodiment 16j, wherein the mGluR5 antagonist is Compound (III) or a pharmaceutically acceptable salt thereof.
The term “opioid tolerance” or “opioid analgesic tolerance”, as used herein, refers to the chronic use of an opioid which leads to a progressively dose increase (e.g. daily dose increase) of the opioid in order to maintain analgesic effect. Evidence of tolerance may be assessed, for example, according to the PEG scale [i.e. assessment of pain intensity (P), enjoyment of life (E), general activity (G); the PEG scale has shown to be sensitive to change and differentiation between patients with and without pain improvement; e.g. in http://mytopcare.org/wp-content/uploads/2013/06/PEG-Pain-Screening-Tool1.pdf, Krebs E E, et. al. in J. Gen. Intern. Med, 2009, 24, 733-8]. In one embodiment, “opioid analgesic tolerance” is selected from the group consisting of alphamethylfentanyl analgesic tolerance, alfentanil analgesic tolerance, buprenorphine analgesic tolerance, butorphanol analgesic tolerance, codeine analgesic tolerance, diacetylmorphine analgesic tolerance, dihydrocodeine analgesic tolerance, dihydroetorphine analgesic tolerance, dihydromorphine analgesic tolerance, ethylmorphine analgesic tolerance, etorphine analgesic tolerance, fentanyl analgesic tolerance, hydrocodone analgesic tolerance, hydromorphone analgesic tolerance, L-acetylmethadol analgesic tolerance, levorphanol analgesic tolerance, methadone analgesic tolerance, meperidine analgesic tolerance, morphine analgesic tolerance, nicomorphine analgesic tolerance, normethadone analgesic tolerance, noroxycodone analgesic, normorphine analgesic tolerance, norlevorphanol analgesic tolerance, oxycodone analgesic tolerance, oxymorphone analgesic tolerance, phenazocine analgesic tolerance, propoxyphene analgesic tolerance, remifentanil analgesic tolerance, tramadol analgesic tolerance associated, thebaine analgesic tolerance, tapentadol analgesic tolerance, levorphanol analgesic tolerance, sufentanil analgesic tolerance, pentazocine analgesic tolerance, carfentanyl analgesic tolerance, ohmfentanyl analgesic tolerance, nocaine analgesic tolerance, ketobemidone analgesic tolerance, allylprodine analgesic tolerance, prodine analgesic tolerance, dextropropoxyphene analgesic tolerance, dextromoramide analgesic tolerance, benzitramide analgesic tolerance, piritramide analgesic tolerance, dipipanone analgesic tolerance, loperamide analgesic tolerance, diphenoxylate analgesic tolerance, nalbuphine analgesic tolerance, levomethorpha analgesic tolerance, dezocine analgesic tolerance, lefetamine analgesic tolerance and tildine analgesic tolerance. In another embodiment, “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 hydrocodone analgesic tolerance and oxycodone analgesic tolerance; in one embodiment hydrocodone analgesic tolerance; in another embodiment oxycodone analgesic tolerance.
1) Opioids are often taken in larger amounts or over a longer period than was intended.
2) There is a persistent desire or unsuccessful efforts to cut down or control opioid use.
3) A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects.
4) Craving, or a strong desire or urge to use opioids.
5) Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home.
6) Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids.
7) Important social, occupational, or recreational activities are given up or reduced because of opioid use.
8) Recurrent opioid use in situations in which it is physically hazardous.
9) Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by opioids.
10) Tolerance, as defined by either of the following: a) A need for markedly increased amounts of opioids to achieve intoxication or desired effect; b) A markedly diminished effect with continued use of the same amount of opioid.
11) Withdrawal, as manifested by either of the following:
The Opioid Craving Scale (OCS) is a modification of the Cocaine Craving Scale and is a short 3-item reported outcome that is used to assess craving experience during opioid consumption. The 3-item scale comprises a visual analogue measure from 1 to 10 and is used to address how much an opioid user craves an opiate; how strong a desire an opioid user desired to use an opiate on a previous day; and if the opioid user has a desire to take opioids at the same time on the current day. Based on the responses on the 1 to 10 scale for the three items, each one-unit increase in the score was associated with a 17% greater odds of using opioids in the following week (e.g. McHugh R K et al., in Assessing craving and its relationship to subsequent prescription opioid use among treatment-seeking prescription opioid dependent patients, Drug and Alcohol Dependency, 2014, Dec. 1; 145: 121-6).
which can be e.g. prepared as described in WO2003/047581, e.g., in Example 1, or as described in WO2010/018154. WO2003/047581, which is incorporated herein by reference, also describes its in-vitro biological data, as per page 7. As used herein, “mavoglurant” refers to the free form. In particular, mavoglurant is in the 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 the any of the embodiments, above or below, and the claims) is thus to be construed to cover both the free form and a pharmaceutically acceptable salt thereof, unless otherwise indicated herein.
