Cebranopadol useful for alleviating pain

Abstract

Provided herein are methods, compositions and uses of cebranopadol compositions for treating patients, in need of analgesic treatment.

Description

[0001] REGIMENS AND COMPOSITIONS USEFUL FOR ALLEVIATING PAIN BACKGROUND OF THE INVENTION

[0002] Moderate to severe acute pain is a prevalent condition in the US. Managing this pain remains a challenge, especially in the postoperative setting, in part due to the limitations of existing treatment options like opioids. Opioid agonists provide analgesic effects by acting on opioid receptors in the central and peripheral nervous systems that block the sensation of pain from signaling to the brain. Opioid agonists are available in different dosage forms. Opioid agonists may be characterized as full agonist opioids or partial agonist opioids. While opioids may provide some effective pain relief, their administration is characterized by undesirable and common side effects including euphoria, abuseability, sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and / or respiratory depression. Treatment challenges are exacerbated by the apprehension of both clinicians and patients to use opioids due to these undesirable and common side effects of opioid administration.

[0003] Cebranopadol (trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-l,r-(3'H)-pyrano[3,4-b]indol]-4-amine) is an analgesic nociceptin / orphanin FQ peptide (NOP) and opioid receptor agonist (WO 2004 / 043967, WO 2008 / 040481, WO 2012 / 016703, WO 2012 / 016699, WO 2012 / 016695, WO 2012 / 016698, WO 2012 / 016697, WO 2013 / 007361). Cebranopadol is a first-in-class dual nociceptin / orphanin FQ peptide (NOP) and mu-opioid peptide (MOP) receptor (dual-NMR) agonist. This dual mechanism leads to potent analgesia while attenuating the negative side effects of euphoria and physical dependence.

[0004] There is an urgent need for an improved therapeutic for the treatment and / or prevention of subjects for whom the standard of care is opioid-based analgesic therapies.

[0005] BRIEF DESCRIPTION OF THE FIGURES FIG 1 provides a bar chart of Primary Endpoint, Pain NRS AUC4-48, in a randomized, placebo-controlled, phase 3 trial of cebranopadol for the treatment of acute pain after abdominoplasty. The first bar (left) represents cebranopadol in patients receiving a first dose of 400 micrograms (pg or mcg) cebranopadol and a second dose 24 hours after the first dose at 400 pg (n=101)(A -59.2 Std Error 10.14 p<0.001). The second bar (middle) represents the population a first dose of 400 micrograms (pg or mcg) cebranopadol and a second dose 24 hours after the first dose at 200 pg (n=98). The third bar (right) represents placebo (standard error 10.12).Cebranopadol 1st 400pg; 2nd 400pg achieved the primary endpoint of statistically significant pain reduction over 44 hours as compared to placebo.

[0006] FIG 2 shows mean pain NRS score over 4-48 hours in a randomized, placebo-controlled, phase 3 trial of cebranopadol for the treatment of acute pain after abdominoplasty. The dotted line represents placebo. Cebranopadol 1st 400pg; 2nd 400pg exhibited an average hourly pain reduction of 1.34 over placebo.

[0007] FIG 3 provides results from a Phase 3 abdominoplasty pain study, using NRS scores. Cebranopadol (circles) was delivered as a single daily 400 ug dose and compared to placebo (diamonds).

[0008] FIG 4 provides results from a Phase 3 bunionectomy pain study, using NRS scores. The y-axis shows mean (SE) pain NRS score, with lower numbers showing reduction in pain plotted over the time course of the study. Cebranopadol (circles) was delivered as a single daily 400 ug dose and compared to placebo (diamonds).

[0009] FIG. 5 shows that in the two hours patients post-administration of an immediate release cebranopadol composition at 600 microgram (mcg or pg), 800 mcg, or 1000 mcg), cebranopadol patients have less respiratory depression and a slower onset of respiratory depression than patients receiving oxycodone at two hours post- administration (placebo (13% reduction VE55 at 1 hour); cebranopadol 600 mgc (13% VE55 reduction after 1 hour) cebranopadol 800 mcg (15% VE55 reduction after 1 hour), cebranopadol 1000 mcg (16% VE55 reduction after 1 hour). At 30 mg and 60 mg, oxycodone patients showed 49% and 55% reduction in VE55, respectively, at one hour post-administration. This figure shows that Cebranopadol patients have less respiratory depression and a much slower onset.

[0010] FIG. 6 shows results from a generated PK / PD model to quantify respiratory depression following doses of 600 mcg, 800 mcg, 1000 mcg of cebranopadol. A PK / PD model predicts the amount of respiratory depression for a given level of analgesic effect of Cebranopadol and Oxycodone. This model shows that cebranopadol patients experience meaningfully lower levels of respiratory depression than Oxycodone at all comparable dose levels therapeutic and supratherapeutic (e.g., Cebranopadol equivalent concentrations; 200 microgram (mcg or pg), 400 mcg, 600 mcg, 800 mcg, 1000 mcg).

[0011] FIG. 7 shows respiratory AEs (respiratory depression and oxygen saturation decrease), plotted as %, at supratherapeutic doses of Cebranopadol in comparison to Oxycodone (60 mg).These results show that milder effects plus slower onset of Cebranopadol lead to drastically lower respiratory AEs than an equivalent opioid comparator.

[0012] FIG. 8 shows mean (SD, standard deviation) O2 saturation peripheral pharmacodynamic analysis population, plotted as percent of O2 saturation peripheral.

[0013] FIG. 9 shows mean (SD, standard deviation) O2 saturation peripheral change from baseline (CFB) pharmacodynamic analysis, plotted as percent O2 saturation peripheral CFB.

[0014] FIG. 10 shows Peak Inspiratory Flow (PIF) as percentage of baseline over time postinjection in rats. The rats received intravenous injections of saline (ImL / kg), Cebranopadol (20ug / kg), Fentanyl (50ug / kg) or Cebranopadol plus Fentanyl. 2-way ANOVA showed no significant difference between groups at baseline (bins -40 to -5) although there was a significant effect of time. 2-way ANOVA showed no significant difference in treatment following injection 1, Cebranopadol or saline (bins 0 to 15), although there was a significant effect of time. 2-way ANOVA showed a significant effect of treatment following injection 2, Fentanyl or saline (bins 20 to 100).

[0015] FIG. 11 shows Apneic Pause (AP) as percentage of baseline over time post-injection in rats. The rats received intravenous injections of saline (ImL / kg), Cebranopadol (20ug / kg), Fentanyl (50ug / kg) or Cebranopadol plus Fentanyl. 2-way ANOVA showed no significant effect between groups at baseline (bins -40 to -5), although there was a significant effect of time. 2-way ANOVA showed no significant difference in treatment, following injection 1, Cebranopadol or saline (bins 0 to 15), although there was a significant effect of time. 2-way ANOVA showed a significant effect of treatment, a significant effect of time, and a significant interaction treatment x time, following injection 2, Fentanyl or saline (bins 20 to 100).

[0016] FIG. 12 shows Tidal Volume (TV) ) as percentage of baseline over time post-injection in rats. The rats received intravenous injections of saline (ImL / kg), Cebranopadol (20ug / kg), Fentanyl (50ug / kg) or Cebranopadol plus Fentanyl. 2-way ANOVA showed no significant effect between groups at baseline (bins -40 to -5). 2-way ANOVA showed no significant difference in treatment, following injection 1, Cebranopadol or saline (bins 0 to 15), although there was a significant effect of time and a significant interaction of treatment x time. 2-way ANOVA showed a significant effect of treatment, a significant effect of time, and a significant interaction treatment x time, following injection 2, Fentanyl or saline (bins 20 to 100).

[0017] FIG. 13 shows Inspiratory Time (Ti) as percentage of baseline over time post-injection in rats. The rats received intravenous injections of saline (ImL / kg), Cebranopadol (20ug / kg),Fentanyl (50ug / kg) or Cebranopadol plus Fentanyl. 2-way ANOVA showed no significant effect between groups at baseline (bins -40 to -5), but a significant effect of time. 2-way ANOVA showed no significant difference in treatment, following injection 1, Cebranopadol or saline (bins 0 to 15), although there was a significant effect of time and a significant interaction of treatment x time. 2-way ANOVA showed a significant effect of treatment, a significant effect of time, and a significant interaction treatment x time, following injection 2, Fentanyl or saline (bins 20 to 100).

[0018] FIG. 14A-FIG.14E shows summaries of minute ventilation (FIG.14A), peak inspiratory flow (FIG. 14B), apneic pause (FIG. 14C), tidal volume (FIG. 14D) and inspiratory time (FIG.

[0019] 14E) as percentage of baseline over time post-injection. Baseline is t=-40 to t=0. Subjects received injection 1 (intravenous Cebranopadol, 20ug / kg) at t=0 and injection 2 (intravenous saline) at t=20.

[0020] SUMMARY OF THE INVENTION

[0021] Use of a composition comprising cebranopadol is provided for reducing pain and reducing or eliminating opioid-related side effects in a subject comprising administering to the patient cebranopadol as the sole analgesic in a 24-hour period. In certain embodiments, the subject is dosed with a composition comprising at least 90% w / w, at least 95%, at least 97%, or at least 99% to 100% cebranopadol in a crystal form characterized by 8.8 ± 0.2 degrees 20, 11.7 ± 0.2 degrees 20, and 18.3 ± 0.2 degrees 20 and a melting point of 298 °C to 308 °C, as determined using differential scanning calorimetry (DSC), as calculated based on the total weight of cebranopadol free base in the composition.

[0022] In certain embodiments, a pharmaceutical composition is provided which comprises a combination product and / or therapy comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof; and an non-opioid analgesic. In certain embodiments, cebranopadol is used in the treatment of moderate to severe acute pain in combination with non-opioid analgesics in adults.

[0023] In certain embodiments, the non-opioid analgesic is a non-steroidal anti-inflammatory (NS AID), a cyclooxygenase- 1 (COX-1) inhibitor, a COX-2 inhibitor. In certain embodiments, the non-opioid analgesic is acetaminophen, ibuprofen, celecoxib, rofecoxib, valdecoxib, etoricoxib, gabapentin, pregabalin, and / or duloxetine. Suitably, no interference has been reported between cebranopadol and such other analgesics. Further, there is nointerference has been reported between cebranopadol and a CYP3A4 inducer (e.g., rifampicin) or a CYP3A inhibitor (e.g., ketoconazole), permitting use of cebranopadol as an analgesic in patients on regimens with these drugs. In certain embodiments, the combination comprises cebranopadol at a daily dose of 400 pg and a non-opioid analgesic, n certain embodiments, cebranopadol in a free base form. In certain embodiments, the composition comprises a greater than 90% w / w cebranopadol Crystal Form A, as calculated based on the total weight of cebranopadol free base in the composition.

[0024] In certain embodiments, an improved method is proved for treating pain in a subject comprising delivering a combination of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof and a non-opioid analgesic. In certain embodiments, the patient is a surgical patient and / or a trauma patient. In certain embodiments, the pain is acute pain. In certain embodiments, the pain is post-operative pain. The cebranopadol may be a free base form. In certain embodiments, the composition comprises a greater than 90% w / w cebranopadol Crystal Form A, as calculated based on the total weight of cebranopadol free base in the composition.

[0025] In certain embodiments, an improved method for treating pain in a subject comprising delivering a combination of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof and a non-opioid analgesic, whereby the combination provides greater pain relief to the subject as compared to treatment with an opioid alone and / or as compared to an opioid in combination with a non-steroidal anti-inflammatory drug. In certain embodiments, pain relief is measured using a Numerical Rating Scale (NRS) rating from 0 (no pain) to 10 (severe pain). In certain embodiments, the composition comprises a greater than 90% w / w cebranopadol Crystal Form A, as calculated based on the total weight of cebranopadol free base in the composition. In certain embodiments, a composition comprises at least 90% w / w cebranopadol in a crystal form characterized by 8.8 ± 0.2 degrees 20, 11.7 ± 0.2 degrees 20, and 18.3 ± 0.2 degrees 20 and a melting point of 298 °C to 308 °C, as determined using differential scanning calorimetry (DSC), as calculated based on the total weight of cebranopadol free base in the composition.

[0026] In certain embodiments, a regimen for treating pain without opioid-related respiratory depression is provided comprising a combination of: cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof; and a non-opioid analgesic. In certainembodiments, the non-opioid analgesic is a non-steroidal anti-inflammatory (NSAID), a cyclooxygenase- 1 (COX-1) inhibitor, a COX-2 inhibitor. In certain embodiments, the non-opioid analgesic is acetaminophen.

[0027] In certain embodiments, a regimen for treating pain without opioid-related respiratory depression is provided comprising a combination of: cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof; and an non-opioid analgesic.

[0028] A method is provided for reducing acute pain and eliminating opioid-related side effects in a patient comprising administering to the patient a single daily dose of 400 ug cebranopadol as the sole analgesic in a 24-hour period, as measured by the Pain Numerical Rating Scale (NRS) Area Under the Curve from 4 to 48 hours (AUC4-48).

[0029] In certain embodiments, the pharmaceutical composition is a solid oral dose.

[0030] Use of a combination of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof and a non-opioid analgesic / anesthetic in a therapeutic regimen for a human is provided.

[0031] Use of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof in a combination regimen with a non-opioid analgesic or anesthetic is provided for treating pain in a human subject. In certain embodiments, the adult dose of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof is in a therapeutic amount of about 200 ug to about 1200 ug per day. In certain embodiments, the cebranopadol is in a free base form. In certain embodiments, the cebranopadol is at least 80%, at least 90%, at least 95%, of the cebranopadol is in crystal form A.

[0032] Still other aspects and advantages of the invention will be apparent from the following detailed description of the invention.

[0033] DETAILED DESCRIPTION OF THE INVENTION

[0034] Provided herein are methods, regimens, and compositions useful in pain therapy in a subject. In certain embodiments, a composition comprising at least 90% w / w, at least 95%, at least 97%, or at least 99% to 100% cebranopadol in a crystal form characterized by 8.8 ± 0.2 degrees 20, 11.7 ± 0.2 degrees 20, and 18.3 ± 0.2 degrees 20 and a melting point of 298 °C to 308 °C, as determined using differential scanning calorimetry (DSC), as calculated based on thetotal weight of cebranopadol free base in the composition. In certain embodiments, cebranopadol is the sole analgesic delivered to a subject in a 24-hour period.

[0035] In other embodiments, the compositions and methods comprise at least one cebranopadol compound in combination with at least one non-opioid analgesic / anesthetic. In certain embodiments, the cebranopadol and the non-opioid analgesic are separately formulated. In such an instance, they may delivered concomitantly with the cebranopadol. Cebranopadol is delivered as a single daily dose, and the non-opioid analgesic may be delivered at suitable time intervals, e.g., consistent with standard use, as needed or instructed for the selected non-opioid analgesic(s), e.g., every 4 to 6 hours, every 6 to 8 hours, every 12 hours, once daily, or as needed.

[0036] The data provided herein support the effectiveness of cebranopadol daily for the treatment of pain following moderate to severe soft tissue pain in surgical patients, providing sufficient pain relief to subjects that the need to dose a subject with a mu agonist opioid is significantly reduced or avoided. For example, efficacy endpoint, cebranopadol demonstrated a greater analgesic effect than the opioid comparator, oxycodone. In certain examples herein, cebranopadol demonstrated a greater analgesic effect than the opioid comparator, oxycodone.

[0037] While cebranopadol has previously been described as providing the activity of a full mu-agonist, it further provides less abuse potential than a partial mu-agonist. The terms “p” or “mu” are used interchangeably in reference to a full agonist or a partial agonist of the p opioid receptor. Full agonists bind tightly to the opioid receptor and may undergo conformational changes to produce effect. Examples of full agonists may include, e.g., codeine, fentanyl, heroin, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, and oxymorphone. These full agonists are typically classified as opioids as a Class (Schedule II) drug. In certain instances, a full agonist may be on Class (Schedule) III drug (e.g., buprenorphine, codeine when mixed with acetaminophen). Examples of partial mu opioid receptor agonists includes tramadol and other opioid-like compounds, e.g., , butorphanol, typically classified as a Class (Schedule) IV drug.

[0038] In certain embodiments, a combination therapy is provided for treating pain, wherein pain is associated with tissue damage following surgery. In certain embodiments, a method, use or composition is provided for treating pain, wherein pain is associated with undergoing surgical procedures (e.g., peri-operative, post-operative pain). In certain embodiments, a method, use or composition is provided for treating pain, wherein pain is trauma pain. In certain embodiments, a method, use or composition is provided for treating pain, wherein pain is associated withhyperalgesia (i.e., increased sensation of pain on a noxious stimulus, typically associated with inflamed tissue.

[0039] In certain embodiments, a method for treating pain with reduced risk of abuse is provided in a patient having nociceptive or neuropathic pain, said regimen comprising dosing a patient once daily with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition is a film-coated tablet.

[0040] In certain embodiments, the cebranopadol used in the compositions and methods provided herein is in free base form. In certain embodiments, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% to 100% of the cebranopadol in the composition is in crystal form A.

[0041] For the purpose of the specification, “treatment of pain” refers to any amelioration of pain, alleviation of pain or pain relief including the prevention thereof. The examples provided herein utilize the Numerical Rating Scale (NRS) is an 11 -point scale to assess pain intensity with anchors at 0 (no pain) and 10 (worst pain imaginable) as an illustrative means for assessing pain levels. For example, 0 (no pain), 1-3 (Mild): Uncomfortable, annoying, minor pain; can be ignored or easily managed; 4-6 (Moderate): Pain that interferes with normal activities, requires attention, but not incapacitating; 7-9 (Severe): Very strong pain, hard to bear, prevents sleep or normal functioning; 10 (Worst): The most severe pain imaginable; unable to function or speak. For example, amelioration, alleviation or pain relief may comprise lowering a patient’s level of pain by 1, 2, 3 or more points, as measured on the NRS. However, other types of assessment may be selected.

[0042] The term “subject” as used herein generally refers to a human and may be used interchangeably with the term “patient”. In certain embodiments, the subject is an adult, e.g., 18 years of age or older. In certain embodiments, the subject is a teen, 13 to 17 years of age, i.e., under 18.

[0043] As used herein, “Cebranopadol” is intended to include trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-l,r-(3'H)-pyrano[3,4-b]indol]-4-amine (also referred to as (lr,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-l,r-pyrano[3,4-b]indol]-4-amine; free base: CAS Number 86351391-1), its pharmaceutically acceptable salts and solvates thereof: See, e.g., US 7799931, incorporated by reference herein. See, also, crystal formsdescribed in US 8895604; US8765800, US8618156, and US8614245, which are incorporated herein by reference.

[0044] In certain embodiments, a free base form of cebranopadol is selected. In certain embodiments, a cebranopadol API composition comprises at least 50% to 100% of crystal form A, or at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or about 100% crystal form A. The crystal form may be present in a pharmaceutically acceptable salt form, e.g., HC1 salt, and / or a hemihydrate, hydrate, solute, or anhydrous form.

[0045] In certain embodiments, the cebranopadol is present in the active pharmaceutical ingredient (API) and / or the pharmaceutical composition as a free base and / or in crystal form A. See, Examples, Part A, incorporated herein by reference herein for the powder x-ray diffraction (PXRD) pattern for cebranopadol crystal form A. In certain embodiments, the cebranopadol crystal form A is characterized by one or more of the following: the PXRD pattern peaks. 8.8 ± 0.2 degrees 20, 11.7 ± 0.2 degrees 20, and 18.3 ± 0.2 degrees 20 and a melting point of 298 °C to 308 °C, as determined using DSC. In certain embodiments, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% to 100% of the cebranopadol in the composition these characteristic peaks and melting point.

