Cyclobenzaprine treatment for acute stress reaction or acute stress disorder

Abstract

The present disclosure relates to methods for treating or preventing one or more of acute stress reaction (ASR), acute stress disorder (ASD), or one or more associated symptoms using a pharmaceutical composition comprising cyclobenzaprine or a pharmaceutically acceptable salt thereof. The present disclosure also relates to methods for treating or preventing ASR, ASD, or one or more associated symptoms in a subject who has experienced a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the commencement of treatment. The present disclosure also relates to methods for preventing the onset of post-traumatic stress disorder and for improving recovery from stress occasioned by a traumatic event.

Description

CYCLOBENZAPRINE TREATMENT FOR ACUTE STRESS REACTION OR ACUTE STRESS DISORDER CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit from United States ProvisionalApplication No. 63 / 625,257, filed January 25, 2024, the contents of which are hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0002] The present disclosure relates to methods for treating or preventing acute stressreaction (ASR) or one or more symptoms thereof or acute stress disorder (ASD) or one or more symptoms thereof after exposure to or experience of a traumatic event comprising administering to a subject in need thereof a pharmaceutical composition comprising cyclobenzaprine or a pharmaceutically acceptable salt thereof. The present disclosure also relates to methods for treating or preventing ASR or one or more symptoms thereof or ASD or one or more symptoms thereof in a subject who has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the commencement of treatment comprising administering to the subject a pharmaceutical composition comprising cyclobenzaprine or a pharmaceutically acceptable salt thereof. The present disclosure also relates to methods for preventing the onset of, or reducing the likelihood of developing, post-traumatic stress disorder (PTSD) or one or more associated symptoms thereof in a subject who has experienced or been exposed to a traumatic event or reducing the frequency or severity of PTSD or its symptoms, in subjects who have developed ASR or ASD or one or more of their associated symptoms. BACKGROUND

[0003] Cyclobenzaprine, or 3-(5H-dibenzola[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1 propanamine, was first approved by the U.S. Food and Drug Administration in 1977 for the treatment of acute muscle spasms of local origin (Katz and Dube. Clin Ther. 1988;10(2):216-28). International Publication Nos. WO2013 / 188847 and WO2014 / 145156, incorporated herein by reference, disclose a low dose, sublingual formulation of a cyclobenzaprine HCl-mannitol eutectic (TNX-102 SL) that provides rapid transmucosal absorption of cyclobenzaprine into the blood and uniquely reduces production of a long half-life active metabolite, norcyclobenzaprine, due to its bypass of first-pass hepatic metabolism. TNX-102 SL has shown efficacy in the treatment of fibromyalgia syndrome (two successful Phase 3 trials completed), post-traumatic stress disorder (PTSD) (several Phase 2 and 3 trials completed), generalized anxiety disorder and depression and has demonstrated the ability to improve sleep quality in individuals with PTSD and those with chronic pain, by acting as a multifunctional antagonist of 5-HT2A, α1-adrenergic, histaminergic-H1, and muscarinic-M1 acetylcholine receptors. Based on clinical studies of fear memory and stress responsiveness, sleep quality, particularly the quality of rapid eye movement sleep and slow wave sleep, has been shown to play a significant role in stress recovery.

[0004] U.S. military personnel are exposed to life-threatening traumatic events (e.g.,intense firefights with multiple casualties) that may result in acute stress reaction (ASR) or acute stress disorder (ASD) and their associated symptoms, which could develop or evolve into post-traumatic stress disorder (PTSD). ASR or ASD symptoms after such events substantially hamper service member resilience, recovery and warfighting performance. Similarly, acute and persistent stress symptoms, and related adverse posttraumatic neuropsychiatric sequelae, are also very common and cause a tremendous burden of suffering in civilian populations following exposure to life-threatening traumatic events (e.g., motor vehicle collisions, violent or accidental death of a loved one, and assault). Although sertraline and paroxetine are FDA approved for the treatment of PTSD, there is currently no FDA approved drug to treat or prevent ASR or ASD or prevent their evolution to the subsequent onset of PTSD. There is, therefore, an unmet need for new treatment options that, when administered in the early aftermath of a traumatic stress exposure or experience, can improve recovery, job performance, and quality of life. As described in the disclosure, cyclobenzaprine (e.g., a cyclobenzaprine HCl sublingual formulation) meets this unmet need for new treatment options for reducing trauma symptoms following a traumatic event and preventing the subsequent development of chronic post-traumatic stress (e.g., PTSD) or reducing the frequency and severity of its symptoms. SUMMARY OF THE DISCLOSURE