As used herein, the compound of the invention, alternatively named Compound (II), as used herein above and below, is the mGluR5 antagonist known as 9-cyclopropyl-10-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one, of formula:
which can be e.g. prepared as described in WO2014/030128, e.g., in Example 96-2, which is incorporated herein by reference, and which also describes its in-vitro biological data, as per page 203. As used in the context of the present invention (especially in the context of the any of the embodiments, above or below, and the claims), the term “Compound (II)” is to be construed to cover both the free form and a pharmaceutically acceptable salt thereof, unless otherwise indicated herein.
In one embodiment, Compound (II) is also intended to represent isotopically labeled forms. Isotopically labeled compounds have structures depicted by the formula above except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into the compound of the invention include, for example, isotopes of hydrogen, namely the compound of formula:
wherein each 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 there is at least one deuterium present in the compound. In other embodiments there are multiple deuterium atoms present in the compound. Isotopically labeled forms of Compound (II) are for example:
whose CAS Number is 96206-92-7 and it is commercially available. As used in the context of the present invention (especially in the context of the any of the embodiments, above or below, and the claims), the term “Compound (III)” is to be construed to cover both the free form and a pharmaceutically acceptable salt thereof, unless otherwise indicated herein.
In one embodiment, Compound (III) is also intended to represent isotopically labeled forms. Isotopically labeled compounds have structures depicted by the formula above except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into the compound of the invention include, for example, isotopes of hydrogen, namely the compound of formula:
wherein each R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 is independently selected from H or deuterium; provided that there is at least one deuterium present in the compound. In other embodiments there are multiple deuterium atoms present in the compound.
For the above-mentioned uses/treatment methods the appropriate dosage may vary depending upon a variety of factors, such as, for example, the age, weight, sex, the route of administration or salt employed. In patients with, for example, of from 50-70 kg body weight, an indicated daily dosage is, for example, 200 mg/b.i.d of mavoglurant, or of from 1 mg/day to 100 mg/day of Compound (II), referring to amounts of the free form, and if a salt thereof is used the amount will be adapted accordingly.
The following Examples serve to illustrate the invention without limiting the scope thereof. The term “Compound (I)” (i.e. 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]isoquinolin-5(4H)-one}, as used in the context of these examples, refers to the free form. The term “Compound (III)” (i.e. MPEP), as used in the context of these examples, refers to the free form.
The method, which detects tolerance to analgesic activity, follows that described by Fernandes et al (Naunyn-Schmiedeberg's Arch. Pharmacol., 297, 53-60, 1977).
Mice were placed onto a hot metal plate maintained at 54° C. surrounded by a Plexiglas cylinder (height: 13 cm; diameter: 19 cm) (Bioseb: model PE34). The latency to the first foot-lick was measured (maximum: 30 seconds). Morphine (32 mg/kg i.p.) or vehicle were administered twice daily for 6 days (at about 9:00 and 15:00), and then administered with morphine 8 mg/kg i.p. (or saline) 30 minutes before the test on Day 7 to assess morphine tolerance.
The test substances were each evaluated at 3 doses (1, 3 and 10 mg/kg for Compound (I) and 0.3, 1 and 3 mg/kg for Compound (II), administered in morphine tolerant mice p.o. acutely 60 minutes before the test on Day 7. The experiment included appropriate control groups to assess the potential effects of the test substances on morphine tolerance. Compound (III) was evaluated at 1 dose (10 mg/kg), administered under the same experimental conditions and was used as comparison substance.
10 mice were studied per group. The test was performed blind. Data were analysed by comparing treated groups with appropriate controls using unpaired Student's t tests.