[0046] In certain embodiments, cebranopadol crystal form A has a PXRD comprising characteristic peaks at 7.8±0.2 degrees 20 and at 31.6±0.2 degrees 20, and wherein the active ingredient comprises (lr,4r)-6'-fluoro-N,N-dimethyl-4-phe- nyl-4',9'-dihydro-3,EI-spiro-[cyclohexane-l,l,-pyrano-[3,4, b]indol]-4-amine at a diastereomeric excess of about 90% de. In certain embodiments, the crystalline form comprises a characteristic peak at 11.7+0.2 degrees 20. In certain embodiments, the crystalline form comprises characteristic peak at 18.3±0.2 degrees 20. In certain embodiments, the crystalline form comprises characteristic peaks at 8.8±0.2 degrees 20 and / or at 15.8±0.2 degrees 20. In certain embodiments, the crystalline form comprises characteristic peaks at about 20.4+0.2 degrees 20 and / or at 23.3+0.2 degrees 20. In certain embodiments, the crystalline form comprises characteristic peaks at 11.7+0.2 degrees 20, at one or both of 8.8+0.2 degrees 20 and / or 15.8+0.2 degrees 20, and at one or both of 20.4+0.2 degrees 20 and / or 23.3+0.2 degrees 20. In certain embodiments, the crystalline form has an endothermal event with a peak temperature at about 298-308° C., as determined by DSC.

[0047] In certain embodiments, the crystalline form A has a Raman peak at about 1569+2cm'1and / or at about 1002+2cm'1. In certain embodiments, the active ingredient comprises a (lr,4r)-6'-fluoro-N,N-dim- ethyl-4-phenyl-4',9,-dihydro-3,H-spiro-[cyclohexane-l,T- pyrano-[3,4,b]indol]-4-amine at a diastereomeric excess of at least about 95%de. In certain embodiments, the active ingredient comprises a (lr,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4', 9, -dihydro-3, H-spiro-[cyclohexane-l,T- pyrano-[3,4,b]indol]-4-amine at a diastereomeric excess of at least about 97%de. In certain embodiments, the active ingredient comprises a (lr,4r)-6'-fluoro-N,N-dim-ethyl-4-phenyl-4',9,-dihydro-3,H-spiro-[cyclohexane-l,T- pyrano-[3,4,b]indol]-4-amine at a diastereomeric excess of at least about 99%de. In certain embodiments, crystalline form A is present in the active ingredient in an amount of at least about 60 wt. % relative to the total weight of all crystalline and non-crystalline forms of (lr,4r-6'-fluoro- N,N-dimethyl-4-phenyl-4',9'-dihydro-3,H-spiro- [cyclohex- ane-1, T-pyrano-[3,4,b]indol] -4-amine. In certain embodiments, crystalline form A is present in the active ingredient in an amount of at least about 80 wt. % relative to the total weight of all crystalline and non-crystalline forms of (lr,4r-6'-fluoro- N,N-dimethyl-4-phenyl-4',9'-dihydro-3,H-spiro-[cyclohex- ane-1, T-pyrano-[3,4,b]indol] -4-amine. In certain embodiments, crystalline form A is present in the active ingredient in an amount of at least about 90 wt. % relative to the total weight of all crystalline and non-crystalline forms of (lr,4r-6'-fluoro- N,N-dimethyl-4-phenyl-4',9'-dihydro-3,H-spiro-[cyclohex- ane-1, T-pyrano-[3,4,b]indol] -4-amine. In certain embodiments, crystalline form A is present in the active ingredient in an amount of at least about 95 wt. % relative to the total weight of all crystalline and non-crystalline forms of (lr,4r)-6'- fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3,H-spiro-[cy-clohexane-1,1' -pyrano - [3,4 ,b] indol] -4 -amine. In certain embodiments, the pharmaceutical composition contains at most about 1.0 wt.-% 4-dimethylamino-4-phenylcyclohexanone, relative to the total content of 6'-fluoro-N,N-dimethyl-4-phenyl-4',9'- dihydro-3 'H-spiro [cyclohexane- 1,T-pyran [3,4b]indol]-4- amine. In certain embodiments, the composition contains at most about 1.0 wt.-% 4-dimethylamino-4-phenylcyclohexanone, relative to the total content of 6'-fluoro-N,N-dimethyl-4-phenyl-4',9'- dihydro-3 'H-spiro [cy cl ohexane-l,T-pyran [3,4b]indol]-4- amine.

[0048] Methods of making the compound are described, e.g., US 8,779,160; US8,658,827;

[0049] US10,323,040, all of which are incorporated by reference herein.

[0050] Although the free base of cebranopadol is preferred, one may select a pharmaceutically acceptable salts of cebranopadol, which may include salts of inorganic acids, such as hydrochloric acid (cebranopadol HC1), hydrobromic acid and sulfuric acid, and salts of organic acids, such as methane sulfonic acid, fumaric acid, maleic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, lactic acid, citric acid, glutamic acid, acetylsalicylicacid, nicotinic acid, aminobenzoic acid, a-liponic acid, hippuric acid and asparaginic acid. In certain embodiments, cebranopadol is present in the non-salt form (free base). In other embodiments, the cebranopadol is present as cebranopadol hemicitrate (CAS number CAS No.863513-92-2).

[0051] In certain embodiments, a cebranopadol compound useful in certain embodiments of the invention has the structure of:

[0052]

[0053] Cebranopadol ’s duration of action following an immediate release dose is long, e.g., up to 7 hours after intravenous dosing (e.g., 5 to 7 hours), or greater than 9 hours after oral dosing (e.g, 8 to 16 hours, 9 to 18 hours, or longer, e.g., 8 to 24 hours.

[0054] For the purpose of the specification, doses of cebranopadol relate to the free base.

[0055] As used herein, “micronized” cebranopadol refers to the size of the drug particle, in which the average size of the drug particles are less than 10 microns.

[0056] Thus, when a pharmaceutically acceptable salt is used instead, its dose has to be adapted to the equivalent dose of the free base. For example, a dose of “200 pg” means an amount of 200 pg of the free base or any equivalent amount of a pharmaceutically acceptable salt, solvate, hydrate, or salt hydrate, corresponding to 200 pg of the free base.

[0057] Provided herein are unit dosage forms, e.g., coated tablets, comprising 100 pg cebranopadol, 200 pg cebranopadol, 300 pg cebranopadol, or 400 pg cebranopadol, wherein the dose is determined based on equivalence to the free base. In certain embodiments, these unit dosage forms comprise micronized cebranopadol free base as the sole active ingredient. In other embodiments, other forms of cebranopadol are present in the unit dosage form.In certain embodiments, the cebranopadol is administered at a dose of at least about 400 pg daily, for at least two consecutive days in the absence of an opioid analgesic. In certain embodiments, the patient receives the same or different daily doses of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof. Optionally, the pain therapy further comprises a non-opioid analgesic such as described herein.

[0058] Cebranopadol or the physiologically acceptable salt thereof may be administered systemically or orally. In certain embodiments, Cebranopadol or the physiologically acceptable salt thereof is administered once daily.

[0059] While the examples provided herein were generated with one illustrative composition comprising the cebranopadol, other compositions may be used in the methods provided herein. See, e.g., US 9289416, which is incorporated by reference herein.

[0060] As used herein, the term micrograms is abbreviated “pg” or “mcg”, which may be used interchangeably.

[0061] As used herein, for a human patient experiencing acute pain, a dose generally involves delivery of a dose in excess of 400 pg to 2000 pg, e.g., at least 450 pg, at least 500 pg, at least 550 pg, at least 600 pg, at least 650 pg, at least 700 pg, at least 750 pg, at least 800 pg, at least 850 pg, at least 900 pg, at least 950 pg, at least 1000 pg, at least 1100 pg, at least 1200 pg, at least 1300 pg, at least 1400 pg, at least 1500 pg, at least 1600 pg, at least 1700 pg, at least 1800 pg, at least 1900 pg, or at least 2000 pg, as equivalent dose relative to Cebranopadol free base. In most instances, the doses provided herein are for use in human adults, e.g., age 18 and above. These doses may be adjusted and / or titrated for patients under about 62 to 70 kg.

[0062] In certain embodiments, a patient may receive a daily dose in the range of about 10 pg to about 2000 pg of cebranopadol free base or equivalent (e.g., a pharmaceutically salt, hydrate, solvate, salt hydrate, or combination thereof). In certain embodiments, the patient may be an adult human, e.g., age 18 or older. In certain embodiments, the patient may be younger, e.g., in the age range of 12 - 17 years old, 12 to 17 years old, 6 to 17 years old, or younger.

[0063] Doses may be titrated, e.g., as described in US Patent 10,022,353 which is incorporated herein by reference, using a subtherapeutic analgesic dose(s) as the starting dose. In certain embodiment, the cebranopadol subtherapeutic analgesic doses are combined into a therapeutic regimen comprising a dosing regimen which comprises starting at a subtherapeutic dose or a therapeutic dose of cebranopadol, and incorporating a therapeutic dose or doses of another drug into the otherwise titrated regimen over 1-3 weeks, or as needed. In certain embodiments, apatient may receive a subtherapeutic dose for 1, 3 or 3 days, followed by therapeutic or subtherapeutic doses on subsequent days. In certain embodiments, cebranopadol may be delivered in a regimen comprising a single daily dosage delivered over a period of days to weeks without a change in daily dosage. Alternatively, cebranopadol may be delivered in a first dose, followed by an increase in daily dose on day 2 and subsequent days. Alternatively, dosage is adjusted as needed.

[0064] The duration of treatment is not particularly limited and may last for several weeks, months, or years, especially when the pain to be treated or prevented is chronic. In certain embodiments, when the pain is chronic, the pain is treated for at least one week or at least two weeks.

[0065] A method for maintaining minute ventilation (MV), peak inspiratory flow (PIF), tidal volume (TV), and / or inspiratory time (Ti), and / or reducing apneic pause (AP) in a subject receiving opioid analgesic / anesthetic therapy is provided. The method comprising treating the subject with a pharmaceutical composition comprising a dual NOP / MOP receptor agonist prior to, or at substantially the same time as delivering an opioid analgesic / anesthetic, whereby the NOP receptor inhibits reduction in MV, PIF, TV and / or Ti and / or reduces AP. In certain embodiments, the method comprises treating the patient with a pharmaceutical, composition comprising cebranopadol in the absence of MOP receptor agonist.

[0066] In certain embodiments, the cebranopadol and non-opioid analgesic provides at least a 5% improvement, or a 5% to 15% improvement in MV as compared to delivering a mu agonist opioid analgesic. In certain embodiments, the compound cebranopadol provides at least a 5% improvement, or a 5% to 15% improvement in PIF as compared to delivering a mu agonist opioid analgesic. In certain embodiments, the cebranopadol provides at least a 5% improvement, or a 5% to 15% improvement in TV. In certain embodiments, the cebranopadol provides at least a 5% improvement, or a 5% to a 15% improvement in TV as compared to opioid alone. In certain embodiments, the cebranopadol prevents any more than a 15% increase, or no more than a 5% increase in AP as compared an opioid alone. In certain embodiments, the improvement is observed within 1 hour to about 4 hours (e.g., for an orally administered cebranopadol or other suitable composition). In certain embodiments, the desired protective effect persists for a longer time period and / or has an faster onset time.

[0067] In certain embodiments, the composition and non-opioid analgesic combination provided herein provides an improvement over a full mu-agonist opioid. For example, the opioid may becodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, morphine, oxycodone, or oxymorphone.

[0068] In certain embodiments, the compound comprising NOP receptor agonist activity is cebranopadol which further has dual MOP activity and the opioid is fentanyl.

[0069] In certain embodiments, the dose of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof is about 200 ug to 1200 ug daily, or about 400 ug to 600 ug daily as determined based on cebranopadol free base.

[0070] In certain embodiments, the cebranopadol comprises at least 80% of the cebranopadol is in crystal form A.

[0071] In certain embodiments, the patient is a surgical patient and / or a trauma patient.

[0072] In certain embodiments, the patient has impaired lung function associated with a decreased lung capacity prior to treatment. In certain embodiments, the patient has a lung disease which is lung cancer, chronic obstructive pulmonary disease (COPD), pneumonia, septic embolization, noncardiogenic pulmonary edema, foreign body granulomatosis, bullous lung disease, emphysema, interstitial lung disease, pulmonary vascular disease, pneumothorax, pneumomediastinum, pulmonary hypertension, asthma, amyloidosis, chronic pulmonary complications associated with injection cocaine use which lung scarring due to repeated pulmonary infections and pulmonary infarction, and / or pulmonary arterial hypertension.

[0073] A pharmaceutical composition is provided which comprises a combination of: (i) cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof; and (ii) a non-opioid analgesic.

[0074] In certain embodiments, a regimen and / or a pharmaceutical composition is provided which comprises cebranopadol in combination with another analgesic, e.g., acetaminophen, a non-steroidal anti-inflammatory (e.g., ibuprofen), Cyclooxygenase- 1 (COX-1) inhibitors (aspirin, Naproxen, flurbiprofen, ibuprofen, salsalate, diclofenac), COX-2 inhibitors (e.g., celecoxib, rofecoxib, valdecoxib, etoricoxib), COX-3 inhibitors, gabapentin / pregabalin, duloxetine (a selective serotonin and norepinephrine reuptake inhibitor). Without wishing to be bound by theory, no interference has been reported between cebranopadol and other analgesics. Further, there is no interference reported between cebranopadol and a CYP3A4 inducer (e.g., rifampicin) or a CYP3A inhibitor (e.g., ketoconazole), permitting use of cebranopadol as an analgesic in patients on regimens with these drugs.In certain embodiments, the prescribed dosage of the selected non-opioid pain medication is selected for a combination composition and / or use. Suitably, there is no interaction or interference between cebranopadol and the selected NSAID or other non-opioid analgesic.

[0075] Suitable dosage amounts for acetaminophen may include, Parenteral: Weight 50 kg or greater: 1000 mg IV every 6 hours, or 650 mg IV every 4 hours; Maximum Single Dose: 1000 mg; Minimum Dosing Interval: every 4 hours; Maximum Dose: 4000 mg per 24 hours. Weight less than 50 kg: 15 mg / kg IV every 6 hours OR 12.5 mg / kg IV every 4 hours; Maximum Single Dose: 15 mg / kg; Minimum Dosing Interval: every 4 hours; Maximum Dose: 75 mg / kg per 24 hours. Oral: Immediate-release: 325 mg to 1 g orally every 4 to 6 hours, Minimum Dosing Interval: every 4 hours, Maximum Single Dose: 1000 mg, Maximum Dose: 4000 mg per 24 hours. Extended-Release: 1300 mg orally every 8 hours, Maximum dose: 3900 mg per 24 hours. Rectal: 650 mg rectally every 4 to 6 hours; Maximum dose: 3900 mg per 24 hours. Other suitable doses may be selected. For ibuprofen, Oral doses may range from 200 to 400 mg orally every 4 to 6 hours as needed; Maximum dose: 3200 mg / day (prescription strength); 1200 mg / day (over-the-counter). Parenteral: IV: doses may be 400 to 800 mg IV every 6 hours as needed; Maximum dose: 3200 mg / day. Other suitable doses may be selected. For COX-1 inhibitors, doses may vary for nonselective NSAIDs such as ibuprofen (e.g., 200-400 mg every 4-6 hours) and naproxen (e.g., 250-500 mg twice daily) Other suitable doses may be selected.

[0076] In certain embodiments, the pharmaceutical composition is a solid oral dose.

[0077] In certain embodiments, the pharmaceutical composition is a liquid composition.

[0078] In certain embodiments, the composition is a liquid composition suitable for injection. Use of a combination of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof and an opioid analgesic / anesthetic in a therapeutic regimen for a human is provided.

[0079] Use of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof in a combination regimen with an opioid analgesic or anesthetic is provided for treating pain in a human subject. In certain embodiments, the dose of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof is in a therapeutic amount of about 200 ug to about 1200 ug per day. In certain embodiments, the cebranopadol in its free base form. In certain embodiments, at least 80% of the cebranopadol is in crystal form A.

[0080] Pain and / or opioid drug dependence are treated or prevented. When pain is to be treated or prevented, the pain may be moderate, moderate to severe, or severe. The pain may be chronicor acute; and / or central and / or peripheral; and / or neuropathic and / or nociceptive. In connection with central / peripheral pain and with nociceptive / neuropathic pain “and / or” reflects the possibility that the overall pain may have different components, e.g., a nociceptive component as well as a neuropathic component. In certain embodiments, the pain is chronic neuropathic pain, which may be peripheral or central; acute neuropathic pain, which may be peripheral or central; chronic nociceptive pain, which may be peripheral or central; or acute nociceptive pain, which may be peripheral or central. In certain embodiments, the pain is chronic, acute, subacute, central, peripheral, neuropathic, and / or nociceptive pain. In certain embodiments pain is visceral pain, skeletal pain, and / or nervous pain. In certain embodiments pain is a deep somatic pain. In certain embodiments pain is a superficial somatic pain. In certain embodiments, pain is head-and-face pain.

[0081] In certain embodiments, pain is associated with tissue damage following surgery. In certain embodiments, pain is associated with undergoing surgical procedures (e.g., peri-operative, post-operative pain). In certain embodiments pain is trauma pain. In certain embodiments, pain is associated with hyperalgesia (i.e., increased sensation of pain on a noxious stimulus, typically associated with inflamed tissue). In certain embodiments, pain is associated with opioid-induced hyperalgesia.

[0082] Nociceptive pain refers to the discomfort that results when a stimulus causes tissue damage to the muscles, bones, skin or internal organs. For the purpose of the specification, nociceptive pain is caused by stimulation of peripheral nerve fibers that respond only to stimuli approaching or exceeding harmful intensity (nociceptors), and may be classified according to the mode of noxious stimulation; the most common categories being “thermal” (heat or cold), “mechanical” (crushing, tearing, etc.) and “chemical” (iodine in a cut, chili powder in the eyes). Nociceptive pain may also be divided into “visceral,” “deep somatic” and “superficial somatic” pain.

[0083] Visceral pain describes a type of nociceptive pain originating in the body's internal organs or their surrounding tissues. This form of pain usually results from the infiltration of harmful cells, as well as the compression or extension of healthy cells. Subjects suffering from visceral pain tend to feel generally achy, as this pain tends to not be localized to a specific area. Cancer is a common source of visceral pain.

[0084] Somatic pain is nociceptive pain that results from some injury to the body. It is generally localized to the affected area and abates when the body repairs the damage to that area. Deepsomatic pain is initiated by stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae and muscles, and is dull, aching, poorly localized pain. Examples include sprains and broken bones. Superficial pain is initiated by activation of nociceptors in the skin or superficial tissues, and is sharp, well-defined and clearly located.

[0085] Pain may be classified as chronic if it has occurred for at least 3 months or extends beyond the time of healing. In certain embodiments, the chronic nociceptive pain is selected from chronic visceral pain, chronic deep somatic pain and chronic superficial somatic pain.

[0086] Causes of nociceptive pain include broken or fractured bones, bruises, bums, cuts, inflammation (from infection or arthritis), and sprains. Thus, nociceptive pain includes postoperative pain, cancer pain, low back pain, pain due to radiculopathy, and inflammatory pain.

[0087] Neuropathic pain is pain that originates from nerve damage or nerve malfunction. In certain embodiments, the neuropathic pain is selected from acute neuropathic pain and chronic neuropathic pain. Neuropathic pain may be caused by damage or disease affecting the central or peripheral portions of the nervous system involved in bodily feelings (the somatosensory system). In certain embodiments, the composition is for use in the treatment of chronic neuropathic pain or acute neuropathic pain, peripheral neuropathic pain or central neuropathic pain, mononeuropathic pain or polyneuropathic pain. When the neuropathic pain is chronic, it may be chronic peripheral neuropathic pain or chronic central neuropathic pain, in certain embodiments, chronic peripheral mononeuropathic pain or chronic central mononeuropathic pain, in certain embodiments, chronic peripheral polyneuropathic pain or chronic central polyneuropathic pain. When the neuropathic pain is acute, it may be acute peripheral neuropathic pain or acute central neuropathic pain, in certain embodiments, acute peripheral mononeuropathic pain or acute central mononeuropathic pain, in certain embodiments, acute peripheral polyneuropathic pain or acute central polyneuropathic pain.

