Cebranopadol useful for treating pain

Abstract

Provided herein are methods, compositions and uses of compositions for treating subjects for pain while providing reduced risk of intranasal abuse. The compositions and methods comprise cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof.

Description

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

[0002] Pain is a prevalent condition in the US, including moderate to severe acute pain, chronic, and other types of pain. However, managing this pain remains a challenge, 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. The human body has three primary opioid receptor types: mu, delta, and kappa. These receptors are found on the surface of cells in the central and peripheral nervous systems. Opioid agonists may be characterized as full agonist opioids or partial agonist opioids. Common examples of full mu agonist opioid drugs include, e.g., morphine, oxycodone, codeine. An example of a partial mu agonist is tramadol. However, undesirable common side effects of opioid administration include euphoria, abuseability, sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression. Healthcare providers have concerns about use of mu agonists as prolonged use can lead to physical dependence and addiction, making such drugs undesirable for treatment not only of chronic pain, but for other types of pain requiring prolonged use.

[0003] Cebranopadol (trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-l,T-(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).

[0004] There remains a need for improved therapies for alleviating pain in patients. Further, there is an urgent need for an improved therapeutic for the treatment and / or prevention of abusability in subjects for whom the current standard of care is opioid-based analgesic therapies.

[0005] BRIEF DESCRIPTION OF THE FIGURES FIG 1 provides the mean “Drug Liking” scores over the course of intranasal Human Abuse Potential (HAP) study of cebranopadol Compared to oxycodone (N=36), described in Example 1.

[0006] FIGs 2 and 3 illustrate that cebranopadol’ s pharmacokinetic (PK) profile is not significantly altered by the route of administration.FIG 2 provides geometric mean (SD) plasma concentration (pg / mL) following intranasal administration of 1000 pg intranasal cebranopadol or intranasal oxycodone IR (40 mg) (n=36). Intranasal administration of oxycodone results in a much faster and higher peak concentration compared to oral administration, which is a key driver of its abuse potential. Intranasal administration of oxycodone results in a much faster and higher peak concentration compared to oral administration, which is a key driver of its abuse potential.

[0007] FIG 3 provides geometric mean (SD) plasma concentration (pg / mL) following oral administration of 1000 pg intranasal cebranopadol or intranasal oxycodone IR (40 mg) (n=36).

[0008] FIGs 4 - 5 illustrate the slower absorption translated to significantly lower “drug liking”. Consistent with its oral PK profile, intranasal cebranopadol produced a small and delayed effect on drug liking that was like its oral route of administration. In contrast, The faster absorption of intranasal oxycodone led to a rapid rise in drug liking scores to a substantial 8-point increase in "Drug Liking" compared to its oral route. Cebranopadol was far less liked than oxycodone, with a mean peak liking score difference of 25.5 points (p<0.001). Critically, the drug liking scores for cebranopadol were similar whether it was administered orally or intranasally, highlighting a key difference from oxycodone, which becomes more "likable" via the intranasal route.

[0009] Fig 4 provides a line chart with mean drug liking score over time following intranasal administration of cebranopadol (1000 ug), oxycodone (40 mg) or placebo (n=35)

[0010] Fig 5 provides a line chart with mean drug liking score over time following oral administration of cebranopadol (1000 ug), oxycodone (40 mg) or placebo (n=35).

[0011] FIG 6 is a bar chart with cebranopadol (1000 ug), oxycodone (40 mg) or placebo (n=35), at mean, max and median of “drug liking”.

[0012] FIGs 7 and 8 illustrate that, consistent with its oral PK profile, intranasal cebranopadol produced a small and delayed effect on drug liking that was like its oral route of administration. In contrast, The faster absorption of intranasal oxycodone led to a rapid rise in drug liking scores to a substantial 8-point increase in "Drug Liking" compared to its oral route.

[0013] FIG 7 is a bar chart showing mean “good effects” VAS. "Good Effects," which quantifies effects such as euphoria, is a key measure of abuse liability. The incidence of euphoric mood was found to be lower with cebranopadol compared to oxycodone.

[0014] FIG 8 is a bar chart showing mean “bad effects” VAS. "Bad Effects" quantifies negative experiences like nausea or dizziness. The summary of measures indicates that higher "bad effects" for cebranopadol support a lower abuse potential.FIG 9 is a bar chart illustrating that subjects showed significantly lower desire to misuse cebranopadol. Mean and median scores for mean “take drug again” VAS are shown for cebranopadol (1000 ug), oxycodone (40 mg) or placebo (n=35). The "Take Drug Again" VAS scale directly assesses a drug's reinforcing properties and addiction potential. Scores for cebranopadol were significantly lower than for oxycodone, suggesting weaker reinforcing properties. The data from these secondary pharmacodynamic endpoints powerfully complements the PK findings. The lower scores on “Good Effects” and “Take Drug Again” suggest cebranopadol has weaker reinforcing properties than oxycodone. This, combined with its slower pharmacokinetic profile, higher “bad effects” and diminished "Drug Liking" scores, solidifies the conclusion that cebranopadol possesses a minimal potential for abuse compared to conventional Schedule II opioids.

[0015] FIG 10 is a line graph plotting the pharmacokinetics of cebranopadol as measured in plasma concentration (pg / mL) delivered via two different routes, intranasally or oral, at the same dose (1000 pg).

[0016] FIG 11 is a line graph plotting the pharmacokinetics of cebranopadol as measured in plasma concentration (pg / mL) delivered via intranasally at three different doses.

[0017] FIG 12 is a line graph plotting the pharmacokinetics of cebranopadol as measured in plasma concentration (pg / mL) delivered orally.

[0018] FIG 13 is a bar chart showing drug liking (at this moment) VAS. Unlike oxycodone, mean drug liking for cebranopadol was similar (less) when administered intranasally (IN) vs orally. Administration of oxycodone IN resulted in an 8 point increase over the oral route suggesting a faster blood concentration of oxycodone.

[0019] FIG. 14 shows Minute Ventilation (MV) 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 treatment differences following injection 1, Cebranopadol or saline (bins 0 to 15). 2-way ANOVA showed no significant difference in treatment following injection 2, Fentanyl or saline (bins 20 to 100), although there was a significant effect of time and a significant treatment x time interaction.

[0020] FIG. 15 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).

[0021] FIG. 16 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).

[0022] FIG. 17 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).

[0023] FIG. 18 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).

[0024] FIG. 19A-FIG. 19E shows summaries of minute ventilation (FIG. 19A), peak inspiratory flow (FIG. 19B), apneic pause (FIG. 19C), tidal volume (FIG. 19D) and inspiratory time (FIG.19E) 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.