Results:
Compound (III) (10 mg/kg), administered p.o. 60 minutes before the test on Day 7 in animals receiving vehicle p.o. and morphine (32 mg/kg) i.p. twice daily from Day 1 to Day 6, significantly increased the foot-licking latency, as compared with animals receiving morphine from Day 1 to Day 6 (+32%, p<0.05) (
Compound (I) (1 mg/kg) administered p.o. 60 minutes before the test on Day 7 in animals receiving vehicle p.o. and morphine (32 mg/kg) i.p. twice daily from Day 1 to Day 6, significantly increased the foot-licking latency, as compared with animals receiving morphine from Day 1 to Day 6 (+44%, p<0.01). It had no significant effects at 3 or 10 mg/kg (
Compound (II) (3 mg/kg) administered p.o. 60 minutes before the test on Day 7 in animals receiving vehicle p.o. and morphine (32 mg/kg) i.p. twice daily from Day 1 to Day 6, significantly increased the foot-licking latency, as compared with animals receiving morphine from Day 1 to Day 6 (+38%, p<0.05). It had the same tendency at 1 mg/kg (+37%, p=0.0555) but had no effects at 0.3 mg/kg (
Conclusion:
These results suggest that Compound (I) (1 mg/kg), Compound (II) (3 mg/kg) and Compound (III) (10 mg/kg), administered p.o. acutely significantly decrease the expression of morphine tolerance.
Study Design
This study is a randomized, subject- and investigator-blinded, placebo-controlled, parallel group study to evaluate the efficacy of Compound (I) in 80 patients with chronic low back- and post-surgical pain patients in reducing opioid intake (hydrocodone, oxycodone) in subjects who have used opioids for less than two years. The study involves out-patient visits to the subjects' usual pain clinic and consists of 3 epochs: Screening with Baseline; Treatment; followed by the Treatment Follow-Up. The total duration for a subject may be up to 122 days (approximately 4 months including screening and baseline) depending on the elected percent opioid reduction.
Screening/Baseline Epoch
The screening/baseline epoch last for 14 days and consists of:
Treatment Epoch
Subjects fulfilling all eligibility criteria will be randomly allocated to either Compound (I) arm or placebo matched arm in a ratio of 1:1. Study drug treatment should start on Day 1 with total treatment lasting approximately 93 days during which time subjects will reduce their opioid dose by a minimum of 10% of their starting dose per week, in consultation with their study physician. Subjects will titrate through 50 mg, 100 mg and 200 mg bid every 4 days (see table 1) to reach 400 mg total daily dose by Day 12. During this titration phase, subjects will be monitored for safety as the study drug dose is increased, which will include visits on Day 1, 5 and 9, to ensure that subjects have reached the maintenance dose of 400 mg per day without tolerability issues.
PK samples will be collected at predose and 4±1 hours post dose on day 13, 55 and 69, respectively and a predose PK sample on day 83. On the day of PK sampling the subjects will take the Compound (I) dose at the site as a predose sampling needs to take place before the dosing.
Following titration up to 400 mg per day, subjects will continue with a daily dose of 400 mg of Compound (I) (200 mg b.i.d) or placebo from Day 13 through Day 82. During this time, subjects will reduce their opioid consumption by a minimum of 10% per week in consultation with their study physician until they reach a daily opioid consumption of at least 50% of their starting opioid MME dose. Subjects who are unable to reduce may remain at the current dose of opioid that they achieved during the preceeding week of the study. Subjects can, under the direction of their study physician, reduce their opioid consumption to more than 50%. Subjects may also aim to reduce their opioid intake by utilizing alternative methods of therapy. However, marijuana use for pain is not permitted under this protocol.
The starting Day for Compound (I) tapering is Day 83 with completion of tapering for Compound (I) at Day 90. Opioid reduction may extend through out the maintenance period of Compound (I) dosing assuming a conservative reduction of opioid of 10% per week or subjects can remain on the dose of opioid that they have achieved during their opioid reduction throughout the remaining Compound (I) maintenance period and tapering. The protocol is flexible to allow the physician and patients to elect to reduce opioid consumption that best suits the subject treatment and medical history. However, Compound (I) treatment is not flexible and should follow the assessment schedule for up-titration, maintenance and tapering. Subjects will taper their study drug (Compound (I) or Placebo) until they reach their last dose of Compound (I) or placebo (Table 2). Subjects will continue with the dose of opioid that they have achieved during the reduction process.