[0005] Some embodiments of this disclosure are:1. A method for treating or preventing (1) acute stress reaction (ASR) or one or moreassociated symptoms thereof or (2) acute stress disorder (ASD) or one or more associated symptoms thereof in a subject in need thereof, comprising administeringto the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of the pharmaceutical composition.The method according to embodiment 1, wherein the subject has experienced orbeen exposed to the traumatic event within about 1, 2, or 3 days prior to the administration of the pharmaceutical composition.The method according to embodiment 1 or 2, wherein the subject has experienced orbeen exposed to the traumatic event within about 1 day prior to the administration of the pharmaceutical composition.The method according to any one of embodiments 1-3, wherein the traumatic event isa criterion A traumatic event.The method according to embodiment 4, wherein the criterion A traumatic event isselected from a motor vehicle collision, military combat, violent personal assault, being kidnapped, being taken hostage, terrorist attack, torture, incarceration as a prisoner of war or in a concentration camp, natural or manmade disasters, or being diagnosed with a life-threatening illness.The method according to any one of embodiments 1-5, wherein the pharmaceuticallyacceptable salt of cyclobenzaprine in the pharmaceutical composition is a cyclobenzaprine acid salt.The method according to embodiment 6, wherein the cyclobenzaprine acid salt iscyclobenzaprine HCl.The method according to embodiment 7, wherein the cyclobenzaprine HCl is in theform of a mannitol-eutectic.The method according to embodiment 8, wherein the mannitol-eutectic is selectedfrom the group consisting of a 75% ± 2% by weight cyclobenzaprine HCl and 25% ± 2% by weight β-mannitol eutectic, a 65% ± 2% by weight cyclobenzaprine HCl and 35% ± 2% by weight δ-mannitol eutectic, a mixture of a 75% ± 2% by weightcyclobenzaprine HCl and 25% ± 2% by weight β-mannitol and a 65% ± 2% by weight cyclobenzaprine HCl and 35% ± 2% by weight δ-mannitol eutectic, and a granule comprising an outer layer of a 65% ± 2% by weight cyclobenzaprine HCl and 35% ± 2% by weight δ-mannitol eutectic and an inner layer of β-mannitol.10. The method according to any one of embodiments 1-9, wherein the pharmaceuticalcomposition further comprises a basifying agent.11. The method according to embodiment 10, wherein the basifying agent is selectedfrom a group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.12. The method according to embodiment 11, wherein the basifying agent is dipotassiumhydrogen phosphate.13. The method according to any one of embodiments 1-12, wherein the pharmaceuticalcomposition comprises between 0.1 mg and 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.14. The method according to embodiment 13, wherein the pharmaceutical compositioncomprises between 1 mg and 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.15. The method according to embodiment 14, wherein the pharmaceutical compositioncomprises less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.16. The method according to embodiment 15, wherein the pharmaceutical compositioncomprises less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.17. The method according to embodiment 15, wherein the pharmaceutical compositioncomprises about 5.6 mg of cyclobenzaprine HCl.18. The method according to embodiment 15 or 16, wherein the pharmaceuticalcomposition comprises about 2.8 mg of cyclobenzaprine HCl.19. The method according to embodiment 17, wherein the pharmaceutical compositionis administered simultaneously or sequentially in two dosage units, and wherein each dosage unit comprises 2.8 mg of cyclobenzaprine HCl.20. The method according to embodiment 17, wherein the pharmaceutical compositionis administered simultaneously or sequentially in two dosage units, and wherein the combined amount of the cyclobenzaprine HCl in the two dosage units is 5.6 mg.21. The method according to any one of embodiments 1-20, wherein the pharmaceuticalcomposition is administered daily.22. The method according to embodiment 21, wherein the pharmaceutical compositionis administered once daily.23. The method according to embodiment 21 or 22, wherein the pharmaceuticalcomposition is administered at bedtime.24. The method according to any one of embodiments 1-23, wherein the pharmaceuticalcomposition is formulated for sublingual, buccal, intranasal, oral, intravenous, intramuscular, subcutaneous, inhalational, transdermal, rectal, vaginal, or palatal administration.25. The method according to embodiment 24, wherein the pharmaceutical composition isformulated as a tablet, a thin film, a liquid, a powder, a spray or a suppository.26. The method according to embodiment 24, wherein the pharmaceutical compositionis formulated for sublingual administration.27. The method according to embodiment 26, wherein the pharmaceutical compositionis formulated as a sublingual tablet, a sublingual film, a sublingual powder, or a sublingual spray.28. The method according to any one of embodiments 1-27, wherein the symptoms ofASD are selected from the group consisting of reexperiencing symptoms, avoidance symptoms, arousal symptoms, difficulty with sleep, nightmares, irritability, difficultyconcentrating, hypervigilance, persistent exaggerated startle response, feelings such as not knowing where you are, and feeling as if you are outside of your body.The method according to any one of embodiments 1-27, wherein the symptoms ofASR are selected from the group consisting of intrusion, avoidance, hyperarousal symptoms, severe anxiety, negative mood, dissociative symptoms, pain, cognitive impairment symptoms, and somatic symptoms.A method for preventing the onset of post-traumatic stress disorder (PTSD) or oneor more associated symptoms thereof in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of the pharmaceutical composition, wherein the subject is suffering from or at risk of developing acute stress reaction (ASR) or one or more associated symptoms thereof or acute stress disorder (ASD) or one or more associated symptoms thereof.A method for preventing the evolution of acute stress reaction (ASR) or one or moreassociated symptoms thereof or acute stress disorder (ASD) or one or more associated symptoms thereof to post-traumatic stress disorder (PTSD) or one or more associated symptoms thereof in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of the pharmaceutical composition.A method for reducing the severity or frequency of one or more post-traumaticstress disorder (PTSD)-associated symptoms in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to theadministration of the pharmaceutical composition wherein the subject is suffering from or at risk of acute stress reaction (ASR) or one or more associated symptoms thereof or acute stress disorder (ASD) or one or more associated symptoms thereof.33. A method for improving stress recovery in a subject, comprising administering tothe subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of the pharmaceutical composition.34. The method according to any one of embodiments 30-33, wherein the subject hasexperienced or been exposed to the traumatic event within about 1, 2 or 3 days prior to the administration of the pharmaceutical composition.35. The method according to any one of embodiments 30-34, wherein the subject hasexperienced or been exposed to the traumatic event less than or equal to about 24 hours prior to the administration of the pharmaceutical composition.36. The method according to any one of embodiments 30-35, wherein the traumaticevent is a criterion A traumatic event.37. The method according to embodiment 36, wherein the criterion A traumatic event isselected from a motor vehicle collision, military combat, violent personal assault, being kidnapped, being taken hostage, terrorist attack, torture, incarceration as a prisoner of war or in a concentration camp, natural or manmade disasters, or being diagnosed with a life-threatening illness.38. The method according to any one of embodiments 30-32 and 34-37, wherein theassociated symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognition and mood symptoms, arousal and reactivity symptoms, difficulty falling sleep, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle response.39. The method according to any one of embodiments 30-32 and 34-37, wherein theassociated symptoms of ASD are selected from the group consisting ofreexperiencing symptoms, avoidance symptoms, arousal symptoms, difficulty with sleep, nightmares, irritability, difficulty concentrating, hypervigilance, persistent exaggerated startle response, feelings such as not knowing where you are, and feeling as if you are outside of your body. 40. The method according to any one of embodiments 30-32 and 34-37, wherein theassociated symptoms of ASR are selected from the group consisting of intrusion, avoidance, hyperarousal symptoms, severe anxiety, negative mood, dissociative symptoms, pain, cognitive impairment symptoms, and somatic symptoms. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figure 1 is a graph depicting the least squares (LS) mean change frombaseline in CAPS-5 derealization scores for subjects who received placebo (diamond), or sublingual cyclobenzaprine HCl (5.6 mg (triangle) and 2.8 mg (square)) over the course of 12 weeks of treatment in the P201 trial. *p <0.05, TNX-102 SL 2.8 mg group vs. placebo; mixed model repeated measures primary approach.#p = 0.053, TNX-102 SL 5.6 mg group vs. placebo; mixed model repeated measures with multiple imputation. CAPS-5 refers to Clinician-Administered PTSD Scale for DSM-5 Item E6. SE refers to standard error.