[0025] FIG 20A provides a Summary of Minute Ventilation (MV) as a percentage (%) of baseline (BSL) in Wistar rats. The x-axis provides a comparison of pre- and post-injection with the tested cebranopadol at 25 pg / kg (TRN-228 on the FIG), as compared to a vehicle containing fentanyl, a combination of cebranopadol and fentanyl, as compared to vehicle with no active drug. There was a significant effect of time, with Cebranopadol providing a faster MV% as compared to fentanyl alone. FIG. 20B shows Peak Inspiratory Flow (PIF) as percentage of baseline over time post-injection in Wistar rats. The rats received intravenous injections of saline (ImL / kg), Cebranopadol (25ug / kg), Fentanyl (50ug / kg) or Cebranopadol plus Fentanyl. 2-way ANOVA showed no significant difference between groups at baseline although there was a significant effect of time.

[0026] FIG 21 A provides a Summary of Minute Ventilation (MV) as a percentage (%) of baseline (BSL) in Wistar rats. The x-axis provides a comparison of pre- and post-injection with the tested cebranopadol at 50 pg / kg (TRN-228 on the FIG), as compared to a vehicle containing fentanyl, a combination of cebranopadol and fentanyl, as compared to vehicle with no active drug. There was a significant effect of time, with Cebranopadol providing a faster MV% as compared to fentanyl alone. FIG. 2 IB shows Peak Inspiratory Flow (PIF) as percentage of baseline over time post-injection in Wistar rats. The rats received intravenous injections of saline (ImL / kg), Cebranopadol (50 ug / kg), Fentanyl (50ug / kg) or Cebranopadol plus Fentanyl. 2-way ANOVA showed no significant difference between groups at baseline although there was a significant effect of time.

[0027] SUMMARY OF THE INVENTION

[0028] In certain embodiments, a method for treating pain with low intranasal abusability is provided which comprises treating pain in a subject with a composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof, thereby providing effective pain relief to the treated subject without intranasal abusability. In certain embodiments, peak plasma levels for cebranopadol are not reached significantly faster when taken intranasally as compared to an oral route of administration. In certain embodiments, the composition comprises cebranopadol in a free base form or as a citrate salt. In certain embodiments, thecomposition is a solid tablet. In certain embodiments, a 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. 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. In certain embodiments, cebranopadol is the sole analgesic. In certain embodiments, the pain is moderate to severe acute pain.

[0029] In certain embodiments, a method for providing opioid-level pain relief to a subject with low intranasal abusability is described. The method comprises delivering a composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof to a subject in need of pain relief, wherein peak plasma levels for cebranopadol are not reached significantly faster when abused intranasally as compared to an oral route of administration. In certain embodiments, the composition comprises cebranopadol in a free base form. In certain embodiments, the composition is a solid tablet. In certain embodiments, a 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. 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. In certain embodiments, the cebranopadol is the sole analgesic. In certain embodiments, the pain is moderate to severe acute pain.

[0030] In certain embodiments, a method provided herein is for use in providing a subject with pain relief of a full mu-opioid receptor (MOP) which does not have greater intranasal abusability than oral abuse potential, said method comprising treating pain in the subject with a composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof, thereby providing effective pain relief to the treated subject. In certain embodiments, the composition is a solid tablet. In certain embodiments, a 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. In certain embodiments, a composition comprisesat 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. In certain embodiments, the cebranopadol is the sole analgesic. In certain embodiments, the pain is moderate to severe acute pain.

[0031] In certain embodiments, a composition is provided for use in treating moderate to severe acute pain effective pain relief without intranasal abusability, said composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof

[0032] In certain embodiments, a composition is provided for use in providing opioid-level pain relief to a subject with low intranasal abusability comprising a cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate, wherein peak plasma levels for cebranopadol are not reached significantly faster when abused intranasally as compared to an oral route of administration.

[0033] In certain embodiments, use a composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof for treating moderate to severe acute pain without intranasal abusability is provided.

[0034] Still other aspects and advantages of the invention will be apparent from the following detailed description of the invention.

[0035] DETAILED DESCRIPTION OF THE INVENTION

[0036] Provided herein are methods, regimens, and compositions useful in pain therapy in a subject while providing decreased risk of intranasal abusability. These compositions and methods utilize cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof. 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 the total 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.It has unexpectedly been found that cebranopadol’s pharmacokinetic profile is not significantly altered by its route of administration, in contrast to solely mu agonist opioid analgesics. Solid doses of Cebranopadol can be administered orally for treatment of pain with minimal risk that it will be abused intranasally, as cebranopadol does not produce the rapid onset of “euphoria” or “high” associated with mu agonist opioids.

[0037] While cebranopadol has previously been described as providing the activity of a full mu-agonist, it provides less abuse potential than sole mu-agonist opioid analgesics and partial mu-agonist, while providing effective pain relief. 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] Compositions, use and method for treating pain in a subject are provided, wherein a composition comprising one or more cebranopadol as defined herein provides effective pain relied with reduced risk of intranasal abuse. In certain embodiments, the pain is chronic, acute, subacute, central, peripheral, neuropathic, nociceptive pain, visceral pain, skeletal pain, and / or nervous pain.

[0039] 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. Suitable methods for measuring pain are known the art. One suitable method is 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.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. 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.

[0040] As used herein, “Cebranopadol” is intended to include trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-l,T-(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,T-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 forms described in US 8895604; US8765800, US8618156, and US8614245, which are incorporated herein by reference.

[0041] 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.

[0042] 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 of the Table in Part A (see, Examples). 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.In certain embodiments, cebranopadol crystal form A has an X-ray powder diffraction pattern (PXRD) comprising characteristic peaks at 7.8±0.2 degrees 20and at 31.6±0.2 degrees 2®, 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 2®. 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 2® and / or at 15.8±0.2 degrees 2®. In certain embodiments, the crystalline form comprises characteristic peaks at about 20.4+0.2 degrees 2® and / or at 23.3+0.2 degrees 2®. In certain embodiments, the crystalline form comprises characteristic peaks at 11.7+0.2 degrees 2®, at one or both of 8.8+0.2 degrees 2® and / or 15.8+0.2 degrees 2®, and at one or both of 20.4+0.2 degrees 2® and / or 23.3+0.2 degrees 2®. In certain embodiments, the crystalline form has an endothermal event with a peak temperature at about 298-308° C., as determined by DSC. 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 activeingredient 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-l,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-py ran [3,4b]indol]-4- amine.