[0088] Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Fibromyalgia is potentially a central pain disorder and is responsive to medications that are effective for neuropathic pain. Aside from diabetic neuropathy and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, genetic, and immune mediated disorders or physical trauma to a nerve trunk (e.g., due to disorders from the spinal disc, joint degeneration, or compression fracture). Neuropathic pain iscommon in cancer as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy, radiation injury or surgery.

[0089] In certain embodiments, the pain is selected from postoperative pain, pain due to bunionectomy, visceral pain, cancer pain, pain due to diabetic polyneuropathy, pain due to osteoarthritis, fibromyalgia, low back pain, pain radiating down the lower limbs, pain due to (cervical or lumbar) radiculopathy, and inflammatory pain.

[0090] In certain embodiments, the pain is selected from the group consisting of pain being or being associated with panic disorder [episodic paroxysmal anxiety]; dissociative [conversion] disorders; persistent somatoform pain disorder; pain disorders exclusively related to psychological factors; nonorganic dyspareunia; other enduring personality changes; sadomasochism; elaboration of physical symptoms for psychological reasons; migraine; other headache syndromes; trigeminal neuralgia [G50.0]; atypical facial pain [G50.1]; phantom limb syndrome with pain [G54.6]; phantom limb syndrome without pain [G54.7]; acute and chronic pain, not elsewhere classified [G89]; ocular pain [H57.1]; otalgia [H92.0]; angina pectoris, unspecified [120.9]; other specified disorders of nose and nasal sinuses [J34.8]; other diseases of pharynx [J39.2]; temporomandibular joint disorders [K07.6]; other specified disorders of teeth and supporting structures [K08.8]; other specified diseases of jaws [K10.8]; other and unspecified lesions of oral mucosa [K13.7]; glossodynia [K14.6]; other specified diseases of anus and rectum [K62.8]; pain in joint [M25.5]; shoulder pain [M25.51]; sacrococcygeal disorders, not elsewhere classified [M53.3]; spine pain [M54.]; radiculopathy [M54.1]; cervicalgia [M54.2]; sciatica [M54.3]; low back pain [M54.5]; pain in thoracic spine [M54.6]; other dorsalgia [M54.8]; dorsalgia, unspecified [M54.9]; other shoulder lesions [M75.8]; other soft tissue disorders, not elsewhere classified [M79]; myalgia [M79.1]; neuralgia and neuritis, unspecified [M79.2]; pain in limb [M79.6]; other specified disorders of bone [M89.8]; unspecified renal colic [N23]; other specified disorders of penis [N48.8]; other specified disorders of male genital organs [N50.8]; mastodynia [N64.4]; pain and other conditions associated with female genital organs and menstrual cycle [N94]; mittelschmerz [N94.0]; other specified conditions associated with female genital organs and menstrual cycle [N94.8]; pain in throat and chest [R07]; pain in throat [R07.0]; chest pain on breathing [R07.1]; precordial pain [R07.2]; other chest pain [R07.3]; chest pain, unspecified [R07.4]; abdominal and pelvic pain [RIO]; acute abdomen pain [R10.0]; pain localized to upper abdomen [R10.1]; pelvic and perineal pain [RIO.2]; pain localized to other parts of lower abdomen [RIO.3]; other and unspecified abdominal pain [RIO.4]; flatulence andrelated conditions [R14]; abdominal rigidity [R19.3]; other and unspecified disturbances of skin sensation [R20.8]; pain associated with micturition [R30]; other and unspecified symptoms and signs involving the urinary system [R39.8]; headache [R51]; pain, not elsewhere classified [R52]; acute pain [R52.0]; chronic intractable pain [R52.1]; other chronic pain [R52.2]; pain, unspecified [R52.9]; other complications of cardiac and vascular prosthetic devices, implants and grafts [T82.8]; other complications of genitourinary prosthetic devices, implants and grafts [T83.8]; other complications of internal orthopedic prosthetic devices, implants and grafts [T84.8]; other complications of internal prosthetic devices, implants and grafts, not elsewhere classified [T85.8]; wherein the information in brackets refers to the classification according to ICD-10.

[0091] The dose of cebranopadol or of the physiologically acceptable salt thereof that is administered to the subject is not particularly limited, as it has been unexpectedly found that cebranopadol is so well tolerated that it may even be administered to subjects with impaired hepatic function and / or impaired renal function without any change of treatment, particularly with respect to dosage, dosing frequency and administration regime. Thus, in certain embodiments, cebranopadol or the physiologically acceptable salt thereof is administered at a dose that would also be administered to a subject in the same condition but without impaired hepatic and / or without impaired renal function.

[0092] In certain embodiments, composition comprising cebranopadol or a pharmaceutically acceptable salt, hydrate, salt hydrate is administered to a subject with impaired lung function without any change of treatment, particularly with respect to dosage, dosing frequency and administration regime. In certain embodiments, impaired lung function is associated with a decreased lung capacity. In certain embodiments, decreased lung function is associated with an existing lung disease in individuals, including, but not limited to, lung cancer, chronic obstructive pulmonary disease (COPD), pneumonia, septic embolization, noncardiogenic pulmonary edema, foreign body granulomatosis, bullous lung disease, emphysema, interstitial lung disease, pulmonary vascular disease, pneumothorax, pneumomediastinum, pulmonary hypertension, asthma, amyloidosis, chronic pulmonary complications associated with injection cocaine use which lung scarring due to repeated pulmonary infections and pulmonary infarction, and pulmonary arterial hypertension..

[0093] In some embodiments, the composition comprising cebranopadol or a pharmaceutically acceptable salt, hydrate, salt hydrate is administered at least one of immediately prior to a surgical procedure, intraoperatively, and / or immediately following a surgical procedure or trauma.For the purpose of the specification, “administration once daily” (sid, OD) in certain embodiments means that the pharmaceutical composition is adapted for being administered according to a regimen comprising the administration of a first pharmaceutical composition and the subsequent administration of a second pharmaceutical composition according to the invention, wherein both, the first and the second pharmaceutical composition are administered during a time interval of about 48 hours, but wherein the second pharmaceutical composition is administered not earlier than 18 hours, not earlier than 20 hours, not earlier than 22 hours and in particular, about 24 hours after the first pharmaceutical composition has been administered.

[0094] Administration regimens “once daily” may be realized by administering a single pharmaceutical composition containing the full amount of the cebranopadol or pharmaceutically acceptable salt thereof to be administered at a particular point in time or, alternatively, administering a multitude of dose units, i.e. two, three or more dose units, the sum of which multitude of dose units containing the full amount of the cebranopadol or a pharmaceutically acceptable salt thereof to be dosed at said particular point in time, where the individual dose units are adapted for simultaneous administration or administration within a short period of time, e.g. within 5, 10 or 15 minutes.

[0095] In certain embodiments, a pharmaceutical composition (e.g., pharmaceutical dosage form) comprises at least one form of cebranopadol and / or a pharmaceutically acceptable salt thereof, or a hydrate of the cebranopadol or salt thereof, or a solvate of a cebranopadol or a salt or hydrate thereof. In certain embodiments, the pharmaceutical composition provides immediate release of the cebranopadol or pharmaceutically acceptable salt thereof (or other active ingredient). Such a pharmaceutical composition may be specifically designed to provide immediate release of the cebranopadol in accordance with Ph. Eur or the equivalent. When the pharmaceutical composition is coated, e.g., with a coating that is soluble in gastric juice, the release kinetic may be monitored after such coating has been dissolved.

[0096] For the purpose of specification, the term “immediate release” refers to any release profile that fulfills at least one, preferably both, of the following requirements. First, the pharmaceutical composition disintegrates in 10 minutes or less following exposure to a disintegrating medium. Methods to determine the disintegration time are known to a person skilled in the art. For instance, they can be determined according to the USP XXIV disintegration test procedure, using, for example, an ErwekaZT-71 disintegration tester. Second, the pharmaceutical composition releases at least 70 wt% of the drug within 15 minutes following exposure to a dissolutionmedium. In certain embodiments, the in vitro release properties of the pharmaceutical composition (dosage form) are determined according to the paddle method with sinker at 50, 75 or 100 rpm, under in vitro conditions at 37±0.5° C. in 900 mL artificial gastric juice at pH 1.2, or under the same conditions in non-artificial gastric juice. In certain embodiments, the pharmaceutical composition releases under in vitro conditions in 900 mL artificial gastric juice at pH 1.2 and 37±0.5° C. after 30 minutes according to the paddle method with sinker at 100 rpm at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 90 wt%, or at least 95 wt% of the cebranopadol or salt thereof, based on the total amount of the cebranopadol or salt thereof originally contained in the pharmaceutical composition.

[0097] Various components for pharmaceutical compositions may be selected. See, e.g., US 9289416 and US 10,912,763, which are incorporated by reference herein. In certain embodiments, the pharmaceutical composition is a tablet, chewable tablet, chewing gum, coated tablet or powder, optionally fdled into a capsule. In certain embodiments, the pharmaceutical composition in multi-particulate form, in form of a micro-tablet, micro capsule, granulate, pellet or active-substance crystal, optionally fdled into a capsule or compressed to form a tablet. A solid pharmaceutical composition may contain pharmaceutical excipients including one or more lubricants, binders, disintegrants, fdlers, diluents, glidants, surfactants, and preservatives.

[0098] One suitable lubricant that may be contained in the pharmaceutical composition is magnesium stearate, the content of the lubricant is within the range of from 0.001 to 5.0 wt%, for example 0.01 to 5 wt.-%, 0.1 to 5 wt.-%, 0.1 to 3 wt.-%, 0.1 to 2 wt.-%, or even 0.5 to 1.5 wt.-% , based on the total weight of the composition (e.g., tablet). In certain embodiments, the pharmaceutical composition further contains a binder. Suitable binders include but are not limited to gelatin, cellulose, modified cellulose such as microcrystalline cellulose, methyl cellulose, polyvinyl pyrrolidone (povidone), starch, sucrose and polyethylene glycol; especially preferred are polyvinyl pyrrolidone and / or microcrystalline cellulose. In certain embodiments, the content of lubricant is within the range of from 0.001 to 30 wt.-%, or 0.1 to 25 wt.-%, based on the total weight of the composition (e.g., tablet). In some embodiments, the composition comprises 1 to 20 wt.-%, 5 to 20 wt.-%, or 10 to 20 wt.-% of binder(s), based on the total weight of the composition (e.g., tablet). In certain embodiments, the pharmaceutical composition further contains a fdler and / or diluent, e.g., selected from the group consisting of but are not limited to cellulose (e.g., microcrystalline cellulose), calcium diphosphate, lactose (e.g., lactose monohydrate), sucrose, glucose, mannitol, sorbitol, and calcium carbonate. In certain embodiments, the content of fdlerand / or diluent is within the range of from 0.001 to 95 wt.-%, 30 wt% to about 90 wt%, 0.01 to 85 wt.-%, 0.1 to 80 wt.-%, or 10 to 75 wt.-% , based on the total weight of the composition (e.g., tablet). In certain embodiments, the pharmaceutical composition further contains a lubricant such as magnesium stearate, stearic acid and stearin. In certain embodiments, the content of the lubricant is within the range of from 0.001 to 5 wt %, e.g., from 0.1 to 3 wt%, or about 0.5 wt% to 1.5% wt%, based on the total weight of the composition (e.g., tablet). In certain embodiments, the pharmaceutical composition further contains a disintegrant such as cross-linked sodium carboxymethyl cellulose (croscarmellose sodium), cross-linked polyvinyl pyrrolidone and sodium starch glycolate. In certain embodiments, the content of the disintegrant is within the range of from 0.001 to 5 wt. %, e.g., from 0.1 to 3 wt. %, based on the total weight of the composition (e.g., tablet). The pharmaceutical composition may further contain at least one preservative. Suitable preservatives include but are not limited to antioxidants, such as vitamin A, vitamin E, vitamin C, retinyl palmitate and selenium; cysteine, methionine, citric acid, sodium citrate, methyl paraben and propyl paraben.

[0099] In certain embodiments, a solid pharmaceutical composition further contains a coating, in particular a polymer-based coating, more in particular a polyvinyl alcohol-based coating such as the ones commercially available under the trade name “Opadry”. In some embodiments, the pharmaceutical composition is a tablet which comprises the cebranopadol or pharmaceutically acceptable salt thereof (e.g., in an amount from 0.6±0.4 wt %, 0.6±0.3 wt -%, 0.6±0.2 wt%, 0.6±0.1 wt %, 0.04±0.03 wt %, 0.04±0.02 wt. %, or 0.04±0.01 wt %), one or more lubricants (e.g., magnesium stearate) in an amount from 0.001 to 5.0 wt. % (e.g., 0.01 to 5 wt %, 0.1 to 5 wt %, 0.1 to 3 wt %, 0.1 to 2 wt %, or even 0.5 to 1.5 wt %), one a more binders (e.g., polyvinyl pyrrolidone and / or microcrystalline cellulose) in an amount from 0.001 to 30 wt % (e.g., from 0.1 to 25 wt %, 1 to 20 wt %, 5 to 20 wt %, or 10 to 20 wt %), and one or more fdlers or diluents (e.g., microcrystalline cellulose and / or lactose) in an amount from 0.001 to 90 wt % (e.g., 0.01 to 85 wt %, 0.1 to 80 wt %, or 10 to 75 wt %), based on the total weight of the composition (e.g., tablet). In some embodiments, the tablet also comprises one or more lubricants (e.g., magnesium stearate, stearic acid and / or stearin) in an amount from 0.001 to 5 wt % (e.g., from 0.1 to 3 wt %) and / or one or more disintegrants (e.g., croscarmellose sodium, cross-linked polyvinyl pyrrolidone and / or sodium starch glycolate) in an amount from 0.001 to 5 wt % (e.g., from 0.1 to 3 wt %), based on the total weight of the composition (e.g., tablet). In certain embodiments, the coating protects the pharmaceutical composition from moisture, but dissolves rapidly in gastric juice. Incertain embodiments, the coated composition has a disintegration time of less than 5 minutes in gastric juice, of at most 4.5 minutes, at most 4 minutes, at most 3.5 minutes, at most 3 minutes, at most 2.5 minutes and / or at most 2 minutes. For the manufacture of the pharmaceutical compositions, the various solid auxiliary substances and the pharmacologically active agent may be homogenized, processed by means of wet, dry or fusion granulation to form granulates, and compressed to form tablets. Alternatively, they are manufactured by direct tableting of the auxiliary substances and the pharmacologically active agent. In certain embodiments, the pharmaceutical composition is prepared by means of wet granulation from a granulating fluid containing the pharmacologically active agent in particular from an aqueous granulating fluid containing said pharmacologically active agent and the surfactant. In certain embodiments, the resulting granulating fluid is then top-sprayed or bottom-sprayed onto a solid formulation containing at least one auxiliary substance to yield compressible granules, which may optionally be mixed with further auxiliary substances before being compressed to tablets.

[0100] Further provided herein are methods and regimens using the pharmaceutical compositions comprising at least cebranopadol or a pharmaceutically acceptable salt, hydrate or solvate thereof. In certain embodiments, the composition comprises cebranopadol free base. In certain embodiments, the composition is an immediate release composition.

[0101] In certain embodiments, the combinations provided herein reduce the risk of apnea and / or preventing oxygen desaturation in a patient receiving pain treatment by administering to the patient a pain composition which comprises an active pain ingredient consisting of at least one form of cebranopadol and a second drug. In certain embodiments, the composition comprising an immediate release cebranopadol composition and the active pain ingredient is at least one form of cebranopadol.

[0102] In certain embodiments, the patient receiving cebranopadol combination treatment has impaired lung function. In certain embodiments, the patient has asthma, chronic obstructive pulmonary disease (COPD), pneumonia, chronic or acute bronchitis, emphysema, cystic fibrosis, interstitial lung disease (ILD), pulmonary embolism, pleural effusion, mesothelioma, tuberculosis, acute respiratory distress syndrome (ARDS), neuromuscular disorders, obesity hypoventilation syndrome, or lung cancer.

[0103] In certain embodiments, the cebranopadol combination therapy prevents apnea and / or oxygen desaturation in a patient receiving pain treatment in the first hour and / or the first two hours post-dosing of an immediate release cebranopadol composition independent of dose. Incertain embodiments, the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate. In certain embodiments, a daily dose in an amount of about 10 pg to about 2000 pg cebranopadol, optionally in more than one form (e.g., free base, salt, hydrate, etc). In certain embodiments, the composition comprises cebranopadol free base. In certain embodiments, the composition comprises at least 80% of the cebranopadol in crystal form A.

[0104] In certain embodiments, the method further comprises dosing the patient with cebranopadol at a dose of about 50 pg to 800 pg or more than 190 pg to 800 pg, i.e., the dosage form a contains the pharmacologically active agent in a daily dose of from 150 pg to 800 pg. In certain embodiments, the dose of the pharmacologically active agent is in the range of from 200 pg to 800 pg, from 210 pg to 750 pg, from 220 pg to 700 ug, from 230 pg to 650 pg, from 240 pg to 600 pg, from 250 pg to 550 pg. In certain embodiments, a supratherapeutic dose may be selected. A supratherapeutic dose may comprise greater than 450 pg to about 1000 pg cebranopadol, as calculated based on equivalence to free base cebranopadol. In certain embodiments, the supratherapeutic dose is about 600 pg to about 1000 pg cebranopadol, as calculated based on equivalence to free base cebranopadol. In certain embodiments, the composition comprises the cebranopadol is a tablet, optionally a film coated tablet.

[0105] In certain embodiments, a regimen comprises dosing a patient once daily with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition used is cebranopadol free base. In certain embodiments, the composition is a film-coated tablet. In certain embodiments, a dosage unit comprises 100 mcg (pg) cebranopadol (equivalent to free base). In certain embodiments, a dosage unit comprises 200 mcg cebranopadol (equivalent to free base). In certain embodiments, a dosage unit is 300 mcg cebranopadol (equivalent to free base). In certain embodiments, a dosage unit is 400 mcg cebranopadol. In certain embodiments, a single daily oral dose may comprise 1, 2, 3, 4, 5, 6, 7, or 8 tablets taken essentially at the same time (e.g., 100 mcg tablet taken within five minutes of each other). In certain embodiments, a single daily oral dose may comprise 1, 2, 3 or 4 tablets (e.g., 200 mcg tablet taken within five minutes of each other). In certain embodiments, a single daily oral dose may comprise 1 or 2 tablets (e.g., 100, 200, 300 or 400 mcg tablets, or combinations thereof, taken within five minutes of each other). Other combinations may be selected.

[0106] In certain embodiments, a pharmaceutical composition provides an immediate release profile for the cebranopadol or pharmaceutically acceptable salt thereof. In certain embodiments,composition comprises cebranopadol in its free base form. In certain embodiments, the composition is delivered once daily for the desired duration of treatment, e.g., 1 day to 14 days, 3 weeks, 4 weeks, or longer, or shorter durations therebetween. In certain embodiments, herein the composition is delivered no more than once a day for three to 14 days.

[0107] The pharmacokinetic parameters of cebranopadol may be calculated from plasma concentration- time data.

[0108] AUCo-t refers to “Area under the concentration-time curve” from administration up to the sampling time t. If it is not replaced by a numerical value, then it is the last sampling time with quantifiable concentration and this parameter will not contain an extrapolated portion.

[0109] AUCinf refers to Area under the concentration-time curve from time 0 to infinite time. Areas under the curves in the study examples below may be calculated using the log-linear trapezoidal rule, i.e., linear up to the maximum concentration and log thereafter. However, others may readily select another method.

[0110] Cmax refers to the maximum observed plasma concentration level.

[0111] Tmax refers to the time post-dosing to attain maximum plasma concentration.

[0112] The PK values may be determined using geometric mean and / or the arithmetic mean. In certain embodiments, mean, individual, and overlay concentration-time profiles are plotted on both linear and semi-logarithmic scales on the same, portrait-oriented page.

[0113] As used herein, the Numerical Rating Scale (NRS) is an 11 -point scale to assess pain intensity with anchors at 0 (no pain) and 10 (worst pain imaginable).

[0114] Pharmacodynamics (PD) may be assessed using the Multi-Tasking Test (MTT), such as described in the examples herein. Additional or alternative tests may be selected.