[0007] Figures 2A and 2B shows forest plots depicting subgroup MMRM analysis ofCAPS-5 total score for subjects who received placebo or sublingual cyclobenzaprine HCl (5.6 mg) based on Time Since Trauma (TST) index at week 4 (Figure 2A) and week 12 (Figure 2B). Square: p < 0.05. CI refers to confidence interval. LS Mean Difference refers to Least squares mean difference. MMRM refers to mixed-effects model repeated measure. DETAILED DESCRIPTION

[0008] This disclosure provides in some embodiments, methods andpharmaceutical compositions for treating or preventing acute stress reaction (ASR) or one or more symptoms associated therewith or for treating or preventing acute stress disorder (ASD) or one or more symptoms associated therewith in a subject who has experienced or been exposed to a traumatic event, wherein the pharmaceutical composition comprises a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Insome embodiments, the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event less than or equal to about 24 hours prior to the administration of a pharmaceutical composition of this disclosure.

[0009] In other embodiments, the present disclosure provides methods ofpreventing the onset of post-traumatic stress disorder (PTSD) and or one or more symptoms associated therewith, or reducing the frequency or severity of those symptoms, in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event less than or equal to about 24 hours prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has developed or is at risk of developing acute stress reaction (ASR) or acute stress disorder (ASD) or one or more of their associated symptoms as the result of experiencing or being exposed to a traumatic event. Definitions

[0010] The term “herein” means the entire application.