[0043] Methods of making the compound are described, e.g., US 8,779,160; US8,658,827; US10,323,040, all of which are incorporated by reference herein.

[0044] Although the free base of cebranopadol is illustrated in the examples herein, 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, acetylsalicylic acid, 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).

[0045] In certain embodiments, a cebranopadol compound useful in certain embodiments of the invention has the structure of:

[0046]

[0047]

[0048] , in the form of a free base or a salt thereof.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.

[0049] For the purpose of the specification, doses of cebranopadol relate to the free base.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] As used herein, the term micrograms is abbreviated “pg” or “mcg”, which may be used interchangeably.

[0056] As used herein, for a human subject experiencing acute pain, a dose generally involves delivery of a dose in excess of 100 pg to 1000 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, and are titratable for teens or other subjects.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, a patient 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.

[0057] 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.

[0058] A method is provided for preventing or reducing opioid induced respiratory depression in a patient receiving opioid analgesia and / or opioid anesthesia. In one embodiment, the compound is cebranopadol and provides protective effect against the opioid compound(s) prior to providing therapeutic analgesic effect.

[0059] As demonstrated in the examples, it has been found that the pharmacokinetic profile of cebranopadol is not significantly impacted by its route of administration. Thus, it provides improved safety against intranasal abuse.

[0060] In certain embodiments, the compositions and methods provided herein further provide improved protection against respiratory depression and related symptoms, permitting a subject to maintain 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.

[0061] In certain embodiments, the cebranopadol composition is not characterized by the respiratory depression associated with opioid administration, and provides protective effect against opioid-associated respiratory depression when co-administered with an opioid, e.g., at least a 5% improvement, or a 5% to 15% improvement in MV as compared the opioid alone. Incertain embodiments, the compound comprising the NOP receptor agonist provides at least a 5% improvement, or a 5% to 15% improvement in PIF as compared the opioid alone. In certain embodiments, the improvement in respiratory depression is observed within 30 minutes. In certain embodiments, the improvement is observed within 1 hour to about 4 hours (e.g., for an orally administered cebranopadol). In certain embodiments, the desired protective effect persists for a longer time period and / or has an faster onset time.

[0062] In certain embodiments, the cebranopadol comprises at least 80%, at least 90%, at least 95%, or at least 97%, each up to 100% is in Crystal Form A. In certain embodiments, cebranopadol is in its free base form. In certain embodiments, cebranopadol is in the form of a citrate salt. In certain embodiments, the total dose of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof is about 200 ug to 1200 ug daily, as determined based on cebranopadol free base.

[0063] In certain embodiments, the patient is a surgical patient and / or a trauma patient.

[0064] 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.

[0065] In certain 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.

[0066] 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, 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 observed between cebranopadol and other analgesics.

[0067] 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.

[0068] Further, there is no interference 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.

[0069] In certain embodiments, the pharmaceutical composition is a solid oral dose.

[0070] In certain embodiments, the pharmaceutical composition is a liquid composition.

[0071] 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. In certain embodiments, the dose of cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof is in an amount of about 200 pg to about 1200 pg per day, or about 400 pg to 800 pg, or about 200 pg to 800 pg. In certain embodiments, the cebranopadol comprises at least 80%, at least 90%, at least 95%, or at least 97%, each up to 100% is in Crystal form A. Pain and / or opioid drug dependence are treated or prevented. When pain is to be treated or prevented, the pain may be moderate, moderate tosevere, or severe. The pain may be chronic or 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] Somatic pain is nociceptive pain that results from some injury to the body. It's 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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..

[0084] 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.Depending upon the type and degree of pain to be treated or prevented, Cebranopadol or the physiologically acceptable salt thereof is administered at a dose that in the subject's perception results in an amelioration of pain at acceptable side effects. A

[0085] In certain embodiments, the dosage form is adapted for administration once daily and contains the pharmacologically active agent in a dose of from 150 pg to 800 pg, more than 190 pg to 800 pg, i.e., the dosage form contains the pharmacologically active agent (e.g, cebranopadol or salt thereof) in a daily dose of from 150 pg to 800 pg. In a certain embodiment, the dose is from 200 pg to 800 pg, from 210 pg to 750 pg, from 220 pg to 700 pg, from 230 pg to 650 pg, from 240 pg to 600 pg, from 250 pg to 550 pg. In certain embodiments, Cebranopadol or the physiologically acceptable salt thereof is administered once daily, this dose corresponds to the daily dose.

[0086] 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. 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.

[0087] 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 apharmaceutical 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.

[0088] 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 dissolution medium. 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.

[0089] 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.

[0090] 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, thepharmaceutical 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 filler and / 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.

[0091] 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 fillers 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. In certain 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.

[0092] 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.

[0093] In certain embodiments, cebranopadol may be selected as a secondary analgesic providing opioid-like analgesic effect by discontinuing opioid treatment within 1 to two hours after administering a cebranopadol composition. In certain embodiments, the patient may have received opioid treatment for less than 24 hours, less than 18 hours, less than 12 hours, less than 8hours, less than 6 hours, less than 4 hours. In certain embodiments, opioid treatment is discontinued after a single dose, followed by cebranopadol. In other embodiments, the first dose of cebranopadol may be delivered concomitantly, or shortly after, the first opioid dose.

[0094] In certain embodiments, the cebranopadol is used for treatment of pain associated with opioid-induced hyperalgesia. In certain embodiments, the cebranopadol is used for treatment of acute pain. In certain embodiments, the pain is associated with tissue damage following surgery. In certain embodiments, the pain is associated with hyperalgesia.

[0095] In certain embodiments, methods, compositions and uses are provided for reducing 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.

[0096] 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.

[0097] Advantageously, it has been demonstrated that cebranopadol has significantly lower abuse potential compared to both Schedule II (oxycodone) and Schedule IV (tramadol) opioids. Further, unlike after treatment with oxycodone and tramadol, administration of cebranopadol did not produce pruritus, hyperhidrosis, feeling hot and / or hot flushing, that have been associated with the use of opioid analgesics. Specifically, when the incidence of subjects experiencing pruritis was analyzed, treatment with cebranopadol 600 pg and 1000 pg resulted in only 6.7% (n=3) and 7% (n=3) verses 29.5% (n=13) after having taken oxycodone 40 mg and 25.6% (n=10) after having taken tramadol 600 mg. A similar trend in frequency was observed for the adverse event (AE) hyperhidrosis; no subjects experienced the AE after taking either dose of cebranopadol verses 11.4% (n=5) after taking oxycodone and 12.8% (n=5) after tramadol.