[0115] The Multi-Tasking Test (MTT) (formerly known as the Attention Switching Task, AST) is a test of executive function which provides a measure of the ability to use multiple sources of potentially conflicting information to guide behavior. In this task the participant is presented with a series of arrows on-screen, pointing in either direction (to the right or to the left). Each trial displays a cue at the top of the screen that indicates to the participant whether they have to press the right or left button according to the “side on which the arrow appeared” or the “direction in which the arrow was pointing”. Some trials display congruent stimuli (e.g., arrow on the right side of the screen pointing to the right) whereas other trials display incongruent stimuli which require a higher cognitive demand (e.g., arrow on the right side of the screen pointing to the left). In the final section, both rules are used, presented in a randomized order, requiring the participantto adjust their response depending on whether the rule is repeated or switched (multitasking). Outcome measures for the Multitasking Test include response latencies and error scores that reflect the participant’s ability to manage multitasking and the interference of incongruent task-irrelevant information on task performance. In certain embodiments, the administration time for the test is about 8 minutes.

[0116] In certain embodiments, a combination therapy comprising cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, is provided which when administered to a subject receiving an opioid analgesic or anesthetic provides the subject with reduced respiratory side effects. In certain embodiments, the subject is being treated for pain. In certain embodiments, the pain is chronic acute; central; peripheral; neuropathic and / or nociceptive pain, or another of the types of pain provided in this specification or known in the art. In certain embodiments, the dose is administered daily in an amount of about 10 ug to about 2000 ug cebranopadol. In certain embodiments, the cebranopadol is a free base. In certain embodiments, at least 80% of the cebranopadol is in crystal form A.

[0117] In certain embodiments, use of combination therapy comprising cebranopadol in treating a subject is provided, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject receiving an opioid analgesic or anesthetic provides the subject with reduced respiratory side effects. In certain embodiments, use of cebranopadol in preparing a medicament for treating a subject is provided, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a full mu agonist therapeutic effect and a lower abuse potential than a partial mu agonist.

[0118] In certain embodiments, a method, use or composition is provided for treating pain while reducing the abuse potential and / or sides effects of Class II, III and Class IV- opioids and opioidlike analgesics over a period of about 8 to 24 hours in a patient in need of analgesic treatment, said method comprising dosing a patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt or hydrate thereof. In certain embodiments, the mu-agonist effect is assessed using a visual analog scale (VAS) rating and / or a Multi-Task Test. In certain embodiments, the patient is dosed with 100 pg to 400 ug cebranopadol, as calculated based on equivalence to free base cebranopadol. In certain embodiments, the cebranopadol is at dose which comprises greater than 450 pg to about 1000 pg cebranopadol, or about 600 pg to about 1000 pg, as calculated based on equivalence to free basecebranopadol. In certain embodiments, the cebranopadol is a tablet unit dosage form. In certain embodiments, the tablet is a fdm coated tablet. In certain embodiments, the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol is crystal form A.

[0119] In certain embodiments, a regimen is provided for providing analgesic treatment while e reducing the abuse potential and / or sides effects of Class II and Class IV- opioids in a patient susceptible thereto, said method comprising: (a) discontinuing treatment of a patient with an opioid or opioid agonist ; and (b) dosing a patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof . In certain embodiments, the regimen (a) comprises titrating down the dosage of a Class II, Class III or Class IV opioid or opioid agonist by decreasing the dose of the opioid or opioid agonist in (a) over the period of 1 to 3 days. In certain embodiments, steps (a) and (b) are performed during the same or overlapping time periods. In certain embodiments, opioid or mu opioid agonist is selected from tramadol, oxycodone, morphine, hydrocodone, fentanyl, oxymorphone, hydromorphone, buprenorphine, codeine, tapentadol, methadone, meperidine, or levorphanol. In certain embodiments, the mu agonist activity (or abuse potential) is assessed using a visual analog scale (VAS) rating and / or a Multi-Task Test. In certain embodiments, composition comprising the cebranopadol is a tablet. In certain embodiments, the tablet is film coated tablet. In certain embodiments, the side effects comprise nausea, vomiting, dizziness, pruritis, hyperhidrosis and / or hot flush sensation. In certain embodiments, the patient is renally or hepatically impaired. In certain embodiments, the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol is crystal form A.

[0120] In certain embodiments, a method, use or composition is provided for treating pain. In certain embodiments, a method, use or composition is provided for treating pain, wherein pain is chronic, acute, subacute, central, peripheral, neuropathic, and / or nociceptive pain. In certain embodiments, a method, use or composition is provided for treating pain, wherein pain is visceral pain, skeletal pain, and / or nervous pain.

[0121] Patients more reliably discontinue the use of Cebranopadol at the end of prescribed treatment periods as compared to known Schedule II, Class III, and class IV opioids and opioidlike analgesics. In certain embodiments, a composition comprising cebranopadol treats a subject by delivering full mu (p) agonist activity (e.g., analgesic or other therapeutic effect), while avoiding addictive properties of full mu agonists (e.g., fentanyl, oxycodone, morphine, heroin, codeine, meperidine, or other Class I, Class II or Class III analgesics) and providing lessaddictive properties and / or less abuse potential than a partial mu agonist (e.g., tramadol or another Class IV opioid-like analgesic).

[0122] In further embodiments, unlike after treatment with oxycodone and tramadol, administration of cebranopadol does not produce pruritus, hyperhidrosis, feeling hot and / or hot flushing, that have been associated with the use of opioid analgesics. Provided herein are methods for providing a patient with opioid-level analgesic effect while preventing pruritus by administering cebranopadol. In certain embodiments, methods are provided for preventing pruritus in a patient receiving an opioid-level analgesic effect, comprising administering an effective amount of cebranopadol. Provided herein are methods for providing a patient with opioid-level analgesic effect while preventing hyperhidrosis by administering an effective amount of cebranopadol. In certain embodiments, methods are provided for preventing hyperhidrosis in a patient receiving an opioid-level analgesic effect, comprising administering an effective amount of cebranopadol. Provided herein are methods for providing a patient with opioid-level analgesic effect while preventing feeling hot and / or hot flushing by administering an effective amount of cebranopadol. In certain embodiments, methods are provided for preventing hot flushing in a patient receiving an opioid-level analgesic effect, comprising administering an effective amount of cebranopadol.

[0123] In certain embodiments, a cebranopadol composition useful for reducing pruritus, hyperhidrosis, feeling hot and / or hot in a subject receiving analgesic treatment for pain is provided, which provides the analgesic therapeutic effect of an opioid. In certain embodiments, the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol in the composition is in crystal form A.

[0124] In certain embodiments, a method for reducing pruritus, hyperhidrosis, feeling hot and / or hot in a subject receiving analgesic treatment for pain is provided, which provides the therapeutic effect of an opioid, comprising administering a composition comprising cebranopadol.

[0125] In certain embodiments, a composition is provided which is useful in treating a subject, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a therapeutic effect of a pharmaceutically acceptable full mu-agonist and a lower potential for abuse than a pharmaceutically acceptable partial mu-agonist. In certain embodiments, the subject is being treated for pain. In certain embodiments, the pain is chronic; acute; central; peripheral; neuropathic and / or nociceptive pain. In certain embodiments, the pain is visceral pain, skeletalpain, and / or nervous pain. In certain embodiments, the dose is administered daily in an amount of about 10 ug to about 2000 ug cebranopadol. In certain embodiments, cebranopadol is a free base. In certain embodiments, at least 80% of the cebranopadol is in crystal form A. In certain embodiments, the partial mu-agonist is tramadol. In certain embodiments, use of cebranopadol in treating a subject is provided, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a full mu-agonist therapeutic effect and a lower abuse potential than a partial mu-agonist. In certain embodiments, use of cebranopadol in preparing a medicament for treating a subject is provided, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate, which when administered to a subject provides the subject with a full mu-agonist therapeutic effect and a lower abuse potential than a partial mu agonist.

[0126] In certain embodiments, a composition, use or method is provided for treating a subject, wherein the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, salt hydrate, which when administered to a subject provides the subject with a full mu-agonist therapeutic effect and a lower abuse potential than a partial mu-agonist. In certain embodiments, the subject is being treated for pain. In certain embodiments, the pain is chronic; acute; central; peripheral; neuropathic and / or nociceptive pain. In certain embodiments, the pain is visceral pain, skeletal pain, and / or nervous pain. In certain embodiments, the mu-agonist activity is assessed using a visual analog scale (VAS rating) and / or a Multi-Task Test. In certain embodiments, the dose is administered daily in an amount of about 10 ug to about 2000 ug cebranopadol. In certain embodiments, the cebranopadol is a free base. In certain embodiments,

[0127] at least 80% of the cebranopadol is in crystal form A. In certain embodiments, the partial mu-agonist is tramadol.

[0128] In certain embodiments, a composition, use or method treating pain in a patient having nociceptive pain with reduced risk of abuse is provided, said regimen comprising dosing a patient once daily with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition is a film-coated tablet. In certain embodiments, the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol in the composition is in crystal form A.

[0129] In certain embodiments, a composition, use or method is provided which is useful for reducing pruritus, hyperhidrosis, feeling hot and / or hot in a subject receiving analgesic treatmentfor pain, while providing the analgesic therapeutic effect of an opioid, wherein the composition comprises cebranopadol. In certain embodiments, the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol in the composition is in crystal form A.

[0130] In certain embodiments, a composition or regimen provided herein comprises cebranopadol as the sole active pharmaceutical ingredient or the sole analgesic in the composition.

[0131] In certain embodiments, a composition, use or method for treatment of pain in humans is provided which provides reduced the abuse potential and reduced sides effects as compared to Class II, III and Class IV- opioids and opioid-like analgesics. The method involves dosing a human patient once a day with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt or hydrate thereof. In certain embodiments, the composition is an immediate release composition administered once daily and provides an analgesic effect over a period of at least about 8 to 24 hour hours post-administration. In certain embodiments, the pain is visceral pain, skeletal pain, and / or nervous pain. In certain embodiments, the mu-agonist activity is assessed using a visual analog scale (VAS rating) and / or a Multi-Task Test. In certain embodiments, patient is dosed with 100 pg to 400 ug cebranopadol, as calculated based on equivalence to free base cebranopadol. In certain embodiments, the patient is dosed with greater than 450 pg to about 1000 pg cebranopadol, as calculated based on equivalence to free base cebranopadol. In certain embodiments, the dose is about 600 pg to about 1000 pg cebranopadol, as calculated based on equivalence to free base cebranopadol. In certain embodiments, the composition comprising the cebranopadol is a tablet unit dosage form. In certain embodiments, the tablet is a fdm coated tablet. In certain embodiments, the cebranopadol is in free base form. In certain embodiments, at least 80% of the cebranopadol is crystal form A.

[0132] In certain embodiments, a method is provided for treating pain in a patient having nociceptive pain with reduced risk of abuse. The regimen comprises dosing a patient once daily with an immediate release composition comprising cebranopadol or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition used is cebranopadol free base. In certain embodiments, the composition is a fdm-coated tablet.

[0133] In certain embodiments, in the method, composition, or use, wherein the patient has impaired lung function. In certain embodiments, the patient has asthma, chronic obstructive pulmonary disease (COPD), pneumonia, chronic or acute bronchitis, emphysema, cystic fibrosis, interstitial lung disease (ILD), pulmonary embolism, pleural effusion, mesothelioma,tuberculosis, acute respiratory distress syndrome (ARDS), neuromuscular disorders, obesity hypoventilation syndrome, or lung cancer.

[0134] In certain embodiments, a method, composition or use is provided, wherein cebranopadol prevents apnea and / or oxygen desaturation in a patient receiving pain treatment in the first two hours post-dosing of an immediate release composition independent of dose. In certain embodiments, the composition comprises cebranopadol or a pharmaceutically acceptable salt, hydrate, or salt hydrate. In certain embodiments, the composition is administered daily at a dose in an amount of about 10 pg to about 2000 pg cebranopadol. In certain embodiments, the cebranopadol is a free base. In certain embodiments, at least 80% of the cebranopadol is in crystal form A. In one or more of these embodiments, uses and / or compositions, cebranopadol may be the sole active pharmaceutical ingredient in the composition and / or regimen.

[0135] The present invention includes a number of embodiments, including, without limitation, El. A pharmaceutical composition comprising a combination of: cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof; and at least one non-opioid analgesic.

[0136] E2. The composition of El, wherein the non-opioid analgesic is a non-steroidal antiinflammatory (NS AID), a cyclooxygenase- 1 (COX-1) inhibitor, or a COX-2 inhibitor.

[0137] E3. The composition of El or E2, wherein the non-opioid analgesic is acetaminophen, ibuprofen, celecoxib, rofecoxib, valdecoxib, etoricoxib, gabapentin, pregabalin, and / or duloxetine.

[0138] E4. The composition of El which comprises cebranopadol in a free base form.

[0139] E5. The composition of El, wherein the composition comprises greater than 90% w / w cebranopadol Crystal Form A, as calculated based on the total weight of cebranopadol free base in the composition.

[0140] E6. The composition of El, wherein the composition comprises at least 90% w / w cebranopadol in a crystal form characterized by 8.8 ± 0.2 degrees 20, 11.7 ± 0.2 degrees 20, and 18.3 ± 0.2 degrees 20 and a melting point of 298 °C to 308 °C, as determined using differential scanning calorimetry (DSC), as calculated based on the total weight of cebranopadol free base in the composition.

[0141] E7. An improved method for treating pain in a subject comprising delivering a combination of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydratethereof and a non-opioid analgesic, whereby the combination provides greater pain relief to the subject as compared to treatment with an opioid alone and / or as compared to an opioid in combination with a non-steroidal anti-inflammatory drug.

[0142] E8. The method of E7, wherein pain relief is measured using a Numerical Rating Scale (NRS) rating from 0 (no pain) to 10 (severe pain).

[0143] E9. The method of E7, wherein the patient is a surgical patient and / or a trauma patient.

[0144] E10. The method of E7, wherein the treatment is improved as compared to treatment of one or more of codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, morphine, oxycodone, or oxymorphone

[0145] Ell. The method of E7, wherein the pain is acute pain.

[0146] E12. The method of E7, wherein the pain is post-operative pain.

[0147] El 3. The method of E7, wherein pain is treated in the absence of an opioid analgesic. E14. The method of E7, wherein the cebranopadol is delivered in a solid tablet.

[0148] El 5. The method of E7, wherein the non-opioid analgesic is a non-steroidal antiinflammatory (NS AID), a cyclooxygenase- 1 (COX-1) inhibitor, a COX-2 inhibitor.

[0149] El 6. The method of E7, wherein the non-opioid analgesic is acetaminophen, ibuprofen, celecoxib, rofecoxib, valdecoxib, etoricoxib, gabapentin, pregabalin, and / or duloxetine.

[0150] El 7. The method of E7 which comprises cebranopadol in a free base form.

[0151] El 8. The method of E7, wherein the composition comprises a greater than 90% w / w cebranopadol Crystal Form A, as calculated based on the total weight of cebranopadol free base in the composition.

[0152] El 9. The method of E7, wherein the composition comprises at least 90% w / w cebranopadol in a crystal form characterized by 8.8 ± 0.2 degrees 20, 11.7 ± 0.2 degrees 20, and 18.3 ± 0.2 degrees 20 and a melting point of 298 °C to 308 °C, as determined using differential scanning calorimetry (DSC), as calculated based on the total weight of cebranopadol free base in the composition.

[0153] E20. A regimen for treating pain without opioid-related respiratory depression comprising a combination of: cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof; and an non-opioid analgesic.E21. The regimen according to E20, wherein the non-opioid analgesic is a nonsteroidal anti-inflammatory (NS AID), a cyclooxygenase- 1 (COX-1) inhibitor, a COX-2 inhibitor.

[0154] E22. The regimen according to E20 or E21, wherein the non-opioid analgesic is acetaminophen, ibuprofen, celecoxib, rofecoxib, valdecoxib, etoricoxib, gabapentin, pregabalin, and / or duloxetine.

[0155] E23. A method for reducing acute pain and eliminating opioid-related side effects in a subject comprising administering to the patient cebranopadol as the sole analgesic in a 24-hour period.

[0156] E24. The method of E23, wherein reduction of acute pain is as measured by the Pain Numerical Rating Scale (NRS) Area Under the Curve from 4 to 48 hours (AUC4-48).

[0157] E25. The method of E23, wherein the subject is treated with a single daily dose of 400 ug cebranopadol as the sole analgesic in a 24-hour period, as measured by the Pain Numerical Rating Scale (NRS) Area Under the Curve from 4 to 48 hours (AUC4-48).

[0158] E26. The method of E23, wherein the subject is age 18 or older.

[0159] E27. The method of E23, wherein the subject is dosed with a composition comprising at least 90% w / w cebranopadol in a crystal form characterized by 8.8 ± 0.2 degrees 20, 11.7 ± 0.2 degrees 20, and 18.3 ± 0.2 degrees 20 and a melting point of 298 °C to 308 °C, as determined using differential scanning calorimetry (DSC), as calculated based on the total weight of cebranopadol free base in the composition.

[0160] E28. A composition of any one of El to E6 for use in treating pain without opioid-related respiratory depression.

[0161] E29. Use of a composition of any one of El to E6, for use in an method for treating acute pain and / or eliminating opioid-related side effects in a patient, and / or treating pain without opioid-related respiratory depression.

[0162] E30. The composition of E28 or use of E29, wherein the subject is a surgical patient and / or a trauma patient.

[0163] E31. The composition of E 18 or E30, or use of E29 or E30, wherein treatment is improved as compared to treatment of one or more of codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, morphine, oxycodone, or oxymorphone.

[0164] E32. The composition of any one of E28, E30 or E31, or use of any one of E29 to E31, wherein the pain is acute pain.E33. The composition of any one of E28 or E30 to E32, or use of any one of E29 to E32, wherein the pain is post-operative pain.

[0165] E34. The composition of any one of E28 or E30 to E33, or use of any one of E29 to E32, wherein pain is treated in the absence of an opioid analgesic.

[0166] E35. The composition of any one of E28 or E30 to E34, or use of any one of E29 to E32, wherein the cebranopadol is delivered in a solid tablet.

[0167] E36. The composition of any one of E28 or E30 to E35, or use of any one of E29 to E32, wherein the non-opioid analgesic is anon-steroidal anti-inflammatory (NSAID), a cyclooxygenase- 1 (COX-1) inhibitor, a COX-2 inhibitor.

[0168] E37. The composition of any one of E28 or E30 to E35, or use of any one of E29 to E32, wherein the non-opioid analgesic is acetaminophen, ibuprofen, celecoxib, rofecoxib, valdecoxib, etoricoxib, gabapentin, pregabalin, and / or duloxetine.

[0169] E38. The composition of any one of E28 or E30 to E36, or use of any one of E29 to E37, which comprises cebranopadol in a free base form.

[0170] E39. The composition of any one of E28 or E30 to E36, or use of any one of E29 to E38, wherein the composition comprises a greater than 90% w / w cebranopadol Crystal Form A, as calculated based on the total weight of cebranopadol free base in the composition.

[0171] E40. The composition or use of E39, wherein the subject is dosed with a composition comprising at least 90% w / w cebranopadol in a crystal form characterized by 8.8 ± 0.2 degrees 20, 11.7 ± 0.2 degrees 20, and 18.3 ± 0.2 degrees 20 and a melting point of 298 °C to 308 °C, as determined using differential scanning calorimetry (DSC), as calculated based on the total weight of cebranopadol free base in the composition.

[0172] It will be understood from the specification that the following examples are not limitations on the various embodiments of the invention.