[0011] Unless otherwise defined herein, scientific and technical terms used in thisapplication shall have the meanings that are commonly understood by those of ordinary skill in the art. In case of conflict, the present specification, including definitions, will control.

[0012] It should be understood that any of the embodiments described herein,including those described under different aspects of the disclosure and different parts of the specification (including embodiments described only in the Examples) can be combined with one or more other embodiments of this disclosure, unless explicitly disclaimed or improper, and are so disclosed as embodiments to the disclosure. Combination of embodiments are not limited to those specific combinations described in the multiple dependent embodiments of this disclosure.

[0013] All of the publications, patents and published patent applications referred to inthis application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0014] Throughout this specification, the word “comprise” or variations such as“comprises” or “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0015] Any example(s) following the term “e.g.” or “for example” is not meant to beexhaustive or limiting.

[0016] The term “including” or “includes” is used to mean “including but not limitedto.” “Including” and “including but not limited to” are used interchangeably.

[0017] Unless otherwise required by context, singular terms shall include pluralitiesand plural terms shall include the singular.

[0018] The articles “a”, “an” and “the” are used herein to refer to one or to more thanone (i.e., to at least one) of the grammatical object of the article.

[0019] As used herein, the term “about” refers to a value or parameter that includes(and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. Numeric ranges are inclusive of the numbers defining the range. Unless specified otherwise, the term “about” when used in the context of a dosage of a compound to be administered to a patient, permits a variation of ±10% of a given value or range. As used herein, the term “about” when used in the context of days since a subject suffering from ASR or ASD has experienced or been exposed to a traumatic event permits a variation of ± 2 days. As used herein, the term “about” when used in the context of administration periods and suspension periods of treatment permits a variation of ±5 days. As used herein, the term “about” when used in the context of time after a traumatic event permits a variation of 5% of a given time. As used herein, the term “within about X day(s)” when used in the context of days after a traumatic event refers to treatment at any time up to about X days after the traumatic event. For example, “within about 1 day” refers to treatment at any time up to about 1 day after the traumatic event, e.g., about 24 hours, less than about 24 hours, less than about 23 hours, less than about 22 hours, less than about 21 hours, less than about 20 hours, less than about 19 hours, less than about 18 hours, less than about 17 hours, less than about 16 hours, less than about 15 hours, less than about 14 hours, less than about 13 hours, less than about 12 hours, less than about 11 hours, less than about 10 hours, less than about 9 hours, less than about 8 hours, less than about 7 hours, less than about 6 hours,less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours or less than about 1 hour after the traumatic event.

[0020] The term “or” as used herein should be understood to mean “and / or,” unless thecontext clearly indicates otherwise.

[0021] Notwithstanding that the disclosed numerical ranges and parameters areapproximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range of “1 to 10” should be considered to include any and all subranges between (and inclusive of) the minimum value of 1 and the maximum value of 10; that is, all subranges beginning with a minimum value of 1 or more, e.g., 1 to 6.1, and ending with a maximum value of 10 or less, e.g., 5.5 to 10.

[0022] Where aspects or embodiments are described in terms of a Markush group or othergrouping of alternatives, the present application encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, and also the main group absent one or more of the group members, notwithstanding such individuals and subgroups are not specifically referred to in this disclosure.

[0023] Exemplary methods and materials are described herein, although methods andmaterials similar or equivalent to those described herein can also be used in the practice or testing of the various aspects and embodiments. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0024] In order that the disclosure may be more readily understood, certain terms are firstdefined. These definitions should be read in light of the remainder of the disclosure as understood by a person of ordinary skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. Additional definitions are set forth throughout the detailed description.

[0025] “Administering” or “administration of” a substance, a compound or an agent to asubject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered in conventional ways known in the art, for example, parenterally (e.g., intravenously, intramuscularly, subcutaneously, inhalationally, intranasally), transmucosally (e.g., sublingually, buccally), orally, rectally, vaginally or transdermally. The administration can also be performed, for example, once, or a plurality of times per day, and / or over one or more longer periods. In some aspects, theadministration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self-administer a drug, or to have the drug administered by another and / or who provides a patient with a prescription for a drug is administering the drug to the patient. The pharmaceutical composition of this disclosure may be administered simultaneously or concurrently (i.e., with a time separation of no more than about 15 minutes and in some embodiments no more than 10 minutes) or sequentially (i.e., with a time separation of more than about 15 minutes and in some embodiments more than one hour or up to 4-6 hours).