[0098] Moreover, only a single subject reported feeling hot after receiving oxycodone (2.3%) and tramadol (2.5%). Finally, while none of the subjects experience hot flush after taking 1000 pg ofcebranopadol, only a single subject (2.2%) experienced hot flush after cebranopadol 600 pg compared to 11.4% (n=5) after taking oxycodone and 12.8% (n=5) after taking tramadol.

[0099] Optionally, abuse potential is assessed using a Multi-Task Test. 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.

[0100] In certain embodiments, a method is provided for treating pain in a patient having nociceptive pain with reduced risk of intranasal abuse.

[0101] 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.In certain embodiments, a method for treatment of opioid use disorder (OUD) in a patient in need thereof is provided, which comprises treating the patient with at least one dose of cebranopadol or a pharmaceutically acceptable salt thereof. 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.

[0102] The pharmacokinetic parameters of cebranopadol may be calculated from plasma concentration- time data.

[0103] 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 t is the last sampling time with quantifiable concentration and this parameter will not contain an extrapolated portion.

[0104] 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.

[0105] Cmax refers to the maximum observed plasma concentration level.

[0106] Tmax refers to the time post-dosing to attain maximum plasma concentration.

[0107] 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.

[0108] Pharmacodynamics (PD) may be assessed using a Visual Analog Scale (VAS), Pupillometry, and / or the Multi-Tasking Test (MTT), such as described in the examples herein. Additional or alternative tests may be selected.

[0109] The VAS assessment is one of the most sensitive indices of abuse liability. See, Babalonis S, Lofwall MR, Nuzzo PA, Siegel AJ, Walsh SL. Abuse liability and reinforcing efficacy of oral tramadol in humans. Drug Alcohol Depend. 2013 Apr 1 ;129(l-2): 116-241; Food and Drug Administration Guidance for Industry. Assessment of Abuse Potential of Drugs.

[0110] January 2017.] The VAS for Drug Liking assesses the subject’s liking of the drug at this momentthe question is asked. The VAS is a bipolar scale. The scale is not administered pre-dose as it refers specifically to the drug.

[0111] Pupillometry may be used as an objective physiological PD measure as it is one of the most sensitive measures of central opioid action and appears to be resistant to tolerance development with repeated opioid administration. NeurOptics Pupillometer (Irvine, CA, USA) or similar equipment will be used to measure pupil diameter. Data from a series of frames will be used in the calculation, and the final display will show the weighted average and standard deviation of the pupil size. Measurements may be collected under mesopic lighting conditions.

[0112] 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 participant to 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.

[0113] 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.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.

[0114] In certain embodiments, a method, use or composition is provided for treating pain while reducing the intranasal abuse potential and / or sides effects of Class II, III and Class IV- opioids and opioid-like 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 base cebranopadol. 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.

[0115] In certain embodiments, a regimen is provided for providing analgesic treatment while 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 certainembodiments, 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 are reduced or eliminated by the cebranopadol composition. 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.

[0116] In our studies, it was demonstrated that cebranopadol has significantly lower abuse potential compared to both Schedule II (oxycodone) and Schedule IV (tramadol) opioids. Further, unlike after treatment with oxycodone and tramadol, administration of cebranopadol did not produce pruritus, hyperhidrosis, feeling hot and / or hot flushing, that have been associated with the use of opioid analgesics. Specifically, when the incidence of subjects experiencing pruritis was analyzed, treatment with cebranopadol 600 pg and 1000 pg resulted in only 6.7% (n=3) and 7% (n=3) verses 29.5% (n=13) after having taken oxycodone 40 mg and 25.6% (n=10) after having taken tramadol 600 mg. A similar trend in frequency was observed for the AE hyperhidrosis; no subjects experienced the AE after taking either dose of cebranopadol verses 11.4% (n=5) after taking oxycodone and 12.8% (n=5) after tramadol. Moreover, a single subject reported feeling hot after receiving oxycodone (2.3%) and tramadol (2.5%). Finally, while none of the subjects experience hot flush after taking 1000 pg of cebranopadol, only a single subject (2.2%) experienced hot flush after cebranopadol 600 pg compared to 11.4% (n=5) after taking oxycodone and 12.8% (n=5) after taking tramadol.

[0117] 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.

[0118] 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 less addictive properties and / or less abuse potential than a partial mu agonist (e.g., tramadol or another Class IV opioid-like analgesic).

[0119] 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.

[0120] 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.

[0121] 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 treatment for 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.

[0122] In certain embodiments, a composition or regimen provided herein comprises cebranopadol as the sole active pharmaceutical ingredient or the sole analgesic in the

[0123] composition.In certain embodiments, a composition, use or method for treatment of pain in humans is provided which provides reduced the intranasal 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 film coated tablet.

[0124] In certain embodiments, a method is provided for treating pain in a patient having nociceptive pain with reduced risk of intranasal 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 film-coated tablet.

[0125] In certain embodiments, in the method, composition, or use, 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. 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 one or more of these embodiments, uses and / orcompositions, cebranopadol may be the sole active pharmaceutical ingredient in the composition and / or regimen.

[0126] The present invention includes a number of embodiments, including, without limitation.

[0127] El. A method for treating pain with low intranasal abusability comprising treating the pain in a subject with a composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof, thereby providing effective pain relief to the treated subject without intranasal abusability.

[0128] E2. The method of El, wherein peak plasma levels for cebranopadol are not reached significantly faster when taken intranasally as compared to an oral route of administration.

[0129] E3. The method of El or E2, wherein the composition comprises cebranopadol in a free base form.

[0130] E4. The method of any one of El to E3, wherein the composition is a solid tablet.

[0131] E5. The method of any one of El to E4, 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.

[0132] E6. The method of any one of El to E5, 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.

[0133] E7. The method of any one of El to E6, wherein the cebranopadol is the sole analgesic. E8. The method of any one of El to E7, wherein the pain is moderate to severe acute pain.

[0134] E9. A method of providing opioid-level pain relief to a subject with low intranasal abusability, the method comprising delivering a composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof to a subject in need of pain relief, wherein peak plasma levels for cebranopadol are not reached significantly faster when abused intranasally as compared to an oral route of administration.

[0135] E10. The method of E9, wherein the composition comprises cebranopadol in a free base form.

[0136] Ell. The method of E9 or El 0, wherein the composition is a solid tablet.E12. The method of any one of E9 to El 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.

[0137] El 3. The method of any one of E9 to El 2, 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.

[0138] E14. The method of any one of E9 to E13, wherein the cebranopadol is the sole analgesic.

[0139] E15. The method of any one of E9 to E14, wherein the pain is moderate to severe acute pain.