[0173] Examples:

[0174] Illustrative Synthesis of Crystalline Form A

[0175] The following abbreviations are used in the examples: iBuOAc iso-butyl acetate; IBuOH n-butanol (1 -butanol); DMSO dimethyl sulfoxide; EtOAc ethyl acetate; EtOH ethanol; Ex example; FT-Raman Fourier transformation Raman spectroscopy; IPE diisopropyl ether; Am change in mass; MeCN acetonitrile; MEK 2-butanone; MeOH methanol; min minute; NMP N-methyl-2-pyrrolidone; IPrOH n-propanol (1 -propanol); 2PrOH iso-propanol (2 -propanol); PXRD powder x-ray diffraction; r.h. relative humidity; RT room temperature, preferably 20-25° C; SCXRD single crystal X-ray diffraction; sec seconds ; t time (duration) ; TBME tert-butyl methyl ether; TG-FTIR thermogravimetry coupled with Fourier transform infrared spectroscopy; THF tetrahydrofuran; XRPD X-ray powder diffraction. Unless otherwise specified, solvent mixtures are always volume / volume.

[0176] 100 mg (lr,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-l,l'-pyrano[3,4,b]indol]-4-amine [crystalline form D according to D)] was suspended in 0.5 mL TBME. The suspension was stirred at RT for six days. The resulting solid was filtered out and dried in air. A crystalline solid of crystalline form A was obtained and characterized by PXRD.

[0177] The following Table shows the peak list for crystalline form A. The uncertainty in the 20 values is ±0.2° in 20; rel. I is the relative intensity of the respective peaks. Maximum intensity is 100.

[0178]

[0179]

[0180] Analysis — DVS

[0181] Crystalline Form A was previously characterized by dynamic vapor sorption (DVS) using a Projekt Messtechnik SPS 1 l-100n multi sample water vapor sorption analyzer. For the DVS analysis, each sample was allowed to equilibrate at 50% r.h. (relative humidity) before starting a pre-defined humidity program during which the change in weight of the sample is determined. All measurements were performed according to the following program: 2 h at 50% r.h.; 50% r.h.^0% r.h. (10% / h); 5 h at 0% r.h.; 0^95% r.h. (5% / h); 3 h at 95% r.h.; 95^50% (10% / h), and 2 h at 50% r.h.

[0182] Although hygroscopicity was measured in a slightly different manner, it was classified according to the European Pharmacopoeia as follows: very hygroscopic (vh): increase of the mass^l5%; hygroscopic (h): increase of the mass is less than 15% and equal or greater than 2%; slightly hygroscopic (sh): increase of the mass is less than 2% and equal or greater than 0.2%; not hygroscopic (nh): increase of the mass is less than 0.2%; deliquescent (d): sufficient water is absorbed to form a liquid.

[0183] DVS with two cycles was performed on a sample of crystalline form A. The first cycle was not symmetric, the sample contained still water when the DVS cycle returned to 50% r.h. (relative humidity in %). The second cycle was reversible. Below 40% r.h. the relative mass returned to '100% (water content=0%). The hysteresis between 40% and 70% r.h. indicates a metastable zone. The second cycle indicated the following transformations: hemi-hydrate^ansolvate (<38% r. h.)^hemi -hydrate (>70% r. h.). The sample was classified to be hygroscopic (Am=3-4% at 85% r. h.; Am: change in mass)

[0184] Example 1: Cebranopadol Free Base Tablets

[0185] A. Cebranopadol film coated tablets, 200 pg: single oral dose of 600 pg

[0186] B. Cebranopadol film coated tablets, 200 pg: single oral dose of 1000 pg

[0187]

[0188] Example 2: Cebranopadol exhibited efficacy comparable to opioids in managing postoperative pain following abdominoplasty, while exhibiting a favorable safety profile A Phase 3 multicenter, randomized, double-blind, placebo-controlled study was performed. This study evaluates the safety and efficacy of cebranopadol in managing acute postoperative pain following abdominoplasty surgery. The primary objective of the study is to evaluate the analgesic efficacy of cebranopadol compared with placebo for the management of moderate-to-severe acute post-operative pain using as a model a full abdominoplasty as measured by pain intensity (11 -point numeric rating scale) assessments. Secondary objectives include assessing the analgesic efficacy of cebranopadol through use of rescue medication, early discontinuations and subject overall assessment of study medication. In summary, the study successfully met its primary endpoint by demonstrating a statistically significant reduction in pain intensity, measured by the Pain Numerical Rating Scale (NRS) Area Under the Curve from 4 to 48 hours (AUC4-48). Specifically, treatment with cebranopadol 400 / 400 pg showed a statistically significant reduction in pain intensity compared to placebo (LS Mean [SE] = 174.0 [10.14] vs.

[0189] 232.8 [10.12]; p<0.001), while cebranopadol 400 / 200 pg did not achieve statistical significance (LS Mean [SE] = 213.8 [10.23] vs. 232.8 [10.12]; p = 0.183. nu

[0190] See, e.g., FIGs 1-3. Results from the pivotal Phase 3 clinical trial demonstrated that cebranopadol-treated patients also required significantly fewer doses of rescue medication than patients receiving placebo (LS mean difference of 2.2; p=<0.001).

[0191] The study achieved a standardized effect size (SES) of 0.58, which surpasses the average SES of 0.54 documented in previous abdominoplasty trials, as reported by Singla et al. emphasizing the substantial impact of cebranopadol in alleviating moderate to severe postoperative pain. Importantly, cebranopadol exhibited a favorable safety profile with no observed respiratory depression and minimal side effects.

[0192] A. Materials and Methods: A Phase 3 double-blind, randomized, placebo-controlled, multi-center study was conducted evaluating cebranopadol compared to placebo. Following ethics board approval, and informed consent, eligible, non-smoking, participants aged 18-75 years were randomized in a 1 : 1 : 1 ratio to receive a dose of cebranopadol 400pg 1 hour prior to the abdominoplasty followed by a second 400pg dose approximately 24 hours (± 30 minutes) after the first dose (400pg / 400pg), 400pg / 200pg, or placebo. Subjects underwent a fullabdominoplasty procedure without liposuction or other collateral procedures under a standardized regimen of anesthesia. Ondansetron 4mg was administered for prophylaxis of nausea and

[0193] vomiting with the possibility of a supplementary dose. Rescue medications included IV morphine for the first 24 hours following study drug administration followed by oral oxycodone thereafter.

[0194] The primary efficacy endpoint was the pain numerical rating scale (NRS) area under the curve from 4 through 48 hours (AUC4-48) of the treatment group compared to placebo. Subjects were also monitored for treatment emergent adverse events (TEAEs).

[0195]

[0196]

[0197] The first dose of study drug was administered approximately 1 hour prior to the abdominoplasty procedure (ie, induction of anesthesia) based on the estimated duration of the procedure (approximately 2 to 3 hours), intraoperative local anesthetic field block (1.0% lidocaine with 1:200,000 epinephrine [up to 7 mg / kg - maximum dose 500 mg]) and intraoperative analgesic administration, and the longer median Tmax of cebranopadol (4 to 6hours). The relative timing was selected to ensure that subjects would have sufficient exposure to cebranopadol as the regional anesthesia and intraoperative analgesia wore off, and pain intensity would be expected to increase. The primary endpoint, AUC4-48, allowed for analysis of analgesic efficacy of cebranopadol outside the expected window of local anesthetic / intraoperative analgesic effect during the immediate postoperative period.

[0198] Selection of Study Population:

[0199] A total of 303 subjects who underwent abdominoplasty were enrolled in 3 treatment groups (100 per treatment group) at 4 sites in the US.

[0200] Subjects withdrawn from the study following randomization may have been replaced at the discretion of the sponsor, unless the investigator determined that this should not have been done for reasons of safety. No subjects were replaced in this study.

[0201] Inclusion Criteria:

[0202] Subjects were required to meet each one of the following inclusion criteria to be eligible for participation in the study:

[0203] 1. Capable of giving signed informed consent which included compliance with the requirements and restrictions listed in the ICF and in the protocol.

[0204] 2. Non-smoking (or quit smoking at least 12 months prior to Screening) males and females, between 18 and 75 years of age, inclusive, at the time of signing the informed consent.

[0205] 3. Scheduled to undergo full abdominoplasty procedure without liposuction or other collateral procedures, using anesthesiologic and surgical procedures planned as described in the protocol.

[0206] 4. Women of childbearing potential (WOCBP) must have been using at least one highly effective method of contraception (failure rate <1% per year) for at least 30 days prior to Screening; they must have also been willing to continue to use at least one highly effective method of contraception throughout the study and for at least 30 days after discontinuation of study drug (Appendix 17.2 of the study protocol). Women of nonchildbearing potential must have been postmenopausal for at least 1 year or surgically sterile [bilateral tubal ligation / occlusion, bilateral oophorectomy, bilateral salpingectomy, or hysterectomy]).

[0207] 5. Women of childbearing potential must have had a negative pregnancy test at Screening and at admission to the Treatment Phase (preoperative).6. Male subjects who had not had a vasectomy >6 months prior to Screening must have agreed to use a double-barrier method (condom and spermicide) or agreed to remain abstinent from heterosexual intercourse at the time of Screening, during the study and for 30 days following the last administration of study drug.

[0208] 7. Body weight of at least 50.0 kg and body mass index (BMI) within the range 18.0 to 35.0 kg / m2(inclusive) at Screening.

[0209] 8. Must have been able to adhere to the visit schedule, complete all study assessments, and protocol requirements including self-reported questionnaires.

[0210] Exclusion Criteria:

[0211] Subjects were not eligible to participate in this study if any one of the following exclusion criteria was met:

[0212] 1. Prolongation of QT / QTc interval with QTcF >450 ms for men, or >470 ms for women at Screening.

[0213] 2. Presence of risk factors for Torsade de Pointes (eg, heart failure, hypokalemia, clinically significant bradycardia, long QT).

[0214] 3. History of uncontrolled hypertension or a resting systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg. Subjects with well-controlled hypertension on a stable dose for at least 3 months of anti-hypertensives were allowed to participate.

[0215] 4. Any clinically significant disease, medical condition or laboratory finding that in the investigator’s opinion may have interfered with the study procedures or data integrity or compromised the safety of the subject. Laboratory tests may have been repeated once (one time) at Screening only, after approval by the medical monitor, if the investigator determined that the abnormal laboratory finding(s) was erroneous or caused by a temporary medical condition, for example an acute infection, or by the temporary use of a prior medication.

[0216] 5. History or presence of malignancy, requiring treatment within 2 years of Screening, with the exception of nonmetastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix within 3 months of Screening.

[0217] 6. History of respiratory depression, with acute or severe bronchial asthma or hypercapnia, or suspected or diagnosed sleep apnea.7. History of seizure disorder (excluding febrile seizures in childhood) or history of clinically significant head injury or syncope of unknown origin.

[0218] 8. Subject had a current painful condition that could have confounded the interpretation of efficacy, safety, or tolerability data in the study, in the opinion of the investigator.

[0219] 9. Any chronic gastrointestinal disease / condition or major previous abdominal surgery (eg, Billroth procedure or enteroanastomosis) that might have affected the absorption, distribution, metabolism or excretion of cebranopadol, or complicated the surgical procedure (eg, fibrous tissue).

[0220] 10. Impaired hepatic function, as determined by alanine aminotransferase or aspartate aminotransferase greater than 3 times the upper limit of normal.

[0221] 11. Positive for hepatitis B surface antigen, hepatitis C, or human immunodeficiency virus at Screening.

[0222] 12. Subjects with impaired renal function with creatinine clearance less than 60 mL / min at Screening (calculated using the Cockcroft Gault formula).

[0223] 13. Subject was taking or had taken an opioid for pain at a dose greater than 10 morphine milligram equivalents (MMEs) more than 1 out of 7 days per week in the 2 months prior to surgery.

[0224] 14. Use of nonsteroidal anti-inflammatory drugs within 72 hours or 5 half-lives prior to surgery, whichever was greater.

[0225] 15. Subjects taking any prohibited medication that could not be discontinued or subjects not being able to follow the guidance for prior and concomitant treatment throughout the study (refer to Section 9.7.1 of the study protocol).

[0226] 16. Use of systemic steroid therapy, excluding inhalers, within 3 months prior to surgery.

[0227] 17. History or presence of any substance or alcohol use disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

[0228] 18. Positive urine drug screen (UDS) or alcohol breathalyzer test at Screening or at admission to the Treatment Phase (preoperative). A repeat UDS may have been conducted once (one time) at Screening only, after approval by the medical monitor, if the investigator believed the initial result was a false positive. If the repeat UDS was positive, the subject was excluded from the study.19. History of suicidal ideation or suicidal behavior in the previous 2 years, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) (Baseline / Screening Version).

[0229] 20. History of allergy, hypersensitivity or intolerance to any opioid analgesics or anesthetics, including opioid-induced nausea and vomiting.

[0230] 21. Female subjects who were pregnant or breastfeeding or who were planning to become pregnant within 30 days of last study drug administration.

[0231] 22. Had donated or lost blood or blood products in excess of 500 mL within 30 days prior to Screening, and / or had donated plasma or platelets within 7 days prior to Screening.

[0232] 23. Any prior exposure to cebranopadol.

[0233] 24. Participation in an investigational trial within 30 days prior to Screening or had a previous abdominoplasty procedure (lifetime).

[0234] 25. Any employee of the sponsor or research site directly affiliated with any study under the direction of the investigator or any immediate family member of the employee or investigator.

[0235] 26. A subject who, in the opinion of the Investigator, was considered unsuitable or unlikely to comply with the study protocol for any reason.

[0236] The primary efficacy endpoint of this study was Pain NRS AUC from 4 through 48 hours (AUC4-48).

[0237] The key secondary efficacy endpoints of this study were:

[0238] • Pain NRS AUC from 4 through 24 hours (AUC4-24)

[0239] • Number of doses of rescue medication through to hour 48

[0240] • Pain NRS AUC from 24 through 48 hours (AUC24-48)

[0241] The other secondary efficacy endpoints of this study were as follows:

[0242] • Pain NRS:

[0243] Partial AUCs: 4-12, 12-24, 24-36, 36-48, and 4-36 hours

[0244] • Rescue medication:

[0245] - Proportion of subjects who required any opioid rescue medication (Days 1 to 7)

[0246] - Proportion of subjects who took at least 1 dose of rescue medication up to hours 12, 24, and 36- Time to first use of rescue medication

[0247] - Proportion of subjects who took any opioid following discharge - Total rescue opioid consumption through hour 48, using MMEs - Total rescue opioid consumption (Days 1 to 7), using MMEs • Proportion of subjects who discontinued early for any reason while in-clinic • Scores on Global Assessment of Satisfaction with Study Treatment

[0248] The safety endpoints included the following:

[0249] • Incidence of treatment-emergent adverse events (TEAEs)

[0250] • Incidence of RSEs, defined as a clinically relevant worsening of respiratory status (respiratory rate <8 breaths per minute, or clinically confirmed hypoxia [oxygen saturation <90%], or MOAA / S score <2)

[0251] • MOAA / S: peak sedation, AUC4-48

[0252] • Use of concomitant medications

[0253] • Changes in vital sign measurements

[0254] • Changes in ECG measurements

[0255] • Changes in clinical laboratory tests

[0256] • Physical examination findings

[0257] • C-SSRS findings

[0258] B. Results of the Randomized, Placebo-Controlled, Phase 3 Trial of Cebranopadol for the Treatment of Acute Pain After Abdominoplasty:

[0259] A total of 300 subjects were included in the study (400pg / 400pg: n=101; 400pg / 200pg: n=98; placebo: n=101). Subjects were predominantly female (98.7%) ranging in age from 22 to 68 years. Baseline characteristics were generally comparable between groups. Both cebranopadol groups demonstrated improvement in pain NRS AUC4-48 compared to the placebo with statistically significant reductions in pain in the 400pg / 400pg group (400pg / 400pg: -59.2, 95%CI[-87.3, -31.1], p<0.001; 400pg / 200pg: -19.2, 95% CI[-47.7, 9.1], p=0.183). See, also FIG 3.

[0260] The trial met its primary endpoint, demonstrating a statistically significant reduction in pain intensity as measured by the Pain Numerical Rating Scale (NRS) Area Under the Curve (AUC) from 4 to 48 hours. These results indicate that cebranopadol, a dual-NMR agonists, is aneffective analgesic in the post-surgical setting. Further, cebranopadol demonstrates improved effect following a second consecutive daily dose of cebranopadol at the same dose.

[0261] Treatments were generally well tolerated and total TEAEs observed were similar between treatment groups (400pg / 400pg: 66.3%; 400pg / 200pg: 69.3%; placebo: 74.3) The most common TEAEs included nausea (400pg / 400pg: 43.6%, 400pg / 200pg: 45.5%, placebo:47.5%), constipation (2%, 15.8%, 12.9%), and headache (5.9%, 5.9%, 11.9%). Similarly, serious TEAEs while not common were similar across treatment arms.

[0262] Cebranopadol 1st 400pg; 2nd 400pg achieved the primary endpoint of statistically significant pain reduction over 44 hours as compared to placebo. This trial represents the first of two registrational, Phase 3 studies highlighting cebranopadol ’s ability to provide a valuable new therapy for acute pain management.

[0263]

[0264] * Full analysis population included all randomized subjects who received at least one dose of the study drug and underwent the abdominoplasty procedure.The following Table provides Patient Demographics and Baseline Characteristics

[0265]

[0266]

[0267] * Protocol induced antiemetic medication administered be anesthesia for surgery and administered as nausea or vomiting occurred.See, Nahin RL, Sayer B, Stussnian BJ, Feinberg TM. Eighteen- Year Trends in the Prevalence of, and Health Care Use for. Noncancer Pam m the United States: Data from the Medical Expenditure Panel Survey. J Pain. 2019;20(7):796-809. doi:10.1016 / j.jpain.2019.01.003; Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC Clinical Practice Guideline for Prescribing Opioids for Pain - United States, 2022. MMWR Recomm Rep. 2022;71(3): 1-95.

[0268] Published 2022 Nov 4. doi:10.15585 / mmwr.rr7103al; VolkowND, McLellan AT. Opioid Abuse in Chronic Pain— Misconceptions and Mitigation Strategies. NEngl J Med. 2016;374(13): 1253-1263. doi:10.1056 / NEJMral 507771; LinzK, Christoph T, Tzschentke TM, et al. Cebranopadol: a novel potent analgesic nociceptin / orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther. 2014;349(3):535-548. doi : 10.1124 / jpet.114.213694; ScholzA, Bothmer J, KokM, Hoschen K, Daniels S. Cebranopadol: A Novel, First-in-Class, Strong Analgesic: Results from a Randomized Phase Ila Clinical Trial in Postoperative Acute Pain. Pain Physician.

[0269] 2018;21(3):E193-E206.

[0270] The primary objective of this Phase 3, multicenter, randomized, double-blind, placebo-controlled parallel-group study was to evaluate the efficacy of cebranopadol 400 / 400 pg and cebranopadol 400 / 200 pg in the treatment of moderate to severe postoperative pain following full abdominoplasty. Analysis of the primary endpoint showed that subjects in the cebranopadol 400 / 400 pg group reported a statistically significantly lower Pain NRS AUC4-48 compared with subjects in the placebo group. The LS mean Pain NRS AUC4-48 in the cebranopadol 400 / 400 pg group was 174.0 (95% CI; 154.1, 193.9) versus 232.8 (95% CI; 212.9, 252.6) in the placebo group. The LS mean treatment group difference (cebranopadol minus placebo) in Pain NRS AUC4-48 was -59.2 (95% CI; -87.3, -31.1) (p<0.001) and had an effect size of 0.58. The statistically significant treatment group difference in favor of cebranopadol 400 / 400 pg was supported by 11 sensitivity analyses.

[0271] Subjects receiving cebranopadol 400 / 200 pg had a lower LS mean Pain NRS AUC4-48 compared with subjects receiving placebo, but the difference did not achieve statistical significance. The LS mean Pain NRS AUC4-48 in the cebranopadol 400 / 200 pg group was 213.8 (95% CI; 193.6, 234.0), with an LS mean treatment group difference (cebranopadol minus placebo) in Pain NRS AUC4-48 of -19.3 (95% CI; -47.7, 9.1) (p = 0.183).