Treatment Follow-Up
Subjects will return to the clinic on Day 97 for an end of treatment completion follow-up visit. Subjects must have tapered the study drug treatment prior to the end of treatment completion follow-up visit.
Dosing in Combination with Forced Opioid Reduction During the Study
Since patients may take different opioids (hydrocodone and oxycodone) in different dosages, these medications should be converted into Morphine Equivalent Dose (MED) and opioid reduction should be done using MED. As opioid reduction plans should be individualized to minimize symptoms of opioid withdrawal while maximizing pain treatment, it will be up to the investigator to reduce according to the criteria noted in the Oxford University Hospitals Guidance for Opioid Reduction in Primary Care (v1.1 Dec. 2017) for reference see Table 3.
Population
A total of approximately 80 patients, aged between 18 and 65 years of age (inclusive) with a diagnosis of Opioid Use Disorder will be enrolled in the study.
The investigator must ensure that all subjects being considered for the study meet the following eligibility criteria. No additional criteria should be applied by the investigator, in order that the study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all eligibility criteria at screening and again at baseline to ensure that the subject remains eligible for entry into the study. A relevant record (e.g., checklist) of the eligibility criteria must be stored with the source documentation at the study site.
Deviation from any entry criterion excludes a subject from enrollment into the study.
Inclusion Criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
Exclusion Criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
Treatment Arms
Subjects will be assigned to one of the following 2 treatment arms in a ratio of 1:1 at baseline.
Efficacy
Clinical efficacy measures (PEG, NRS and TLFB-Opioid) will be collected. In addition, domains suggested within the draft FDA Guideline for opioid reduction will also be assessed by the COWS, OCS, and NOSE, and the DSM-5 defined severity of opioid use disorder.
Analysis of the Primary Endpoint(s)
The purpose of the study is to evaluate the efficacy of Compound (I) in reducing consumption of opioids in chronic low back- and post-surgical pain patients taking between 60 and 100 milligram morphine equivalent dose per day. This will be evaluated by measuring the daily consumption using the TLFB. A subject showing a decrease of the mean weekly consumption between baseline and the last week on treatment of at least 50% will be considered as a responder. PEG assessment at baseline, at week 4, 8, and at end of the study will provide evidence of treatment response over time.
Definition of Primary Endpoint(s)
The primary endpoint of the study is a binary endpoint (responder/non responder). Response is defined as reduction of at least 50% in the mean weekly consumption between baseline (the week preceding and including the baseline visit)) and the last week on-treatment at the maintenance dose (i.e. of 200 mg bid, days 76 to 82) if the subject completes the treatment maintenance period per protocol or any last 7 days on treatment if the subject discontinued treatment before day 82.
Statistical Model, Hypothesis, and Method of Analysis
The number of subjects who are responders in each treatment group is assumed to be a random variable following a binomial distribution Bin(ni, pi) where ni is the number of subjects in treatment group i, and pi is the true underlying proportion of subjects responders in treatment/(i=1 for Compound (I), i=2 for placebo).
Assuming non-informative Beta(1/3, 1/3) priors for the responder rates pi and p2, the posterior probability of the difference in the rates of responders will be used to calculate Prob (p1−p2>0/data) and Prob (p1−p2>0.2/data).
Sample Size Calculation
Primary Endpoint(s)
The sample size is assessed based on the chances of “success”, i.e. that the true difference between Compound (I) and placebo responder rates is >0 with least 90% confidence and is >20% with at least 50% confidence at the interim analysis or at final analysis.
The efficacy criteria are formulated in terms of posterior probability statements about the true responder rate difference Δ=p1−p2, where p1 denotes the true responder rate of Compound (I)-treated patients and p2 the true responder rate of placebo-treated patients. The posterior probability distributions for both arms are calculated using a standard binomial probability model with a conjugate noninformative Beta distribution priors Beta(a, a) with a=1/3 for both p1 and p2.
Efficacy Decision Criteria
The decision rule used at final analysis to claim efficacy consists of the following two statements that must be true simultaneously:
1. Posterior probability of Δ>0 is larger than 90%;
2. Posterior probability of Δ>0.20 is larger than 50%.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2020/050637 | 1/28/2020 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62798415 | Jan 2019 | US |