[0140] E16. A method providing a subject with pain relief of a full mu-opioid receptor (MOP) which does not have greater intranasal abusability than oral abuse potential, said method comprising treating pain in the subject with a composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof, thereby providing effective pain relief to the treated subject.

[0141] El 7. The method of El 6, wherein the composition comprises cebranopadol in a free base form.

[0142] E18. The method of E16 or E17, wherein the composition is a solid tablet.

[0143] El 9. The method of any one of El 6 to El 7, 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.

[0144] E20. The method of any one of El 6 to El 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.

[0145] E21. The method of any one of El 6 to El 7, wherein the cebranopadol is the sole analgesic.E22. The method of any one of El 6 to El 7, wherein the pain is moderate to severe acute pain.

[0146] E23. A composition for use in treating moderate to severe acute pain effective pain relief with low intranasal abusability, said composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof

[0147] E24. A composition for use in providing opioid-level pain relief to a subject with low intranasal abusability comprising a cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate, wherein peak plasma levels for cebranopadol are not reached significantly faster when abused intranasally as compared to an oral route of administration.

[0148] E25. A composition for use in providing a subject with pain relief of a full mu-opioid receptor (MOP) which does not have greater intranasal abusability than oral abuse potential, said composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof.

[0149] E26. Use of a composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof for treating moderate to severe acute pain without intranasal abusability.

[0150] E27. Use of a composition comprising a cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof for providing opioid-level pain relief to a subject with low intranasal abusability, wherein peak plasma levels for cebranopadol are not reached significantly faster when abused intranasally as compared to an oral route of administration.

[0151] E28. Use of a composition comprising a cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof for providing a subject with pain relief of a full mu-opioid receptor (MOP) which does not have greater intranasal abusability than oral abuse potential.

[0152] E29. The composition of any one of E23 to E25, or Use of any one of E26 to E28, wherein peak plasma levels for cebranopadol are not reached significantly faster when taken intranasally as compared to an oral route of administration.

[0153] E30. The composition of E23 to E25, or E29, or use of claim E26 to E29, which comprises cebranopadol in a free base form.

[0154] E31. The composition of any one of E23 to E25, E29 or E30, or use of any one of E26 to E30, wherein the composition is a solid tablet.E32. The composition of any one of E23 to E25 or E29 to E31, or use of any one of E26 to E31, wherein the comprises greater than 90% w / w cebranopadol Crystal Form A, as calculated based on the total weight of cebranopadol free base in the composition.

[0155] E33. The composition of any one of E23 to E25 or E29 to E32, or use of any one of E26 to E32, 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.

[0156] E34. The composition of any one of E23 to E25 or E29 to E33, or use of any one of E26 to E32, wherein the cebranopadol is the sole analgesic.

[0157] E35. The composition of any one of E23 to E25 or E29 to E34, or use of any one of E26 to E32, wherein the pain is moderate to severe acute pain.

[0158] !!

[0159] Cmax" is the maximum observed plasma concentration, and may be calculated as the geometric or arithmetic mean of the individual maximum blood plasma concentrations.

[0160] The term "mean maximum plasma concentration" (mean Cmax) is defined for the purposes of the present invention as the maximum mean plasma drug concentration.

[0161] “Mean plasma concentration" may be the geometric or arithmetic mean blood plasma concentration.

[0162] The term "Tmax" is the time at which the peak (maximum) observed blood plasma drug concentration for each individual participating in the bioavailability study.

[0163] The term "AUC0-co" or “AUCinf ’ is the mean area under the plasma concentration-time curve extrapolated to infinity. It is calculated as the mean of the area under the plasma concentration-time curve from time 0 extrapolated to infinity, calculated for each individual participating in the bioavailability study and may be the geometric or arithmetic mean. Partial AUC may be useful in determining bioequivalence, where the AUC is determined based on a specific fragment of the AUC0-co. These fragments may be, e.g., from 0-3, 0-4, 4-18 hours, 4-24 hours, or 4-48 hours.

[0164] In one embodiment, a composition of the invention has no food effect, i.e. there is no statistical difference in one or more of the pharmacokinetic parameters, including, e.g., Cmax, AUCO-co", and / or one or more partial AUCs, when patients are administered a dose under fasted conditions as compared to fed conditions.AUCO-t is the area under the plasma / serum / blood concentration-time curve from time zero to time t, where it is the last time point with measurable concentration for individual formulation.

[0165] “Bioequivalent” means the pharmacokinetic profde of a test composition is within the range of about 80% to about 125%, when compared to the values of one or more of the AUC values or the Cmax of the reference composition.

[0166] The words "comprise", "comprises", and "comprising", and “contain”, “containing”, and “contains” are to be interpreted inclusively rather than exclusively. The words “consist”, “consisting”, and its variants, are to be interpreted exclusively, rather than inclusively.

[0167] As used herein the term “about” means a variability of 10% from the reference given, unless otherwise specified.

[0168] It will be understood from the specification that the following examples are not limitations on the various embodiments of the invention.

[0169] Examples:

[0170] Illustrative Synthesis of Crystalline Form A

[0171] 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.

[0172] 100 mg (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 [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.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.

[0173]

[0174]

[0175] Analysis — DVS

[0176] 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.

[0177] 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.

[0178] 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.j^hemi -hydrate (>70% r. h.). The sample was classified to be hygroscopic (Am=3-4% at 85% r. h.; Am: change in mass)

[0179]

[0180] Example 1 : A Double-Blind, Randomized, Crossover Study to Assess the Abuse Potential of Intranasal Cebranopadol Compared to Oxycodone and Placebo in Healthy, Nondependent Recreational Opioid Users

[0181] Objectives:

[0182] The primary objective of this study was: • To evaluate the abuse potential of a single intranasal dose of cebranopadol compared to intranasal oxycodone hydrochloride (HC1) immediate-release (IR) and intranasal placebo in healthy, nondependent recreational opioid users.

[0183] The secondary objectives of this study were: • To evaluate the safety and tolerability of intranasal cebranopadol in healthy, nondependent recreational opioid users. • To evaluate the pharmacokinetics of intranasal cebranopadol in healthy, nondependent recreational opioid users.

[0184] Treatment PhaseThe Treatment Phase consisted of 3 treatment periods. Subjects remained confined throughout the Treatment Phase. Subjects received each of the following 3 treatments (1 per treatment period) in a randomized, double-blind crossover manner, following a fasting period of at least 8 hours:

[0185] J Treatment A: Crushed cebranopadol, dose determined in Part A

[0186] Treatment B: Crushed oxycodone IR 40 mg

[0187] □ Treatment C: Placebo powder

[0188] Subjects were required to complete dosing within 5 minutes and were permitted to use both nostrils to administer the treatments. Serial pharmacodynamic, pharmacokinetic and safety assessments were conducted for up to 48 hours after each study drug administration.