[0026] As used herein, “administering daily” refers to the administration of apharmaceutical composition of this disclosure according to any one of the administration methods stated herein once or multiple times daily. For example, a daily amount of 5 mg / day can be administered in one dose or in several doses totaling 5 mg over the course of a day. In some embodiments the dosage regime of the one or several doses is once daily.

[0027] As used herein, the term “acute stress reaction” or ASR refers to a stress responseoccurring within 72 hours of a traumatic event, including a criterion A traumatic event. In some embodiments, ASR comprises symptoms selected from one or more of ringing ears, feeling faint, nausea, blurred vision, dizziness, trembling, light sensitivity, noise sensitivity, headache, fatigue, restlessness, intrusion, avoidance, hyperarousal symptoms, sadness, numbness, severe anxiety, dissociative symptoms, pain, cognitive impairment symptoms, re- experiencing the traumatic event, or somatic symptoms. If symptoms persist for more than about 72 hours after the traumatic event, the ASR is classified as ASD and the symptoms are classified as ASD symptoms. If symptoms persist longer than about one month after the traumatic event, the disorder is considered to have evolved or developed into PTSD.

[0028] As used herein, the term “acute stress disorder” or ASD refers to a disorder thatdevelops after experience of or exposure to a traumatic event, including a criterion A traumatic event and is characterized by severe anxiety, dissociation, reexperiencing the traumatic event, avoidance, and distress and other symptoms associated with ASR which persist longer than 72 hours. ASD is associated with many of the same symptoms as ASR or PTSD, however ASD lasts from about 3 days to about one month and generally occurs within a few days to about one month after the traumatic event. The subject must also have at least 9 symptoms from any of the following five categories of symptoms: (1) intrusion symptoms (e.g., recurrent, involuntary, and intrusive distressing memories of the event; recurrent distressing dreams of the event; dissociative reactions; or feeling intense psychological or physiologic distress when reminded of the event); (2) negative mood (e.g., persistent ability to experience positiveemotions); (3) dissociative symptoms (e.g., an altered sense of reality, or an inability to remember an important part of the traumatic event); (4) avoidance symptoms (e.g., efforts to avoid distressing memories, thoughts, or feelings associated with the event; or efforts to avoid external reminders associated with the event); or (5) arousal symptoms (e.g., sleep disturbance, irritability or angry outbursts, hypervigilance, difficulty concentrating or exaggerated startle response) to be diagnosed with ASD. Additionally, further derealization and depersonalization symptoms such as feelings such as not knowing where you are or feeling as if you are outside of your body are more likely to be associated with ASD than with PTSD. While ASD is not necessarily a predictor for the development of PTSD, those who suffer from ASD frequently develop PTSD.

[0029] As used herein, the term “post-traumatic stress disorder” or PTSD refers to adisorder that develops after experience of or exposure to a traumatic event, including a criterion A traumatic event and is characterized by symptoms including, but not limited to, difficulty with sleep, nightmares, irritability, difficulty concentrating, hypervigilance, and a persistent exaggerated startle response. Those suffering from PTSD must have: (1) at least one intrusion symptom (e.g., recurrent, involuntary, and intrusive distressing memories of the event; recurrent distressing dreams of the event; acting or feeling as if the event were happening again, ranging from having flashbacks to completely losing awareness of the present surroundings; or feeling intense psychological or physiologic distress when reminded of the event); (2) at least one avoidance symptom (e.g., efforts to avoid distressing memories, thoughts, or feelings associated with the event; or efforts to avoid external reminders associated with the event); (3) at least two symptoms of negative effect on cognition and mood (e.g., memory loss for significant parts of the event (dissociative amnesia); persistent and exaggerated negative beliefs or expectations about oneself, others, or the world; persistent distorted thoughts about the cause or consequences of the trauma that lead to blaming self or others, persistent negative emotional state (e.g., fear, horror, anger, guilt, shame); markedly diminished interest or participation in significant activities; feeling of detachment or estrangement from others; or persistent inability to experience positive emotions (e.g., happiness, satisfaction, loving feelings)); or (4) at least two arousal or reactivity symptoms (e.g., sleep disturbance, irritability or angry outbursts, reckless or self-destructive behavior, problems with concentration, hypervigilance, or exaggerated startle response). PTSD can be subtyped further as dissociative PTSD. This subtype is characterized by symptoms such as depersonalization and derealization. Depersonalization symptoms include feelings as if oneself is not real, and derealization symptoms include feelings as if the world is not real.