[0272] The statistically significant treatment group difference in favor of cebranopadol 400 / 400 pg was supported by 11 sensitivity analyses, including:

[0273] • An analysis excluding the cebranopadol 400 / 200 pg group (p<0.001);• An analysis with a 3 -hour censoring window for morphine as rescue medication on Day 1 and a 6-hour censoring window for oxycodone as rescue medication on Day 2 (p<0.001);

[0274] • An analysis with an alternative censoring (in the case of a second rescue dose within the censoring period, subsequent values in the censoring period were replaced with the NRS collected just prior to the second rescue dose) (p<0.001);

[0275] • An analysis with MI of NRS in the censoring period (p<0.001);

[0276] • An analysis with an alternative estimand (discussed in Section 9.2.4.2 of the SAP) to assess the impact of subjects who withdrew from the study prior to surgery (p<0.001);

[0277] • A post-hoc analysis with an alternative estimand excluding the cebranopadol 400 / 200 pg group (p<0.001);

[0278] • A post-hoc analysis with an alternative estimand with a 1-hour censoring window for morphine as rescue medication on Day 1 (p<0.001);

[0279] • A post-hoc analysis with an alternative estimand with a 1-hour censoring window for morphine as rescue medication on Day 1 excluding the cebranopadol 400 / 200 pg group (p<0.001);

[0280] • A post-hoc analysis that used an alternate MI approach where for any rescue medication use, the last observed pain intensity score prior to taking rescue medication was carried forward to replace the observed pain intensity scores during the window following the rescue medication intake and a 1-hour censoring window for morphine as rescue medication on Day 1 (p<0.001);

[0281] • A post-hoc analysis that used the alternate MI approach discussed above and a 1-hour censoring window for morphine as rescue medication on Day 1 excluding the cebranopadol 400 / 200 pg group (p<0.001);

[0282] • And a post-hoc analysis where the MI approach was based on pooled data for the cebranopadol 400 / 400 pg and placebo groups (p<0.001).

[0283] An exploratory analysis of the primary efficacy endpoint revealed the statistically significant treatment group difference in favor of cebranopadol 400 / 400 pg remained when controlling for study site. There was a trend in favor of cebranopadol 400 / 200 pg versus placebo, but this difference did not achieve statistical significance when controlling for study site.As stipulated in the SAP, the key secondary endpoint analyses were to be conducted in a fixed sequence only if the primary efficacy endpoint was significant for both cebranopadol versus placebo comparisons. As the primary efficacy endpoint achieved significance for the cebranopadol 400 / 400 pg group, results of the key secondary efficacy endpoints were considered nominal only.

[0284] There were 9 other secondary efficacy endpoint analyses conducted as follows:

[0285] • Partial AUCs for Pam NRS (4-12, 12-24, 24-36, 36-48, and 4-36 hours).

[0286] • The proportion of subjects who required opioid rescue medication from Day 1 to Day 7.

[0287] • The proportion of subjects who required rescue medication up to 12, 24, and 36 hours postdose.

[0288] • The time to first rescue medication use after the first dose of study drug.

[0289] • The proportion of subjects who took any opioid rescue medication following discharge.

[0290] • The total opioid rescue medication consumed up to 48 hours after the initial study dose using MMEs.

[0291] • The total opioid rescue medication consumed from Day 1 to Day 7.

[0292] • The proportion of subjects who for any reason discontinued from the study while inclinic.

[0293] • The SGA of satisfaction with the study treatment.

[0294] All reported p-values for the other secondary efficacy endpoints were nominal only.

[0295] Overall, these data strongly support the effectiveness of cebranopadol 400 pg daily for the treatment of moderate to severe soft tissue pain following abdominoplasty surgery.

[0296] An exploratory analysis of the primary efficacy endpoint revealed the statistically significant treatment group difference in favor of cebranopadol 400 / 400 pg remained when controlling for study site. As stipulated in the SAP, the key secondary endpoint analyses were to be conducted in a fixed sequence only if the primary efficacy endpoint was significant for both cebranopadol versus placebo comparisons. As the primary efficacy endpoint only achievedsignificance for the cebranopadol 400 / 400 pg group, results of the key secondary efficacy endpoints were considered nominal only.

[0297] There were 9 other secondary efficacy endpoint analyses conducted (, and all reported p-values for the other secondary efficacy endpoints were nominal only.

[0298] The first secondary objective of this study was to assess the efficacy of cebranopadol through use of rescue medication, early discontinuation, and subject overall assessment of study medication.

[0299] The results of the other secondary efficacy endpoints demonstrate treatment with cebranopadol 400 / 400 pg, and to a lesser extent cebranopadol 400 / 200 pg, following full abdominoplasty lowers the frequency of rescue medication consumption while having no impact on the rate of discontinuation from the study for any reason or the overall satisfaction with study treatment compared with placebo.

[0300] In this study of subjects with moderate to severe pain following full abdominoplasty, only treatment with cebranopadol 400 / 400 pg was associated with a highly significant and clinically meaningful lower Pain NRS compared with placebo over the period of the study, meeting the primary endpoint in this adequate and well-controlled trial. The 11 sensitivity analyses demonstrate the robustness of the primary efficacy analysis for cebranopadol 400 / 400 pg. The other secondary efficacy endpoint analyses support cebranopadol 400 / 400 pg treatment in lowering the use of additional pain medication following full abdominoplasty without impacting treatment satisfaction.

[0301] Taken together, these data strongly support the effectiveness of cebranopadol 400 pg daily for the treatment of pain following abdominoplasty surgery, which is a proxy for moderate to severe soft tissue pain.

[0302] Cebranopadol treatment was well tolerated in the study, and the safety profile did not reveal new signals or raise concerns. The low incidence of serious TEAEs associated with cebranopadol suggests a favorable risk benefit profile.

[0303] Example 3 : Significant Pain Reduction in Cebranopadol-Treated Patients Undergoing Bunionectomy Surgery

[0304] A. Phase 3 Study Design: A Phase 3 multicenter, randomized, double-blind, placebo-and active-controlled study was performed. The primary objective of the study is to evaluate the analgesic efficacy of cebranopadol compared with placebo for the management ofmoderate-to-severe acute pain following bunionectomy as measured by pain intensity (11 -point numeric rating scale) assessments, which serves as a model of hard-tissue pain. Secondary objectives include assessing the analgesic efficacy of cebranopadol through use of rescue medication, including the need for opioid rescue medication, early discontinuations and subject overall assessment of study medication.

[0305] This study was performed using cebranopadol (free base) supplies at 400 ug film-coated tablets. In the present study, use of opioids during the procedure and a nerve block following the procedure was avoided in order to assess the time to onset of analgesic effect.

[0306] The Primary Outcome Measure is Pain NR.S area under the curve: cebranopadol vs. placebo at 2-48 hours. The Secondary Outcome Measures are assessed for days 1-7. These include: Proportion of subjects who require opioid rescue medication; Global Assessment of Satisfaction; and Total oxycodone rescue consumption. Other measures include Incidence of Respiratory Safety Events at 1-7 days.

[0307] Eligibility Criteria

[0308] Description

[0309] Key Inclusion Criteria Before Surgery:

[0310] • Scheduled to undergo primary unilateral bunionectomy with first metatarsal osteotomy and internal fixation with no collateral procedures, using anesthesiologic and surgical procedures planned.

[0311] • Must be able to adhere to the visit schedule, complete all study assessments and protocol requirements, including self-reported questionnaires.

[0312] Key Exclusion Criteria Before Surgery:

[0313] • Any clinically significant disease, medical condition, or laboratory finding that in the investigator's opinion may interfere with the study procedures or data integrity, or compromise the safety of the subject.

[0314] • Secondary (i.e., unrelated to bunion) current painful condition that could confound the interpretation of efficacy, safety, or tolerability data in the study, in the opinion of the investigator.

[0315] • Subjects who require any analgesic for secondary (i.e., unrelated to bunion) painful condition that might impact the subject's ability to properly assess their postoperative pain, or that may require treatment during the Treatment Phase.• History of allergy or hypersensitivity to any opioid analgesics, anesthetics, ibuprofen, or other NSAIDs.

[0316] Immediate Postoperative Exclusion Criteria:

[0317] • Surgical, postsurgical, or anesthetic complication that could confound the interpretation of efficacy, safety, or tolerability data in the study.

[0318] • Deviation from the surgical, postsurgical, or anesthetic protocol that could confound the interpretation of efficacy, safety, or tolerability data in the study.

[0319] • Evidence of hemodynamic instability or respiratory insufficiency.

[0320] Treatment Phase

[0321]

[0322] The Treatment Phase began on the day of the primary unilateral bunionectomy procedure (Day 1) and ended on postoperative Day 4. As cebranopadol and oxycodone IR are administered under different schedules (QD vs. q6h, respectively), treatments are over-encapsulated and administered in a double-blind manner. The first dose of study drug was administered approximately 30 minutes (up to 1 hour) after completion of the primary unilateral bunionectomy procedure (last suture); subjects were awake and capable of taking oral medication.

[0323] As cebranopadol and oxycodone IR are administered under different schedules (QD vs. q6h, respectively), treatments are over-encapsulated and administered in a double-blind manner as shown in the table below. The first dose of study drug is administered approximately 30 minutes (up to 1 hour) after completion of the primary unilateral bunionectomy procedure (last suture); subjects must be awake and capable of taking oral medication. Qualified medical personnel and / or investigators who are ACLS (Advanced Cardiovascular Life Support) certified will be present in the clinic during the inpatient treatment phase when subjects are administered opioid medications.Time 0 is defined as the time of first study drug administration. Each dose of study drug / placebo will be separated by approximately 6 hours (±15 minutes). Treatments will be overencapsulated to maintain blinding.

[0324] Subjects undergo a primary unilateral bunionectomy with first metatarsal osteotomy and internal fixation procedure under a standardized regimen of regional anesthesia (Mayo block, consisting of a 50:50 mixture of 2% lidocaine and 0.2% ropivacaine, administered in 12 to 20 mL total volume). Subjects remain non- weight-bearing for the first 24 hours following completion of the primary unilateral bunionectomy; thereafter, subjects will be encouraged to ambulate.

[0325] Subjects are asked, but not required, to wait a minimum of 2 hours after the first dose of study drug prior to receiving rescue medication.

[0326] A graduated rescue medication protocol is implemented such that subjects may receive ibuprofen 400 mg every 6 hours as the first line rescue medication, if needed. Subjects who receive ibuprofen will not be permitted to receive additional ibuprofen for a minimum of 6 hours (“lockout period”). In cases where ibuprofen does not provide adequate pain relief within approximately 1 hour of administration, subjects may receive oxycodone 5 mg as a second line rescue medication. If oxycodone is administered, subjects will not be eligible to receive additional oxycodone for the following 6 hours but may be permitted to receive additional ibuprofen provided that they are still not within an ibuprofen lockout period.

[0327] Pain intensity (11 -point NR.S) assessments are recorded at scheduled times during the 72-hour period at and after Time 0 and immediately before each use of rescue medication. Scheduled pain assessments should be preceded by a period of inactivity of at least 15 minutes. Study drug will be administered after assessment of pain at each time point when dosing and pain assessments overlap. Pain intensity is recorded before early study discontinuation. Observer rated- assessments of sedation (using the Modified Observer’s Assessment of Alertness / Sedation Scale [MOAA / S]) will be conducted at pre-specified time points. Subjects will complete a Global Assessment of Satisfaction with Study Treatment at the end of the Treatment Phase (Day 4) before discharge from the study center or early discontinuation. Before discharge from the study center on Day 4, study personnel provides subjects with ibuprofen 400 mg (every 6 hours, as needed, up to a maximum of 1600 mg / 24 hours) for analgesia and an electronic outpatient subject diary. If additional analgesia is required, subjects may contact the clinical site to obtain a prescription for oxycodone 5 mg (every 6 hours as needed, up to a maximum of 20 mg / 24 hours). Subjects will be instructed to record use of any concomitant medications and adverse events(AEs) experienced after discharge in the electronic outpatient subject diaries. Subjects will also be instructed to return the device used for the outpatient subject diaries, if applicable, to study personnel at the Follow up Visit, scheduled to occur 7 (±2) days after the primary unilateral bunionectomy procedure.

[0328] AUC2-48, is analyzed using an analysis of variance (ANOVA) model, with treatment as the main effect. Model results across the MI replicates are combined using Rubin’s method [Biometrika (1976), 63, 3, pp. 581-92581 - JSTOR], Least Square (LS) Means, standard errors, and 95% confidence intervals (Cis) presented for each treatment group. The differences in treatment groups are presented along with associated p-values comparing groups, including the exploratory comparison between cebranopadol and oxycodone groups. Two-sided alpha=0.05 will apply to all tests.

[0329] B. Phase 3 Results: The results of a Phase 3 clinical study achieved its primary endpoint of demonstrating a statistically significant reduction in pain intensity as measured using the Pain Numeric Rating Scale (NRS) Area Under the Curve for two (2) to 48 hours (AUC2-48) following dosing. Specifically, treatment with oral cebranopadol 400 pg once per day resulted in a statistically significant reduction in pain intensity compared to placebo (LS Mean difference [SE] of 56.1 [13.49]; p<0.001; see Table below, FIG 4). A separate arm of the study, oxycodone immediate release (IR) 10 mg was administered orally, four times per day. While as expected, oxycodone demonstrated more pain relief compared to placebo, its mean activity was much lower than the mean activity observed by cebranopadol - as measured by NRS score.

[0330] Additionally, cebranopadol was generally well tolerated and exhibited a favorable safety profile, with no serious adverse events observed. The most common adverse event was nausea.

[0331]

[0332] <

[0333]

[0334] Patients were allowed the use of additional analgesic options, or “rescue medication,” if analgesia was not sufficient; first line rescue was ibuprofen, and second line was oxycodone immediate release (IR) 5 mg. The use of rescue medication was a secondary endpoint in the bunionectomy trial.

[0335] The results demonstrated that over the course of the seven-day study period the proportion of patients receiving cebranopadol who did not require opioid rescue was significantly higher than those patients receiving placebo (57.5% versus 28.4%; p<0.001). In addition, total doses of rescue medication were lower for cebranopadol compared to placebo (LS mean difference [SE] of 7.8 [2.68]; p=0.004).

[0336] The following Table provides a comparison between the cebranopadol and oxycodone group.

[0337]

[0338]

[0339] The time to first rescue medication (ibuprofen) for the patients receiving cebranopadol was longer than the time to first rescue for patients receiving immediate release oxycodone.

[0340]

[0341] AUC = area under the curve; ANOVA = Analysis of variance; MI = multiple imputation; LS = least squares; SE = standard error; CI = confidence interval; PI = pain intensity;

[0342] Note: Missing values due to subjects discontinuing early are imputed using an MI approach, taking into account the reasons for discontinuation. For any rescue medication use, the last observed PI score prior to taking rescue medication was carried forward to replace the observed PI scores during the 6-hour window following the rescue medication intake.If a second rescue use was required within the 6-hour window, the most recent pre-rescue score, prior to the scheduled pain assessment within the 6-hour window, was used to replace the scheduled assessment. Full details are provided in the study SAP.

[0343] Note: LS means, differences, Cis and p-values are based on an ANOVA model with treatment (Cebranopadol and Oxycodone) as the main effect.

[0344] [1] 95% CI. 2-sided p-value.

[0345] Further, cebranopadol demonstrates improved effect following a second consecutive daily dose of cebranopadol at the same dose. A similar effect is not observed for the patients receiving the control opioid treatment.

[0346] Efficacy Conclusions A total of 242 subjects were randomized into the study and administered study drug. The majority of subjects (97.5%) completed the study. A total of 6 subjects discontinued the study, consisting of 1 subject in the cebranopadol group and 5 subjects in the oxycodone group. Overall, the treatment groups were balanced with respect to demographic and other baseline characteristics. The primary efficacy endpoint of the study was Pain NRS AUC2-48 in the cebranopadol group versus the placebo group. Subjects receiving cebranopadol achieved a significantly lower Pain NRS AUC2-48 compared with subjects receiving placebo. The LS mean (SE) Pain NRS AUC2-48 was 223.4 (9.58) in the cebranopadol group and 279.5 (9.51) in the placebo group. The LS mean treatment group difference (cebranopadol minus placebo) in Pain NRS AUC2-48 was -56.1 (95% CI: -82.5, -29.7), which was statistically significant (p <0.001) in favor of cebranopadol. The effect size of the cebranopadol and placebo comparison was 0.66.

[0347] The statistically significant treatment group difference in favor of cebranopadol (versus placebo) was supported by 8 sensitivity analyses, including:

[0348] • An analysis with a 4-hour censoring window for pain scores following rescue medication use (LS mean treatment group difference [cebranopadol minus placebo] in Pain NRS AUC2-48 of -57.4 [95% CI: -83.9, -30.8]);

[0349] • An analysis with alternative censoring for pain scores following rescue medication use (-54.6 [95% CI: -80.8, -28.4]);

[0350] • An analysis with MI of NRS in the censoring period, following rescue medication use (-54.9 [95% CI: -79.2, -30.6]);• An analysis with no censoring of pain scores following rescue medication use (-44.4 [95% CI: -69.4, -19.4]);

[0351] • A post-hoc analysis excluding oxycodone (-56.1 [95% CI: -82.1, -30.1]);

[0352] • A post-hoc analysis with alternate MI (-56.1 [95% CI: -82.5, -29.7]);

[0353] • A post-hoc analysis with alternate MI excluding oxycodone (-56.1

[0354] [95% CI: -82.1, -30.1]);

[0355] • And a post-hoc pooled analysis for cebranopadol and placebo (-56.1

[0356] [95% CI: -82.1, -30.1]).

[0357] Exploratory analysis of the primary efficacy endpoint with site as fixed class effect revealed a treatment group difference in favor of cebranopadol compared with placebo remained when controlling for study site (LS mean in Pain NRS AUC2-48 of -53.4 [95% CI: -79.7, -27.1]). Exploratory analysis of the primary efficacy endpoint comparing cebranopadol versus oxycodone showed a group difference in favor of cebranopadol (LS mean in Pain NRS AUC2-48 of -27.0 [95% CI: -53.4, -0.5]).

[0358] Key Secondary Efficacy Endpoints

[0359] The key secondary endpoints were analyzed in a hierarchical manner; both key secondary endpoints showed statistically significant treatment group differences in favor of cebranopadol compared with placebo.

[0360] The key secondary endpoint 1, proportion of subjects who required any opioid rescue medication from Days 1 to 7, achieved a statistically significant difference versus placebo in favor of cebranopadol (p <0.001). Subgroup analyses of key secondary endpoint 1 by age, sex, and race were conducted. The age subgroup analysis showed group differences versus placebo in favor of cebranopadol in both <65 years old and >65 years old age groups; however, it should be noted that the sample size for the >65 years old subgroup was too small to make meaningful comparisons between treatment groups. The sex subgroup analysis of key secondary endpoint 1 showed group difference versus placebo in favor of cebranopadol in female subjects. The race subgroup analysis of key secondary endpoint 1 showed group difference versus placebo in favor of cebranopadol in White subjects.

[0361] The key secondary endpoint 2, total oxycodone rescue consumption from Days 1 to 7, also achieved a statistically significant difference versus placebo in favor of cebranopadol (p = 0.004). Other Secondary Efficacy Endpoints

[0362] • Partial AUCs for Pam NRS (2-12, 2-24, 2-36, 2-72, 12-24, 24-36, 24-48, 36-48, and48-72 hours): all showed treatment group differences in favor of cebranopadol compared with placebo, except for AUC 12-24.

[0363] • Time to the first rescue medication administration after the first dose of study drug: a greater amount of time taken for subjects to take rescue medication in the cebranopadol group, when compared with the placebo group.

[0364] • Proportion of subjects who required opioid rescue medication from 6 hours after initial dose of study drug: a greater proportion of opioid free subjects in the cebranopadol

[0365] groups compared with the placebo group.

[0366] • Proportion of subjects who required rescue medication over time up to 72 hours postdose: a greater proportion of subjects in cebranopadol group remained rescue medication free up to 24 hours postdose compared with the placebo group.

[0367] • Total ibuprofen rescue consumption (mg) up to 48 hours after initial dose of study drug: treatment group difference in favor of cebranopadol compared with placebo.