[0189] Pharmacodynamic assessments included subjective effects visual analog scales (VAS) (including the primary measure of Drug Liking), Subject-Rated Assessment of Intranasal Irritation (SRAII), and pupillometry as an objective measure. Safety monitoring included assessments of AEs, vital signs, clinical laboratory results, 12-lead ECG, physical and nasal cavity examinations, concomitant medications, and Columbia-Suicide Severity Rating Scale (C-SSRS) up to 48 hours after study drug administration; pulse oximetry / telemetry was continuously monitored for at least 12 hours. Each study drug administration was separated by a washout interval of at least 7 days (up to 30 minutes earlier was acceptable). A follow-up phone call was conducted 7 to 12 days after last administration of study drug.

[0190] Main Criteria for Inclusion: Subjects were recreational opioid users who reported use of opioids for nontherapeutic purposes (i.e., for psychoactive effects) on at least 10 occasions in the year prior to Screening and at least once in the 12 weeks prior to Screening. Subjects must also have reported intranasal use of drugs of abuse on at least 3 occasions in the year prior to Screening. Subjects must not have been physically dependent on opioids, as demonstrated by the naloxone challenge test, and must have had a negative urine drug screen, with the exception of being positive for cannabinoids (THC).

[0191] Cebranopadol was supplied as 200 pg film-coated tablets (Batch number 1308 A).

[0192] Part A: 600 (3 x 200 pg tablets), 800 (4 x 200 pg tablets), or 1000 pg (5 x 200 pg tablets), crushed and administered as a single intranasal dose.

[0193] Part B:

[0194] Treatment A: Cebranopadol dose determined during Part A. Tablets were crushed and administered as a single intranasal dose.Part B:

[0195] Qualification Phase

[0196] Treatment X: Oxycodone HC1 immediate-release (IR) 40 mg (4 x 10 mg tablets; Batch number 1016874), crushed and administered as a single intranasal dose.

[0197] Treatment Y : Placebo containing microcrystalline cellulose (MCC; Batch number 2174528989), matching the approximate weight / volume of oxycodone IR HC1 tablets, administered as a single intranasal dose.

[0198] Treatment Phase

[0199] Treatment B: Oxycodone HC1 IR 40 mg (2 x 20 mg tablets; Batch number 18121 A), crushed and administered as a single intranasal dose.

[0200] Treatment C: Placebo containing MCC, matching the approximate weight / volume of oxycodone HC1 IR and cebranopadol tablets, administered as a single intranasal dose.

[0201] Naloxone Challenge Test (Part A and Part B):

[0202] Naloxone was used for the Naloxone Challenge Test on Day -1 of the Treatment Phase in Part A and Day -1 of the Qualification Phase in Part B, to confirm that subjects were not physically dependent on opioids. The subcutaneous dose in the upper arm was 0.8 mg (2.0 mL) of naloxone.

[0203] Primary Endpoint: The primary endpoint of this study was Emax for Drug Liking (“at this moment”), as assessed by a bipolar (0 to 100 point) VAS.

[0204] Key Secondary Endpoints:

[0205] The key secondary endpoints were: Overall Drug Liking VAS (Emax); Take Drug Again VAS (Emax)

[0206] Other Secondary Pharmacodynamic Endpoints

[0207] Other secondary pharmacodynamic endpoints included Emax, minimum effect (Emin), time to maximum and minimum effect (TEmax and TEmin), area over or under the effect curve from 0 to x8 hours (AOE0-8h or AUE0-8h), and partial AUEs, as applicable, for the following assessments: Balance of effects; Drug Liking (“at this moment”) VAS (Emin, TEmax, TEmin, AUEO-lh, AUEO-2 h, and AUE0-8h); Overall Drug Liking VAS (Emin); Take Drug Again VAS (Emin),

[0208] Positive effects: High VAS (Emax, TEmax and AUE0-8h); Good Drug Effects VAS (Emax, TEmax, and AUE0-8h).Negative effects: Bad Drug Effects VAS (Emax, TEmax, and AUE0-8h); SRAII (Emax for burning, need to blow nose, runny nose / nasal discharge, facial pain / pressure and nasal congestion)

[0209] Other effects: Alertness / Drowsiness VAS (Emin, TEmin, and AOEO-8h); Any Drug

[0210] Effects VAS (Emax, TEmax, and AUE0-8h); Pupillometry (maximum pupil constriction [MPC], time to MPC [TMPC], and pupillometry area over the curve [PAOC]); Percent of dose insufflated (calculated or estimated in cases where subjects failed to insufflate more than a negligible amount of the total dose administered)

[0211] Pharmacokinetic Endpoints:

[0212] Following is a list of the pharmacokinetic endpoints for cebranopadol, its metabolites

[0213] (M2, M3 and M6) and oxycodone: Plasma concentrations over time; Cmax; Tmax; AUCo-xh,

[0214] where x=l hour, 2 hours; AUCiast; AUCinf; Xz; t' / a

[0215] Safety Endpoints

[0216] Safety measures were collected over 48 hours postdose. The following safety endpoints were evaluated: incidence, severity and relatedness of TE AEs, clinical laboratory assessments (hematology, chemistry, and urinalysis), vital signs (pulse rate, blood pressure, respiratory rate, oxygen saturation, and oral temperature), 12-lead ECG, physical examination results, C-SSRS findings, and concomitant medications.

[0217] Abuse potential was determined based on participant-reported likeability using a 100-point Visual Analog Scale (VAS) with 50 being neutral and numbers greater than 50 indicating liking.

[0218]

[0219]

[0220] See, also, FIGs 1 - 13.

[0221] The data demonstrate that cebranopadol possesses significantly less likeability when

[0222] crushed and taken intranasally than oxycodone. The results of the clinical study demonstrated statistically significantly less drug liking for cebranopadol at a supra-therapeutic dose of 1000 pg, which is 2.5 times higher than the proposed therapeutic dose studied for the treatment of pain.

[0223] This was determined by measuring the maximum drug liking (VAS Emax) compared to oxycodone 40 mg (difference of 24.8, P-value=<0.001, FIG 42 and Table above). In addition, all secondary endpoints designed to measure positive subjective effects of the drugs showed a large disparity between cebranopadol and oxycodone, including the key secondary endpoints of “take drug

[0224] again” and “overall drug liking”.