[0030] As used herein, the term “treat” and its cognates refer to a full or partialamelioration of at least one of the symptoms associated with ASR, ASD or PTSD, and in some aspects remission of ASR or ASD, and in some aspects prevention of their evolution to PTSD, or in the likelihood of developing PTSD, or a reduction in the severity or frequency of the resulting PTSD symptoms. In other aspects of this disclosure, the term “treat” means to aid in the recovery from the stress effects of a traumatic event. Methods to measure the full or partial improvement or amelioration of ASR, ASD or PTSD symptoms are known by the skilled in the art and include the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), the Patient Reported Outcomes Measurement Information System (PROMIS) scales for anxiety and depression, the Insomnia Severity Index (ISI), the Life Events Checklist (LEC), the Clinician Global Impression-Improvement (CGI-I) scale, the Sheehan Disability Scale (SDS), the Patient Global Impression of Change scale (PGIC), the PTSD Check List for DSM-5 (PCL-5), the Numerical Rating Scale (NRS) and the general mental and physical health (SF- 12) scale. An improved score using these methods is indicative of successful “treatment.”

[0031] As used in the present disclosure, the Clinician-Administered PTSD Scale forDSM-5 (CAPS-5) is a 30-item structured interview that is used to assess ASD or PTSD symptoms. The first 20 questions target the symptoms of PTSD as defined in DSM-5, and some of the remaining items target the onset, duration, and impact of symptoms on the social and occupational functioning of the subject. The final two items (items 29 and 30) focus on derealization symptoms and depersonalization symptoms to allow subtyping of PTSD, the ‘dissociative’ subtype, if either or both is present at a clinically significant level. These two symptoms also are among the nine or more required for a diagnosis of ASD. A decrease of about 5 ±3 points in the subject’s CAPS-5 score is indicative of a successful “treatment.”

[0032] As used in the present disclosure, the Numerical Rating Scale (NRS) is a numericassessment of worst pain severity, or 20 other common somatic symptoms, including “post- concussive” symptoms within 24-hour recall using an 11-point scale ranging from 0 (least) to 10 (worst).

[0033] As used in the present disclosure, the Patient-Reported Outcome MeasurementInformation System (PROMIS) is a National Institutes of Health (NIH) funded initiative to develop instruments to be used across chronic conditions. Three PROMIS scales include the PROMIS-Sleep disturbance scale, the PROMIS-Fatigue scale, and the PROMIS-Cognitive function scale. The scales provide questions for assessing sleep quality, severity of fatigue and cognitive function abilities, respectively, over the past 7 days using a 5-point scale ranging from 1 (not at all) to 5 (very much).

[0034] As used in the present disclosure, the Insomnia Severity Index (ISI) is a 7-itemself-reported questionnaire assessing the nature, severity, and impact of insomnia. The dimensions evaluated are severity of sleep onset, sleep maintenance and early morning awakening problems, sleep dissatisfaction, interference of sleep difficulties with daytime functioning, noticeability of sleep problems by others and distress caused by the sleep difficulties. The scores range from 0 (no problem) to 4 (very severe problem) yielding a total score ranging from 0 to 28 which is interpreted as: 0-7 = Absence of insomnia, 8-14 = Sub- threshold insomnia, 15-21 = Moderate insomnia, or 22-28 = Severe insomnia.

[0035] As used in the present disclosure, the SF-12 is a 12-item survey which is a genericassessment of health-related quality of life from the subject’s perspective. The survey is administered as a questionnaire and can be self-administered or completed through an interview.

[0036] As used in the present disclosure, the Life Events Checklist (LEC) is a self-reportmeasure designed to screen for potentially traumatic events in a subject’s lifetime. The LEC assesses exposure to 16 events known to potentially result in PTSD or distress and includes one additional item assessing any other extraordinarily stressful event not captured in the first 16 items.

[0037] As used in the present disclosure, the Clinician Global Impression-Improvement(CGI-I) scale is a 7-point scale that assesses how much the subject’s illness has improved or worsened relative to a baseline state at the beginning of the intervention.

[0038] As used in the present disclosure, the Sheehan Disability Scale (SDS), is a brief,5-item self-report tool that assesses functional impairment in work / school, social life, and family life. The scores range from 0 to 10 for each dimension for a total score ranging from 0 (unimpaired) to 30 (highly impaired).

[0039] As used in the present disclosure, the Patient Global Impression of Change scale(PGIC), is a 7 point scale depicting a patient’s rating of overall improvement after administration of a therapy. Patients rate their change as “1 or very much improved,” “much 2 or improved,” “3 or minimally improved,” “4 or no change,” “5 or minimally worse,” “6 or much worse,” or “7 or very much worse.”