[0368] • SGA of satisfaction with the study treatment: treatment group difference in favor of cebranopadol.

[0369] • Proportion of subjects who discontinued from the study for any reason while in-clinic: One (1.3%), 3 (3.7%), and 0 subjects discontinued from the study for any reason while in-clinic in the cebranopadol, oxycodone, and placebo groups, respectively.

[0370] All reported p-values for the other secondary efficacy endpoints were nominal only. Taken together, consistent and statistically significant pain reductions versus placebo across the primary and key secondary efficacy endpoints highlight the analgesic efficacy of cebranopadol in managing moderate to severe pain following primary unilateral bunionectomy.

[0371] In addition, in an exploratory analysis of the primary efficacy endpoint, cebranopadol demonstrated a greater analgesic effect than the opioid comparator, oxycodone.

[0372] Cebranopadol treatment was well tolerated in the study and the safety profile did not reveal new signals or raise concerns. No serious TEAEs associated with cebranopadol were observed during the study, suggesting a favorable risk benefit profile.

[0373] Pharmacokinetic Summary and Discussion Cebranopadol showed peak concentrations occurring 6 hours following the first study drug administration. The mean peak plasma concentration of cebranopadol increased steadily after study drug administration on Day 2 andDay 3, with geometric mean (CV) Cmax of 210.1 (37.5%) pg / mL and median Tmax was 59.92 hours. Geometric mean (CV) overall exposure of cebranopadol as measured by AUCO-t was 7981.13 (40.15%) pg*h / mL.

[0374] Example 4: A Randomized, Open-label, Fixed-sequence Crossover Study to Assess the Effects of Cebranopadol on Fentanyl-induced Respiratory Depression (RD) in Opioid-tolerant Adults

[0375] The effect of cebranopadol on fentanyl-induced RD is critical to understand considering the current mortality rate due to fentanyl overdose (U.S. Overdose Deaths In 2021 Increased Half as Much as in 2020 - But Are Still Up 15%. National Center for Health Statistics (2022)). The primary objective of this study is to evaluate the effect of cebranopadol on fentanyl-induced RD in opioid-tolerant adults, as determined by a change in isohypercapnic minute ventilation. Using doses identified in Study 1, the effect of cebranopadol at steady-state concentrations on fentanyl-induced (0.25, 0.35, 0.50 and 0.70 mg / 70 kg IV doses) RD are assessed in opioid-tolerant participants (Moss, L.A.-O., et al. Effect of sustained high buprenorphine plasma concentrations on fentanyl-induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients. PloS one 17, e0256752 (2022). Minute ventilation after fentanyl dosing is compared with pre-fentanyl baseline (primary outcome), incidence of apnea and requiring verbal stimulation to breathe, and oxygen desaturation (<92%). The secondary objectives of this study are: (1) to evaluate the effect of cebranopadol on fentanyl-induced RD in opioid-tolerant adults, as determined by the secondary outcome measures; (2) to evaluate steadystate plasma cebranopadol concentrations in opioid-tolerant adults; and (3) to examine the safety and tolerability of cebranopadol when co-administered with fentanyl.

[0376] Study Title: A Randomized, Open-label, Fixed-sequence Crossover Study to Assess the Effects of Cebranopadol on Fentanyl -induced Respiratory Depression in Opioid-tolerant Adults.

[0377] Objectives: The primary objective of this study is to evaluate the effect of cebranopadol on fentanyl-induced respiratory depression in opioid-tolerant adults, as determined by change in isohypercapnic minute ventilation. The secondary objectives of this study are:

[0378] To evaluate the effect of cebranopadol on fentanyl-induced respiratory depression in opioid-tolerant adults, as determined by the secondary outcome measures.□ To examine the safety and tolerability of cebranopadol when co-administered with fentanyl.

[0379] To evaluate steady-state plasma cebranopadol concentrations in opioid-tolerant adults.

[0380] Methodology: This is a randomized, open-label, fixed sequence crossover study to evaluate the effect of cebranopadol on fentanyl-induced respiratory depression in opioid-tolerant adults. The study will involve 4 phases: Screening, Morphine Stabilization, Treatment, and Follow-up.

[0381] Within approximately 28 days of initiating outpatient Screening, subjects will be admitted to the clinical research unit (CRU). Following check-in to the CRU, subjects will be transitioned to an oral immediate-release (IR) opioid, morphine 30 mg, 4 times daily (QID) for a minimum of 3 days and a maximum of 7 days prior to the first treatment period. Prior to the first treatment period, subjects will not receive their late evening or early morning doses of morphine-IR; therefore, the last active dose of morphine-IR will be administered a minimum of 12 hours before first administration of study drug (placebo).

[0382] Subjects receive placebo and cebranopadol, administered intravenously (IV), in an openlabel, fixed sequence manner following an overnight fast. Subjects will receive placebo in Period 1 and cebranopadol in Period 2. A washout period of 48 hours will separate each treatment period. Subjects will receive maintenance morphine-IR during the washout period, with the last morphine-IR dose administered a minimum of 12 hours before administration of cebranopadol. Subjects will be randomized to receive 1 of 3 cebranopadol doses in Period 2. cebranopadol will be administered IV at an infusion rate of TBD pg / kg / hour to target steady-state plasma concentrations of A, B, or C (based on doses identified in the MAD study) for 360 minutes; the placebo infusion rate and duration will be matched. Escalating IV fentanyl doses of 0.25, 0.35, 0.50, and 0.70 mg / 70 kg will be administered over 90 seconds at 120, 180, 240, and 300 minutes after the start of the cebranopadol / placebo infusion. If a subject does not tolerate a lower fentanyl dose, higher doses will not be administered. Only fentanyl doses the subject tolerated under the placebo condition will be evaluated under the cebranopadol condition. Isohypercapnic ventilation will be measured during cebranopadol / placebo infusion for approximately 360 minutes using the dynamic end-tidal forcing technique. Minute ventilation (L / min), respiratory rate (breaths / min), oxygen saturation (SpO2), tidal volume (L), end-tidal PCO2 (kPa; PEiCO2) and end tidal PO2 (kPa; PEiO2) will be collected at baseline and during study drug administration. Pulse oximetrywill continuously SpO2 up to 8 hours postdose. Safety monitoring will include assessments of adverse events (AEs), vital signs, clinical laboratory results, 12-lead electrocardiogram (ECG), physical examinations, concomitant medications. Pharmacokinetic samples will be collected up to 8 hours postdose in Period 2.

[0383] Subjects will be discharged on Day 3 and a follow-up visit will be conducted on Day 7. Discussion of Study Design (Including Choice of Control Groups)

[0384] Subjects who are opioid-tolerant will be enrolled in this study as they may have higher levels of tolerance to the respiratory depressant effects of opioids. As cebranopadol is under investigation for the treatment of moderate to severe opioid use disorder (OUD), understanding the potential interactions between cebranopadol and an opioid such as fentanyl in an opioid-experienced population is critical. A broader inclusion of opioid-tolerant subjects will facilitate recruitment and feasibility rather than limiting enrollment to participants with moderate to severe OUD.

[0385] In the current study, all subjects will be stabilized on a 30 mg dose QID of short- acting morphine prior to enrollment in the Treatment Phase to ensure that any opioids that the subjects have recently used will be washed out, to establish a consistent schedule of opioid administration, and to ensure a similar level of physical dependence among subjects.

[0386] Due to the long elimination half-life of cebranopadol, which would require an approximately 14- day washout, a fixed-sequence crossover design, with placebo administered first, has been selected to reduce the overall duration and burden of study participation. As a crossover design, each subject will act as his / her own control. The respiratory depressant effects of fentanyl were shown to be reproducible in a recent study using a similar design in opioid-tolerant subjects (Moss et al., 2022). While cebranopadol is under development as an oral tablet formulation, the IV route of administration was selected to achieve steady-state concentrations of cebranopadol in a short period of time, which will reduce the overall burden to subjects, and enable evaluation of multiple dose levels of fentanyl at stable cebranopadol concentrations.

[0387] Fentanyl doses will be administered in an escalating manner for safety purposes and were selected based on (Moss et al., 2022).

[0388] Number of Subjects (Planned): The study will enroll a sufficient number of subjects to ensure that at least 18 subjects complete the study. Replacement subjects may be added at the discretion of the Sponsor with the agreement of the Investigator.Criteria for Inclusion / Exclusion:

[0389] Inclusion criteria:

[0390] 1. Must provide written informed consent prior to the initiation of any protocol-specific procedures.

[0391] 2. Male and female adults, between 18 and 55 years of age, inclusive.

[0392] 3. Body mass index (BMI) within 18.0 to 32.0 kg / m2, inclusive (minimum weight of at least 50.0 kg).

[0393] 4. Must be using daily doses of opioids >90 mg oral milligram morphine equivalents per day (MME / day) for at least 3 (or 6) months with no more than 20% (or 30%) fluctuation in dose for the 3 months prior to Screening.

[0394] 5. Subjects must be medically stable as determined by medical history, physical examination, 12-lead electrocardiogram (ECG), and vital signs (pulse rate, systolic blood pressure and diastolic blood pressure, respiratory rate, and SpO2 using pulse oximetry) at Screening.

[0395] 6. Females who participate in this study will be of childbearing or non-childbearing potential.

[0396] a. Childbearing potential: Physically capable of becoming pregnant

[0397] b. Non-childbearing potential:

[0398] i. Permanently sterile (i.e., both ovaries removed, uterus removed, or bilateral tubal ligation for at least 6 weeks or documented successful hysteroscopic sterilization) ii. Post-menopausal (no menstrual period for at least 12 consecutive months without any other medical cause)

[0399] 7. Females of childbearing potential must be non-lactating and must have a negative serum pregnancy test at Screening.

[0400] 8. Willing to use acceptable, effective methods of contraception.

[0401] 9. Male subjects must agree not to donate sperm for the duration of the study and at least 4 weeks after the final visit.

[0402] 10. Able to speak, read, and understand English sufficiently to allow completion of all study assessments.11. Is willing and able to comply with the study requirements (including blood sampling), complete study assessments, visit the clinic and remain confined in the CRU for up to 11 consecutive days.

[0403] Exclusion criteria:

[0404] 1. History or presence of any clinically significant psychiatric, endocrine, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, renal, or other major disease or illness at Screening, which in the opinion of the Investigator would jeopardize the safety of the subject or the validity of the study results.

[0405] 2. Prolongation of QTcF (after repeated assessment) at Screening, i.e., >450 ms for men or >470 ms for women, or presence of additional risk factors for torsade de pointes (e.g., heart failure, hypokalemia), or use of concomitant medications that prolong the QT interval.

[0406] 3. Subjects who currently meet the criteria for a diagnosis of moderate or severe substance use disorder according to DSM-V criteria for any substances other than opioids, caffeine, or tobacco. Subjects seeking treatment for opioid use disorder or to decrease / taper off opioids will also be excluded.

[0407] 4. Subjects with positive urine drug screens (UDS) for buprenorphine, barbiturates, benzodiazepines, or methadone or positive breath or urine alcohol test on the day of check-in to the CRU.

[0408] 5. Positive serology tests for HIV, acute hepatitis B, or acute hepatitis C (subjects with asymptomatic hepatitis B or C infection may be enrolled).

[0409] 6. History or current evidence of suicidal ideation, or active suicidality, based on the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0410] 7. Subject is currently using an investigational drug or monoamine oxidase inhibitor (MAOI) or has used such within the last 30 days (or 5-times the half-life of the drug, if known and longer) prior to first drug administration (i.e., IR morphine sulfate).

[0411] 8. Requires concomitant treatment with any prescription or non-prescription medications (with the exception of hormonal contraceptives, hormone replacement, and acetaminophen) or natural health products (herbal remedies), including strong cytochrome P450 (CYP) 3A4 inhibitors or respiratory depressants, or cannot safely discontinue these medications within 7 days or 5 half-lives (whichever is longer) prior to first drug administration (i.e., IR morphine sulfate).

[0412] 9. Females who are pregnant, are breastfeeding or who have a positive pregnancy test.10. Subject has a prior history of any significant adverse reactions (including rash) to fentanyl, naloxone, or related drugs (i.e., other opioids or opioid antagonists).

[0413] 11. Subject has unsuitable or difficult venous access or is unwilling or unable to undergo an IV catheter insertion.

[0414] 12. Subject is an employee of the Sponsor or research site personnel directly affiliated with this study or their immediate family member defined as a spouse, parent, child or sibling, whether biological or legally adopted.

[0415] 13. A subject who, in the opinion of the Investigator, is considered unsuitable or unlikely to comply with the study protocol for any reason.

[0416] Studies of Respiratory Depression

[0417] A study has been conducted to evaluate the respiratory drive by measuring ventilatory response to hypercapnia (maximum decrease in minute ventilation). In this randomized, doubleblind, four-period, six-treatment, placebo controlled partial crossover study, a number of parameter associated with respiratory function is analyzed in approximately 30 adult (18-45 years) completer participants after the administration of cebranopadol, oxycodone and placebo. Other measures include, but are not limited to, expired minute volume, respirator rate (breaths / min), flow rates, tidal volume, end tidal CO2 and peripheral oxygen saturation.

[0418] The abuse potential of cebranopadol via oral and intranasal routes was evaluated in recreational opioid users. Cebranopadol at doses up to 2.5 times the anticipated maximum therapeutic dose showed lower abuse potential compared with Schedule II (hydromorphone, oxycodone) and Schedule IV (tramadol) opioids. The intrinsic slow onset of cebranopadol (Tmax ~6 hours) likely also contributed to its lower abuse potential. Analysis of potential abuse-related adverse events (AEs) across 30 clinical studies showed that cebranopadol is associated with a low incidence of euphoria-like events. Withdrawal-related AEs were rarely reported and not more common than seen with placebo in clinical studies of up to 14 weeks even after abrupt discontinuation, suggesting lower physical dependence risk. Cebranopadol may have reduced risk for inducing respiratory depression, based on results of a ventilatory response to hypercapnia (VRH) study in which there was a reduced magnitude and delay in onset of respiratory effects vs. oxycodone at equianalgesic doses.Based on the characterization of tramadol in the literature, the overall abuse potential of cebranopadol is less than Schedule II and IV full and partial MOP agonists, suggesting a less restrictive schedule than Schedule II is appropriate.

[0419] Example 5 : Effect of cebranopadol and fentanyl co-administration

[0420] Study: To establish the respiratory depression of cebranopadol and fentanyl, administered intravenously (i.v.), in Wistar rats under highly standardized and controlled experimental conditions.

[0421] Experimental Procedure:

[0422] Fentanyl: obtained from commercial source (Pharmacy). Dose: Injectable fentanyl is used at a concentrations 50ug / mL

[0423] Cebranopadol is prepared fresh every week. Img of cebranopadol is weighed out and dissolved thoroughly into 5 mL of dimethyl sulfoxide (DMSO). This solution is added to 2.5 mL of cremophore, and mixed thoroughly until integrated. The mixture is diluted with 47.5 mL sterile saline and mixed completely to create a total of 50 mL of 20 ug / ml-cebranopadol solution.

[0424] Injections are administered i.v. at 1 mL solution / kg rat over a period of about 30 seconds.

[0425] Leftover drug at the end of the week is disposed of.

[0426] After 5-9 days of recovery from intravenous surgery, the animals (male Wistar Rats) are placed into the plethysmography chambers to be tested in a within subjects Latin Square design, such that all rats (n=10) receive all treatments. The four treatment combinations administered are: cebranopadol alone, fentanyl alone, cebranopadol plus fentanyl, vehicle plus vehicle.

[0427] The testing chambers are calibrated and parameter ranges are set to a standard at the beginning of each treatment session. The animals are flushed with heparin daily to maintain catheter patency. Rats are weighed once a week. The animals acclimate to the test chamber for a period of 20 minutes at the start of each session, during which time no data is recorded. After acclimatation, data recording is started on the computer, to record a 40-minute period of baseline data during which no drugs are onboard. After baseline recording is complete, a comment is inserted to the computer program to indicate the time of first injection. The animals each receive cebranopadol (20 mg / mL / kg, i.v.) or saline vehicle (ImL / kg i.v.) injection at this point (time point 0). Twenty minutes after cebranopadol or saline injection, a second comment is inserted to the computer program to indicate the time of second injection. The animals each receive afentanyl (50 mg / mL / kg, i.v.) or saline vehicle (ImL / kg, i.v.) injection at this point. Before and during each injection point, the tubing is observed by the experimenter to ensure no leakage or breakage in the i.v. tubing. After the second injection, data continues recording for an additional 80 minutes, for a total of 140 recorded data minutes. Animals are then removed from the test chambers and returned to their home cages.

[0428] The plethysmography provides values for each measured parameter every 5 milliseconds during the experiment. Therefore, to allow the analysis, the raw plethysmography data are automatically grouped in 5 minutes bins by means of an app created in python programming language, called pyvent. Catheter patency is periodically tested by intravenous infusion of 200-300 pl of thiopental. If the rats lose consciousness within a few seconds after thiopental administration, the catheter is considered patent.

[0429] Main evaluation items:

[0430] A. Minute ventilation: The amount volume breathed in one minute, computed on a breath-by -breath basis (mL / min)

[0431] B. Peak Inspiratory Flow (PIF): The maximum negative flow during one breath (mL / sec)

[0432] C. Apnoeic Pause (AP): A unitless indicator of bronchoconstriction, computed as (The time from start of expiration to beginning of next inspiration / The time to expire a defined percentage of tidal volume - 1)

[0433] D. Tidal Volume (TV): The amount of air breathed in during inspiration (mL) E. Inspiratory Time (Ti): The time from start to end of inspiration (msec)

[0434] Statistical analysis: All evaluation items are expressed as mean ± S.E.M.

[0435] The MV, PIF, AP, TV and Ti for all animals in each treatment group are analyzed after averaging each parameter into 5 -minute bins over the course of the experiment using pyvent code. They are then expressed as a percentage of the baseline value for each individual animal in order to standardize the values for comparison between animals. (The raw values fluctuate greatly according to animal sex and body weight). These standardized values are analyzed by means of a 2-way Anova, followed by post-hoc Dunnett's tests when appropriate. The periods after cebranopadol / vehicle injections (20 min) and the periods after the second infusion of fentanyl or vehicle (80 min.) are analyzed separately. The MV, PIF, AP, TV are analyzed separately. Tworats did not complete the study due to heath issues and were not included in the statistical analysis. Statistical significance is set at p<0.05.

[0436] Results

[0437] A. Minute ventilation:

[0438] A 2-way ANOVA showed no significant difference between groups at baseline [F(3, 28) = 0.7935; p = 0.5078], although there was a significant effect of time [F(4.121,115.4) = 32.32; p <0.0001],

[0439] For the period immediately after injection of cebranopadol or vehicle (bins 0 to 15): A 2-way ANOVA showed no significant effect of treatment [F(3, 28) = 1.134; p = 0.3522],

[0440] For the period immediately after injection of fentanyl or vehicle (bins 20 to 100): A 2-way ANOVA showed no significant difference in treatment [F(3, 28) = 2.754; p = 0.0611], although there was a significant effect of time [F(5.133,143.7) = 3.012; p = 0.0122] and a significant treatment x time interaction [F(48, 448)= 2.062; p < 0.0001], At time point 20 (corresponding to the infusion of fentanyl / vehicle), Dunnett's post-hoc analysis revealed a significant MV depression following fentanyl compared to the control group (vehicle + vehicle; p<0.0001). Also at time points 70 min, 75 min, 95 min and 100 min fentanyl produced a significant decrease of MV compared to controls (p<0.05). Administration of cebranopadol prevented these effects of fentanyl and when the two drugs were combined no significant difference from controls were detected. Compared to controls cebranopadol alone evoked a delayed decrease in MV at 55 min and 70 min (p<0.05) as well as 75 min (p<0.01).