[0225] These results show that cebranopadol is neither more rapidly absorbed, nor does it

[0226] produce greater liking when taken via intranasal administration compared to oral administration.

[0227] The mean and median Emax numerically decreased for cebranopadol between the oral and intranasal studies (69.2 to 67.3 and 68.0 to 60.5 for mean and median, respectively) (see Table above), and peak effects occurred hours after administration in both cases. This is in sharp

[0228] contrast to oxycodone 40 mg which saw an increase in drug liking when administered

[0229] intranasally (83.9 to 92.1 and 85.0 to 100.0 for mean and median respectively) and a rapid onset of effect. In addition, a comparison of the pharmacokinetic results of the two trials shows that intranasal administration of cebranopadol did not result in more rapid uptake into the

[0230] bloodstream.

[0231] A comparison of the pharmacokinetic results from the two trials shows that intranasal administration of cebranopadol did not result in more rapid uptake into the bloodstream. In the intranasal study, peak plasma levels for cebranopadol occurred at approximately six hours after administration, compared to approximately five hours when administered orally. This contrasts with oxycodone, which reached peak levels after approximately 33 minutes when taken

[0232] intranasally, and about one and a half hours when taken orally.If a first-period analysis was conducted, Drug Liking VAS Emax was analyzed using an ANOVA model containing treatment as the fixed effect. Least squares means and 95% Cis was provided for each treatment, and difference in LS mean, 2-sided 90% and 95% Cis of the difference, and p-values was provided for each treatment comparison subject to a hypothesis test.

[0233] The treatment comparisons to assess the intranasal abuse potential of cebranopadol included the following:

[0234] □ Crushed oxycodone 40 mg vs. placebo (study validity)

[0235] J Crushed cebranopadol vs. crushed oxycodone 40 mg (relative abuse potential) Crushed cebranopadol vs. placebo (absolute abuse potential)

[0236] For study validity, the primary endpoint, Drug Liking VAS Emax, was compared between crushed oxycodone (positive control) and placebo, the following hypothesis was tested:

[0237] Ho: pC - pP < 15 vs. Ha: pC - pP > 15(1)

[0238] where pC is the mean for crushed oxycodone and pP is the mean for placebo. The margin of 15 was selected based on previous studies of this type. If the treatment difference of crushed oxycodone compared to placebo was statistically significant at a 1-sided alpha level of 0.05, validity was established for the study.

[0239] The primary treatment comparison for the relative intranasal abuse potential of cebranopadol was the comparison of Drug Liking VAS Emax between crushed cebranopadol and crushed oxycodone. The following hypothesis was tested:

[0240] Ho: pC - pT < 0 vs. Ha: pCl - pT > 0 (2) where pC is the mean for crushed oxycodone and pT is mean for crushed cebranopadol.

[0241] The evaluation of absolute intranasal abuse potential of cebranopadol was the comparison of crushed cebranopadol versus placebo. The following hypothesis was tested:

[0242] Ho: pT - pP > 11 vs. Ha: pT - pP < 11 (3)

[0243] where pT is the mean for crushed cebranopadol and pP is mean for placebo. The margin of 11 was selected based on Chen and Bonson, “An Equivalence Test for the Comparison Between a Test Drug and Placebo in Human Abuse Potential Studies”, Journal of Biopharmaceutical Statistics 23(2):294-306 (2013).

[0244] All secondary pharmacodynamic endpoints, including the key secondary endpoints, were analyzed with the same approach as described above for the primary endpoint analysis, using the Modified Completer Population. From the model, LS means and Cis were provided for each treatment.

[0245]

[0246] This measure to quantify the peak subjective experience of drug-induced “high” or intoxication. Oxycodone induces a rapid and 2x greater “high” than cebranopadol.

[0247] The peak “high” after cebranopadol administration occurs between 6-8 hours after insufflation.

[0248] Good or “Positive” Subjective Effects, are pleasurable or desired experiences induced by the drug, e.g., Euphoria, Sensory Alterations, Relaxation, etc. For cebranopadol, good effects were the same despite the route of administration. To the contrary, a dramatic increase in good effects were reported for the IN ROA compared to Oral providing further validity to the study.

[0249] Conclusions:

[0250] In the Dose Selection Phase (Part A), a total of 21 subjects were screened, with 7 screening failures. Twelve (12) subjects were enrolled in the Dose Selection Phase (3 for each of 4 dose cohorts). All 12 subjects completed this phase of the study and were included in the Dose Selection Safety Population and Dose Selection Pharmacokinetic Population.

[0251] In the Main Study (Part B), a total of 114 subjects were screened for enrollment and 74 subjects were randomized to the Qualification Phase. A total of 73 (98.6%) subjects completed the Qualification Phase and 36 (48.6%) subjects passed Drug Discrimination Test criteria. Thirty-six subjects were randomized and completed the Treatment Phase and study, including follow-up.All 36 subjects who were randomized in the Treatment Phase were included in the Safety Population, the Pharmacokinetic Population, and the Completer Population. One subject was excluded from the Modified Completer Population because their Drug Liking VAS Emax values for each treatment were within 5 points of each other, for a total of 35 subjects.

[0252] While oral ingestion is the most common route of prescription opioid abuse, a significant proportion of individuals abuse these products by non-oral routes, including via intranasal insufflation. Therefore, this study assessed the abuse potential of cebranopadol when crushed and administered intranasally to determine whether it also has lower abuse potential than a Schedule II opioid via this riskier route of administration.

[0253] Based on the primary endpoint, key secondary endpoints, and other secondary endpoints in the current study, crushed cebranopadol has lower abuse potential following intranasal administration compared with crushed oxycodone, a Schedule II opioid, in nondependent, recreational opioid users. The pharmacokinetic profile observed in the present study is consistent with prior studies of oral cebranopadol demonstrating slower kinetics compared with oxycodone, which may in part contribute to its observed lower abuse potential following both oral and intranasal administration. Although a direct comparison across studies cannot be made, the results of the current intranasal abuse potential study were similar to those reported in the oral abuse potential studies, including magnitude of effect and delayed onset relative to the positive controls. These findings suggest that there would be little incentive for drug users to abuse cebranopadol via the intranasal route to achieve a faster onset of effect.

[0254] This study’s findings demonstrate considerable promise of cebranopadol for treating moderate-to-severe acute pain, with markedly reduced addictive potential compared to classical opioids. Some people misuse opioids intranasally to generate a faster and more intense high compared to the oral route, which can be a precursor to using other opioids such as heroin or fentanyl, or the injection route. These results suggest that opioid misusers would be unlikely to do that with cebranopadol.