[0040] As used in the present disclosure, the PTSD Check List for DSM-5 (PCL-5), is a20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD which are categorized into four symptom clusters and represented in the PCL-5 by the following subscales: 1) Re-experiencing (Criterion B; items 1-5): which measures the persistent re- experiencing of the traumatic event(s) through intrusive thoughts, nightmares, flashbacks, ordistressing memories.; 2) Avoidance (Criterion C; items 6-7): which assesses efforts to avoid thoughts, feelings, or reminders associated with the traumatic event; 3)Negative Alterations in Cognition and Mood (Criterion D, items 8-14): which measures the negative impact on thoughts and feelings that began or worsened after the traumatic event; and 4) Hyperarousal (Criterion E; items 15-20): which measures heightened arousal and reactivity that may present as difficulty sleeping, irritability, angry outbursts, difficulty concentrating, hypervigilance, and an exaggerated startle response .Responses for each symptom are answered using a five-point scale (where 4 = extremely, and 0 = not at all), for a total score ranging from 0 to 80. A PCL- 5 cut-off score between 31-33 is indicative of probable PTSD.

[0041] As used in the present disclosure, the “Post-traumatic stress (PTS) predictiontool” is an 8-question predictive tool that can be completed within 1-2 minutes and identifies individuals at high risk of ASR, ASD, and PTSD symptoms.

[0042] As used in the present disclosure, “adverse event” or AE refers to any untowardmedical occurrence associated with the use of an intervention in a subject, whether or not considered intervention-related. An adverse event can be any symptom, sign, illness or experience that develops or worsens in severity during the course of the study. Intercurrent illness or injuries are regarded as adverse events. Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: results in study withdrawal, is associated with a serious adverse event, is associated with clinical signs or symptoms, leads to additional treatment or to further diagnostic tests, or is considered by the investigator to be of clinical significance. An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator or sponsor, it results in any of the following outcomes: death, life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly / birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.

[0043] As used herein, the terms “prevent”, “preventing” and “prevention” refer to theelimination of the recurrence or onset of, or a reduction in one or more symptoms of a condition or disorder (e.g., ASR, ASD or PTSD) in a subject as a result of the administration of a therapy(e.g., a therapeutic agent such as cyclobenzaprine or a pharmaceutically acceptable salt thereof).

[0044] As used herein, the term “subject”, “patient”, or “individual” are usedinterchangeably and preferably refer to a human being.

[0045] As used herein, the term “stress recovery” refers to the improvement oramelioration of a stress response resulting from a traumatic event which may evolve into ASR, ASD or PTSD.

[0046] As used herein, the term “cyclobenzaprine” or 3-(5H-dibenzola[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1 propanamine, refers to cyclobenzaprine in the form of the free base. In some embodiments, the cyclobenzaprine is a pharmaceutically acceptable salt. In some embodiments, the cyclobenzaprine is an acid salt. In some embodiments, the cyclobenzaprine acid salt is cyclobenzaprine hydrochloride (cyclobenzaprine HCl). See e.g., WO2013 / 188847, incorporated herein by reference). In some embodiments of this disclosure, the cyclobenzaprine HCl may also be in the form of a eutectic of cyclobenzaprine HCl and mannitol, wherein the eutectic ratio is either 75%±2% cyclobenzaprine HCl by weight and 25%±2% β-mannitol by weight, or 65%±2% cyclobenzaprine HCl by weight and 35%±2% δ-mannitol by weight. In some embodiments of this disclosure, the cyclobenzaprine HCl may also be in the form of a granule comprising a β-mannitol core and a δ-mannitol-cyclobenzaprine HCl eutectic outer surface wherein the eutectic ratio is 65%±2% cyclobenzaprine HCl by weight and 35%±2% δ- mannitol by weight. Exemplary cyclobenzaprine HCl-mannitol eutectic compositions can be found in U.S. Pat. No.9,636,408, U.S. Pat. No.9,956,188, U.S. Patent No.10,357,465, U.S. Patent No.10,117,936, U.S. Patent No.10,864,175, and U.S. Patent No.11,839,594 which are hereby incorporated by reference in their entireties. In some embodiments of this disclosure, the cyclobenzaprine acid salt (e.g., cyclobenzaprine HCl) or the cyclobenzaprine HCl-mannitol eutectic is combined with a basifying agent.

[0047] As used herein, the term a “eutectic” or “in the form of a eutectic” refers to amixture of chemical compounds or elements that has a single chemical composition that melts at a lower temperature than any other composition made up of the same ingredients. A composition comprising a eutectic is known as a eutectic composition and its melting temperature is known as the eutectic temperature. Eutectic compositions often have a higher stability and / or dissolution rates than their non-eutectic counterparts. Because eutectics enhance dissolution, they can be employed to increase permeability in solid dispersions and dispersion systems.