[0441] Peak Inspiratory Flow (PIF)

[0442] A 2-way ANOVA showed no significant difference between groups at baseline [F(3, 28) = 2.528; p = 0.0076], although there was a significant effect of time [F(3.546,99.28) = 35.26; p <0.0001],

[0443] For the period immediately after injection of cebranopadol or vehicle (bins 0 to 15): A 2-way ANOVA showed no significant effect of treatment [F(3, 28) = 2.283; p = 0.1008], although there was a significant effect of time [F(2.177,60.95) = 3.322; p =0.0389],

[0444] For the period immediately after injection of fentanyl or vehicle (bins 20 to 100): A 2-way ANOVA showed a significant difference in treatment [F(3, 28) = 12.89; p < 0.0001], At time point 20 (corresponding to the infusion of fentanyl / vehicle), Dunnett's post-hoc analysis revealed a significant PIF depression following fentanyl compared to the control group (vehicle + vehicle; p<0.0001), as well as for cebranopadol + fentanyl ( p=0.0358), Also at time points 30 - 100 minfentanyl produced a significant decrease of PIF compared to controls (p<0.05). At timepoints 35-85, 95 and 100 min, cebranopadol + fentanyl produced a significant decrease of PIF compared to controls (p<0.05). Compared to controls cebranopadol alone evoked a delayed decrease in PIF at 55 min, 65 min, 70 min, 90 min, 95 min, and 100 min (p<0.05).

[0445] Fentanyl evoked a significant PIF depression. Cebranopadol per se evokes a modest delayed PIF depression. Difference between the fentanyl treated group and controls (****p<0.0001, **p<0.01, *p<0.05. Difference between the cebranopadol treated rats and controls (## p<0.01; # p<0.05). Difference between the cebranopadol + fentanyl treated rats and controls (J J J p<0.0001, $$ p<0.01; $ p<0.05). Values are expressed as Mean ± S.E.M.

[0446] Apneic Pause (AP)

[0447] A 2-way ANOVA showed no significant effect between groups at baseline [F(3, 28) = 0.4262; p = 0.7357], although there was a significant effect of time [F(3.733, 104.5) = 4.365; / ? = 0.0033],

[0448] For the period immediately after injection of cebranopadol or vehicle (bins 0 to 15): A 2-way ANOVA showed no significant difference in treatment [F(3, 28) = 1.052; p = 0.3850], although there was a significant effect of time [F(1.262, 35.35) = 15.31; / ? = 0.0002], For the period immediately after injection of fentanyl or vehicle (bins 20 to 100): 2-way ANOVA showed a significant effect of treatment [F(3, 28) = 11.43; p <0.0001], a significant effect of time [F(4.277, 119.8) = 4.806; p =0.0010], and a significant interaction treatment x time [F(48,448) = 1.964; p =0.0002], At time point 25 (in the minutes following the infusion of fentanyl / vehicle), Dunnett's post-hoc analysis revealed a significant increase in apneic pause following fentanyl compared to the control group (vehicle + vehicle; p=0.0470). Also at time points 30 min, 35min, 40 min, 65 min, 70min, 75min, 80 min, 90min, 95 min, and 100 min fentanyl produced a significant increase of AP compared to controls (p<0.05). At timepoints 35-100, cebranopadol + fentanyl produced a significant increase of AP compared to controls (p<0.05). Compared to controls cebranopadol alone did not induce any increase in AP (p>0.05).

[0449] Fentanyl and Cebranopadol + Fentanyl evoked a significant AP increase compared to controls. Cebranopadol per se does not evoke any respiratory depression. Difference between the fentanyl treated group and controls (****p<0.0001, **p<0.01, *p<0.05. Difference between the cebranopadol + fentanyl treated rats and controls (J J J p<0.0001, $$ p<0.01; $ p<0.05). Values are expressed as Mean ± S.E.M.

[0450] Tidal Volume:A 2-way ANOVA showed no significant effect between groups at baseline [F(3, 28) = 0.6856; = 0.5684],

[0451] For the period immediately after injection of cebranopadol or vehicle (bins 0 to 15): A 2-way ANOVA showed no significant difference in treatment [F(3, 28) = 1.152; / ? = 0.3456], although there was a significant effect of time [F(2.621, 73.39) = 27.46; p < 0.0001] and a significant interaction of treatment x time [F(9, 84) = 3.804; p = 0.0005],

[0452] For the period immediately after injection of fentanyl or vehicle (bins 20 to 100): 2-way ANOVA showed a significant effect of treatment [F(3, 28) = 3.493; p = 0.0286], a significant effect of time [F(5.160, 144.5) = 7.242; p < 0.0001], and a significant interaction treatment x time [F(48,448) = 2.530; p < 0.0001], At time point 20 (corresponding to the infusion of fentanyl / vehicle), Dunnett's post-hoc analysis revealed a significant TV depression following fentanyl compared to the control group (vehicle + vehicle; p=0.0001]. At timepoint 70min, 75 min, 80min, and 95 min cebranopadol + fentanyl produced a delayed decrease of TV compared to controls (p<0.05). Compared to controls cebranopadol alone evoked a delayed decrease in TV at 95 min only (p<0.05).

[0453] Fentanyl evokes a significant TV depression. Cebranopadol + Fentanyl and Cebranopadol per se evokes a modest delayed respiratory depression. Difference between the fentanyl treated group and controls (****p<0.0001, **p<0.01, *p<0.05. Difference between the cebranopadol treated rats and controls (## p<0.01; # p<0.05). Difference between the cebranopadol + fentanyl treated rats and controls (JJJ pO.OOOl, $$ p<0.01; $ p<0.05). Values are expressed as Mean ± S.E.M.

[0454] Inspiratory Time:

[0455] A 2-way ANOVA showed no significant effect between groups at baseline [F(3, 28) = 0.2585; p = 0.8546], but a significant effect of time [F(3.905, 109.3) = 11.79; p < 0.0001], For the period immediately after injection of cebranopadol or vehicle (bins 0 to 15): A 2-way ANOVA showed no significant difference in treatment [F(3, 28) = 2.743; p = 0.0618], although there was a significant effect of time [F(2.460, 68.87) = 21.42; p < 0.0001] and a significant interaction of treatment x time [F(9, 84) = 2.881; p = 0.0052],

[0456] For the period immediately after injection of fentanyl or vehicle (bins 20 to 100): 2-way ANOVA showed a significant effect of treatment [F(3, 28) = 8.619; p = 0.0003], a significant effect of time [F(5.469, 153.1) = 4.984; p = 0.0002], and a significant interaction treatment x time [F(48,448) = 1.956; p = 0.0003], Dunnett's post-hoc analysis revealed a significant Ti increase attimepoints 35min, 40 min, 45 min, 50 min, 55min, 60min, 65min, 70min, 75min, 80min,95min, and lOOmin following fentanyl compared to the control group (vehicle + vehicle; p<0.05]. At timepoints 40min, 45 min, 50min, 55 min, 60min, 65min, 70min, 75min, 80min, 85min, 90min, 95min and lOOmin cebra + fentanyl produced an increase of Ti compared to controls (p<0.05). Compared to controls cebranopadol alone evoked a delayed decrease in TV at 55 min, 65min, 70min, 90min, and 95min (p<0.05).

[0457] Fentanyl and Cebra+ Fentanyl both evoke a Ti increase. Cebranopadol per se evokes a delayed Ti increase. Difference between the fentanyl treated group and controls (****p<0.0001, **p<0.01, *p<0.05. Difference between the cebranopadol treated rats and controls (## p<0.01; # p<0.05). Difference between the cebranopadol + fentanyl treated rats and controls (J J J pO.OOOl, $$ p<0.01; $ p<0.05). Values are expressed as Mean ± S.E.M.

[0458] Conclusions: The results indicate that fentanyl induced significant respiratory depression as observed through minute ventilation, peak inspiratory flow, apneic pause, tidal volume and inspiratory time, compared to control. This effect was apparent immediately upon injection. However, pre-treatment with cebranopadol demonstrates reduction on fentanyl-induced respiratory depression parameter. Interestingly, cebranopadol alone caused a delayed modest respiratory depression. These findings suggest that cebranopadol despite possessing delayed respiratory depression properties it has a protective effect against fentanyl-induced respiratory depression during the acute phase. Even though to a lesser extent this protective effect is maintained also during the delayed phase.

[0459] Reference of fentanyl and cebranopadol for dose setting: Marchette, R. C. N., Carlson, E. R., Frye, E. V., Hastings, L. E., Vendruscolo, J. C. M., Mejias-Torres, G., Lewis, S. J., Hampson, A., Volkow, N. D., Vendruscolo, L. F., & Koob, G. F. (2023). Heroin- and Fentanyl-Induced Respiratory Depression in a Rat Plethysmography Model: Potency, Tolerance, and Sex Differences. The Journal of pharmacology and experimental therapeutics, 385(2), 117-134. https: / / doi_org / 10_1124 / jpet_122_001476; Linz, K., Schroder, W., Frosch, S., & Christoph, T. (2017). Opioid-type Respiratory Depressant Side Effects of Cebranopadol in Rats Are Limited by Its Nociceptin / Orphanin FQ Peptide Receptor Agonist Activity. Anesthesiology, 126(A), 708-715. https: / / doi_org / 10_1097 / ALN_0000000000001530

[0460] Effects of cebranopadol on fentanyl-induced respiratory depression (RD) in opioid-tolerant participants.The effect of cebranopadol on fentanyl-induced RD is critical to understand considering the mortality rate due to fentanyl (U.S. Overdose Deaths In 2021 Increased Half as Much as in 2020 - But Are Still Up 15%. National Center for Health Statistics (2022)). Using doses identified in the dose-escalation study (Study 3), the effect of cebranopadol at steady-state concentrations on fentanyl -induced RD (0.25, 0.35, 0.50 and 0.70 mg / 70 kg IV) is assessed in opioid-tolerant participants (Moss, L.A.-O., et al. Effect of sustained high buprenorphine plasma concentrations on fentanyl -induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients. PloS one 17, e0256752 (2022)). Hypothesis: The primary objective of this study is to evaluate the effect of cebranopadol on fentanyl-induced RD in opioid-tolerant adults, as determined by change in isohypercapnic minute ventilation. The secondary objectives of this study are: (1) to evaluate the effect of cebranopadol on fentanyl-induced RD in opioid-tolerant adults, as determined by the secondary outcome measures; (2) to evaluate steady-state plasma cebranopadol concentrations in opioid-tolerant adults; and (3) to examine the safety and tolerability of cebranopadol when co-administered with fentanyl.

[0461] This is a randomized, open-label, fixed-sequence crossover study to evaluate the effect of cebranopadol on fentanyl-induced RD in opioid-tolerant adults. The study involves 4 phases: Screening, Morphine Stabilization, Treatment, and Follow-up. Within approximately 28 days of initiating outpatient Screening, subjects are admitted to the clinical research unit (CRU).

[0462] Following check-in to the CRU, subjects are transitioned to an oral immediate-release (IR) opioid, morphine 30 mg, 4 times daily (QID) for a minimum of 3 days and a maximum of 7 days prior to the first treatment period. Prior to the first treatment period, subjects do not receive their late evening or early morning doses of morphine-IR; therefore, the last active dose of morphine-IR is administered a minimum of 12 hr before first administration of study drug (placebo).

[0463] Subjects receive placebo and cebranopadol, administered IV, in an open-label, fixed-sequence following an overnight fast. Subjects receive placebo in Period 1 and cebranopadol in Period 2. A washout period of 48 hr separates each treatment period. Subjects receive maintenance morphine-IR during the washout period, with the last morphine-IR dose administered a minimum of 12 hr before administration of cebranopadol. Subjects are randomized to receive 1 of 3 cebranopadol doses in Period 2. Cebranopadol is administered IV to achieve steady-state plasma concentrations based on doses identified in the MAD study (Study 3)); the placebo infusion rate and duration are matched. Escalating IV fentanyl doses of 0.25, 0.35, 0.50, and 0.70 mg / 70 kg are administered over 90 sec at 120, 180, 240, and 300 min after the start of the cebranopadol / placebo infusion.Isohypercapnic ventilation is measured during cebranopadol / placebo infusion for approximately 360 min using the dynamic end-tidal forcing technique. Minute ventilation (L / min), respiratory rate (breaths / min), oxygen saturation (SpO2), tidal volume (L), end-tidal PCO2 (kPa; PEiCO2) and end tidal PO2 (kPa; PEiO2) are collected at baseline and during study drug administration. Pulse oximetry continuously monitors oxygen saturation (SpO2) up to 8 hr postdose. Safety monitoring include assessments of AEs, vital signs, clinical laboratory results, 12-lead ECG, physical exams, concomitant medications. Pharmacokinetic samples are collected up to 8 hr postdose in Period 2. Subjects are discharged on Day 3 and a follow-up visit is conducted on Day 7.

[0464] Given the long half-life of cebranopadol, it might be operationally more feasible to administer it after placebo so that the treatment period can be shortened and there is only 1 morphine stabilization period. If a subject does not tolerate a lower fentanyl dose, higher doses are be administered. Only fentanyl doses the subject tolerated under the placebo condition is evaluated under the cebranopadol condition.

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[0518] All patents, patent publications, and other publications listed in this specification are incorporated herein by reference. While the invention has been described with reference to a particularly preferred embodiment, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims

CLAIMS:

1. A pharmaceutical composition comprising a combination of:cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof; andat least one non-opioid analgesic.

2. The composition of claim 1, wherein the non-opioid analgesic is a nonsteroidal anti-inflammatory (NS AID), a cyclooxygenase- 1 (COX-1) inhibitor, or a COX-2 inhibitor.

3. The composition of claim 1 or 2, wherein the non-opioid analgesic is acetaminophen, ibuprofen, celecoxib, rofecoxib, valdecoxib, etoricoxib, gabapentin, pregabalin, and / or duloxetine.

4. The composition of claim 1 which comprises cebranopadol in a free base form.

5. The composition of claim 1, wherein the composition comprises greater than 90% w / w cebranopadol Crystal Form A, as calculated based on the total weight of cebranopadol free base in the composition.

6. The composition of claim 1, wherein the composition comprises at least 90% w / w cebranopadol in a crystal form characterized by 8.8 ± 0.2 degrees 20, 11.7 ± 0.2 degrees 20, and 18.3 ± 0.2 degrees 20 and a melting point of 298 °C to 308 °C, as determined using differential scanning calorimetry (DSC), as calculated based on the total weight of cebranopadol free base in the composition.

7. An improved method for treating pain in a subject comprising delivering a combination of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof and a non-opioid analgesic, whereby the combination provides greater painrelief to the subject as compared to treatment with an opioid alone and / or as compared to an opioid in combination with a non-steroidal anti-inflammatory drug.

8. The method of claim 7, wherein pain relief is measured using a Numerical Rating Scale (NRS) rating from 0 (no pain) to 10 (severe pain).

9. The method of claim 7, wherein the patient is a surgical patient and / or a trauma patient.

10. The method of claim 7, wherein the treatment is improved as compared to treatment of one or more of codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, morphine, oxycodone, or oxymorphone11. The method of claim 7, wherein the pain is acute pain.

12. The method of claim 7, wherein the pain is post-operative pain.

13. The method of claim 7, wherein pain is treated in the absence of an opioid analgesic.

14. The method of claim 7, wherein the cebranopadol is delivered in a solid tablet.

15. The method of claim 7, wherein the non-opioid analgesic is a non-steroidal anti-inflammatory (NS AID), a cyclooxygenase- 1 (COX-1) inhibitor, a COX-2 inhibitor.

16. The method of claim 7, wherein the non-opioid analgesic is acetaminophen, ibuprofen, celecoxib, rofecoxib, valdecoxib, etoricoxib, gabapentin, pregabalin, and / or duloxetine.

17. The method of claim 7 which comprises cebranopadol in a free base form.

18. The method of claim 7, wherein the composition comprises a greater than 90% w / w cebranopadol Crystal Form A, as calculated based on the total weight of cebranopadol free base in the composition.

19. The method of claim 7, wherein the composition comprises at least 90% w / w cebranopadol in a crystal form characterized by 8.8 ± 0.2 degrees 20, 11.7 ± 0.2 degrees 20, and 18.3 ± 0.2 degrees 20 and a melting point of 298 °C to 308 °C, as determined using differential scanning calorimetry (DSC), as calculated based on the total weight of cebranopadol free base in the composition.

20. A regimen for treating pain without opioid-related respiratory depression comprising a combination of:cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof; andan non-opioid analgesic.

21. The regimen according to claim 20, wherein the non-opioid analgesic is a nonsteroidal anti-inflammatory (NS AID), a cyclooxygenase- 1 (COX-1) inhibitor, a COX-2 inhibitor.

22. The regimen according to claim 20 or 21, wherein the non-opioid analgesic is acetaminophen, ibuprofen, celecoxib, rofecoxib, valdecoxib, etoricoxib, gabapentin, pregabalin, and / or duloxetine.

23. A method for reducing acute pain and eliminating opioid-related side effects in a subject comprising administering to the patient cebranopadol as the sole analgesic in a 24-hour period.

24. The method of claim 23, wherein reduction of acute pain is as measured by the Pain Numerical Rating Scale (NRS) Area Under the Curve from 4 to 48 hours (AUC4-48).

25. The method of claim 23, wherein the subject is treated with a single daily dose of 400 ug cebranopadol as the sole analgesic in a 24-hour period, as measured by the Pain Numerical Rating Scale (NRS) Area Under the Curve from 4 to 48 hours (AUC4-48).

26. The method of claim 23, wherein the subject is age 18 or older.

27. The method of claim 23, wherein the subject is dosed with a composition comprising at least 90% w / w cebranopadol in a crystal form characterized by 8.8 ± 0.2 degrees 20, 11.7 ± 0.2 degrees 20, and 18.3 ± 0.2 degrees 20 and a melting point of 298 °C to 308 °C, as determined using differential scanning calorimetry (DSC), as calculated based on the total weight of cebranopadol free base in the composition.

28. A composition of any one of claims 1 to 6 for use in treating pain without opioid-related respiratory depression.

29. Use of a composition of any one of claims 1 to 6, for use in an method for treating acute pain and / or eliminating opioid-related side effects in a patient, and / or treating pain without opioid-related respiratory depression.

30. The composition of claim 28 or use of claim 29, wherein the subject is a surgical patient and / or a trauma patient.

31. The composition of claim 18 or30, or use of claim 29 or 30, wherein treatment is improved as compared to treatment of one or more of codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, morphine, oxycodone, or oxymorphone.

32. The composition of any one of claims 28, 30 or 31, or use of any one of claims 29 to 31, wherein the pain is acute pain.

33. The composition of any one of claims 28 or 30 to 32, or use of any one of claims 29 to 32, wherein the pain is post-operative pain.

34. The composition of any one of claims 28 or 30 to 33, or use of any one of claims 29 to 32, wherein pain is treated in the absence of an opioid analgesic.

35. The composition of any one of claims 28 or 30 to 34, or use of any one of claims 29 to 32, wherein the cebranopadol is delivered in a solid tablet.

36. The composition of any one of claims 28 or 30 to 35, or use of any one of claims 29 to 32, wherein the non-opioid analgesic is a non-steroidal anti-inflammatory (NS AID), a cyclooxygenase- 1 (COX-1) inhibitor, a COX-2 inhibitor.

37. The composition of any one of claims 28 or 30 to 35, or use of any one of claims 29 to 32, wherein the non-opioid analgesic is acetaminophen, ibuprofen, celecoxib, rofecoxib, valdecoxib, etoricoxib, gabapentin, pregabalin, and / or duloxetine.

38. The composition of any one of claims 28 or 30 to 36, or use of any one of claims 29 to 37, which comprises cebranopadol in a free base form.

39. The composition of any one of claims 28 or 30 to 36, or use of any one of claims 29 to 38, wherein the composition comprises a greater than 90% w / w cebranopadol Crystal Form A, as calculated based on the total weight of cebranopadol free base in the composition.

40. The composition or use of claim 39, wherein the subject is dosed with a composition comprising at least 90% w / w cebranopadol in a crystal form characterized by 8.8 ± 0.2 degrees 20, 11.7 ± 0.2 degrees 20, and 18.3 ± 0.2 degrees 20 and a melting point of 298 °C to 308 °C, as determined using differential scanning calorimetry (DSC), as calculated based on the total weight of cebranopadol free base in the composition.

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