[0255] Example 2: Effect of cebranopadol and fentanyl co-administration

[0256] Study: To establish the respiratory depression of cebranopadol and fentanyl, administered intravenously (i.v.), in Wistar rats under highly standardized and controlled experimental conditions.

[0257] Experimental Procedure:Fentanyl: obtained from commercial source (Pharmacy). Dose: Injectable fentanyl is used at a concentrations 50ug / mL

[0258] 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.

[0259] Injections are administered i.v. at 1 mL solution / kg rat over a period of about 30 seconds.

[0260] Leftover drug at the end of the week is disposed of.

[0261] 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.

[0262] 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 a fentanyl (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.

[0263] 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 .1 of thiopental. If the rats lose consciousness within a few seconds after thiopental administration, the catheter is considered patent.

[0264] Main evaluation items:

[0265] A. Minute ventilation: The amount volume breathed in one minute, computed on a breath-by -breath basis (mL / min)

[0266] B. Peak Inspiratory Flow (PIF): The maximum negative flow during one breath (mL / sec)

[0267] 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)

[0268] 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)

[0269] Statistical analysis: All evaluation items are expressed as mean ± S.E.M.

[0270] 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. Two rats 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.

[0271] Results

[0272] A. Minute ventilation:

[0273] 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],

[0274] 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],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).

[0275] Peak Inspiratory Flow (PIF)

[0276] 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],

[0277] 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],

[0278] 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 min fentanyl 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).

[0279] 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 pO.0001, $$ p<0.01; $ p<0.05). Values are expressed as Mean ± S.E.M.Apneic Pause (AP)

[0280] 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],

[0281] 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).

[0282] 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.

[0283] Tidal Volume:

[0284] A 2-way ANOVA showed no significant effect between groups at baseline [F(3, 28) = 0.6856; / = 0.5684],

[0285] 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; / < 0.0001] and a significant interaction of treatment x time [F(9, 84) = 3.804; / = 0.0005],

[0286] 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; / = 0.0286], a significant effect of time [F(5.160, 144.5) = 7.242; / < 0.0001], and a significant interactiontreatment 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).

[0287] 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.

[0288] Inspiratory Time:

[0289] 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],

[0290] 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 at timepoints 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 a 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).

[0291] 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.

[0292] 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.

[0293] 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.

[0294] 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

[0295] 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

1. CLAIMS:

1. A method for treating pain with low intranasal abusability comprising treating the pain in a subject with a composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof, thereby providing effective pain relief to the treated subject with low intranasal abusability.

2. The method of claim 1, wherein peak plasma levels for cebranopadol are not reached significantly faster when taken intranasally as compared to an oral route of administration.

3. The method of claim 1 or 2, wherein the composition comprises cebranopadol in a free base form.

4. The method of any one of claims 1 to 3, wherein the composition is a solid tablet.

5. The method of any one of claims 1 to 4, 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 method of any one of claims 1 to 5, 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. The method of any one of claims 1 to 6, wherein the cebranopadol is the sole analgesic.

8. The method of any one of claims 1 to 7, wherein the pain is moderate to severe acute pain.

9. A method of providing opioid-level pain relief to a subject with low intranasal abusability, the method comprising delivering a composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof to a subject in need of pain relief, wherein peak plasma levels for cebranopadol are not reached significantly faster when abused intranasally as compared to an oral route of administration.

10. The method of claim 9, wherein the composition comprises cebranopadol in a free base form.

11. The method of claim 9 or 10, wherein the composition is a solid tablet.

12. The method of any one of claims 9 to 11, 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.

13. The method of any one of claims 9 to 12, 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.

14. The method of any one of claims 9 to 13, wherein the cebranopadol is the sole analgesic.

15. The method of any one of claims 9 to 14, wherein the pain is moderate to severe acute pain.

16. A method providing a subject with pain relief of a full mu-opioid receptor (MOP) which does not have greater intranasal abusability than oral abuse potential, said method comprising treating pain in the subject with a composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof, thereby providing effective pain relief to the treated subject.

17. The method of claim 16, wherein the composition comprises cebranopadol in a free base form.

18. The method of claim 16 or 17, wherein the composition is a solid tablet.

19. The method of any one of claims 16 to 17, 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.

20. The method of any one of claims 16 to 17, 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.

21. The method of any one of claims 16 to 17, wherein the cebranopadol is the sole analgesic.

22. The method of any one of claims 16 to 17, wherein the pain is moderate to severe acute pain.

23. A composition for use in treating moderate to severe acute pain effective pain relief with low intranasal abusability, said composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof24. A composition for use in providing opioid-level pain relief to a subject with low intranasal abusability comprising a cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate, wherein peak plasma levels for cebranopadol are not reached significantly faster when abused intranasally as compared to an oral route of administration.

25. A composition for use in providing a subject with pain relief of a full mu-opioid receptor (MOP) which does not have greater intranasal abusability than oral abuse potential, said composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof.

26. Use of a composition comprising cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof for treating moderate to severe acute pain without intranasal abusability.

27. Use of a composition comprising a cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof for providing opioid-level pain relief to a subject with low intranasal abusability, wherein peak plasma levels for cebranopadol are not reached significantly faster when abused intranasally as compared to an oral route of administration.

28. Use of a composition comprising a cebranopadol and / or a pharmaceutically acceptable salt, hydrate, or salt hydrate thereof for providing a subject with pain relief of a full mu-opioid receptor (MOP) which does not have greater intranasal abusability than oral abuse potential.

29. The composition of any one of claims 23 to 25, or Use of any one of claims 26 to 28, wherein peak plasma levels for cebranopadol are not reached significantly faster when taken intranasally as compared to an oral route of administration.

30. The composition of claim 23 to 25, or 29, or use of claim 26 to 29, which comprises cebranopadol in a free base form.

31. The composition of any one of claims 23 to 25, 29 or 30, or use of any one of claims 26 to 30, wherein the composition is a solid tablet.

32. The composition of any one of claims 23 to 25 or 29 to 31, or use of any one of claims 26 to 31, wherein the comprises greater than 90% w / w cebranopadol Crystal Form A, as calculated based on the total weight of cebranopadol free base in the composition.

33. The composition of any one of claims 23 to 25 or 29 to 32, or use of any one of claims 26 to 32, 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.

34. The composition of any one of claims 23 to 25 or 29 to 33, or use of any one of claims 26 to 33, wherein the cebranopadol is the sole analgesic.

35. The composition of any one of claims 23 to 25 or 29 to 34, or use of any one of claims 26 to 34, wherein the pain is moderate to severe acute pain.

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