[0048] As used herein, “basifying agent” is selected from a group consisting of potassiumdihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KH2PO4),dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K2HPO4), tripotassium phosphate (K3PO4), sodium dihydrogen phosphate (monosodium phosphate, monobasic sodium phosphate, NaH2PO4), disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, Na2HPO4), trisodium phosphate (Na3PO4), bicarbonate or carbonate salts, dipotassium citrate, tripotassium citrate, disodium citrate, trisodium citrate, borate, hydroxide, silicate, nitrate, dissolved ammonia, the conjugate bases of some organic acids (including bicarbonate), and sulfide. In some embodiments, the basifying agent is dipotassium hydrogen phosphate (K2HPO4). In some embodiments, the basifying agent is potassium dihydrogen phosphate (KH2PO4). In some embodiments, the basifying agent is disodium hydrogen phosphate (Na2HPO4). In some embodiments, the basifying agent is tripotassium citrate. In some embodiments, the basifying agent is trisodium citrate.

[0049] As used herein, “TNX-102 SL” refers to a low dose, sublingual formulation of a75% by weight cyclobenzaprine HCl-25% by weight β-mannitol eutectic and a basifying agent, as described in PCT Application No. WO2014 / 145156, which is incorporated herein by reference. TNX-102 SL is formulated to allow transmucosal absorption of the cyclobenzaprine free base into the blood, and without wishing to be bound by theory, uniquely reduces production of a long half-life active metabolite of cyclobenzaprine, norcyclobenzaprine, due to its bypass of first-pass hepatic metabolism. This allows much improved long-term efficacy. See, e.g., WO2013 / 188847, incorporated herein by reference.

[0050] As used herein, “pharmaceutically acceptable carrier” refers to any diluent orexcipient that is compatible with the other ingredients of the formulation, and which is not deleterious to the recipient. The pharmaceutically acceptable carrier can be selected on the basis of the desired route of administration, in accordance with standard pharmaceutical practices.

[0051] As used herein, the term “therapeutically effective amount” of cyclobenzaprineor a pharmaceutically acceptable salt thereof refers to the amount of the compound (or in the context of a pharmaceutically acceptable salt, a eutectic or a composition of this disclosure, that comprises an amount of the compound) that treats or prevents the development of ASR or ASD or eliminates or alleviates at least one of the symptoms associated with ASR or ASD. In some aspects of this disclosure, the “therapeutically effective amount” prevents the development of PTSD or its evolution from ASR or ASD, or reduces the likelihood of that development. In some aspects of this disclosure, the “therapeutically effective amount” reduces the severity or frequency of one or more symptoms associated with PTSD. A physician can readily determine when symptoms are prevented or alleviated or eliminated, for examplethrough clinical observation of a subject, or through reporting of symptoms by the subject or its caregiver during the course of treatment. One skilled in the art can readily determine the amount of a cyclobenzaprine or pharmaceutically acceptable salt thereof to be administered, by taking into account factors such as the size, weight, age and sex of the subject, the extent of disease penetration or persistence and severity of symptoms, and the route of administration.

[0052] As used herein, the term “traumatic event”, as the causative factor of ASR, ASDor PTSD refers to a direct or indirect personal experience, or exposure to an event, that causes physical, emotional, spiritual or psychological harm. Traumatic events may preferentially include criterion A traumatic events which involve actual or threatened death or serious injury, or other threat to a subject’s physical integrity; or witnessing an event that involves death, injury, or a threat to the physical integrity of another person; or learning about unexpected or violent death, serious harm, or threat of death or injury experienced by a family member or other close associate. Examples of traumatic events that are experienced directly include, but are not limited to, military combat, violent personal assault, being kidnapped, being taken hostage, terrorist attack, torture, incarceration as a prisoner of war or in a concentration camp, natural or manmade disasters, severe automobile accidents or motor vehicle collisions, or being diagnosed with a life-threatening illness. Traumatic events may also include exposure to divorce, abandonment, and imprisonment. For children, sexually traumatic events may include developmentally inappropriate sexual experiences without threatened or actual violence or injury. Witnessed, or indirect, events include, but are not limited to, observing the serious injury or unnatural death of another person due to violent assault, accident, war or disaster or unexpectedly witnessing a dead body or body parts. Events experienced by another that are learned about include, but are not limited to, violent personal assault, serious accident, or serious injury experienced by a family member or a close friend; learning about the sudden, unexpected death of a family member or a close friend; or learning that one’s child has a life- threatening disease or through exposure to aversive details of trauma usually through the course of professional duties, e.g., first responders or medics. The disorder may be especially severe or long lasting when the stressor is of human design (e.g., torture, rape). Shortly after the trauma occurs, people may develop symptoms such as nightmares, avoidance, hyperarousal, severe anxiety, pain, cognitive impairment, somatic symptoms, intrusive memories, exaggerated startle response, feelings such as not knowing where you are, or feelings as if you are outside of your body. If these symptoms develop within about 72 hours of the traumatic event, the response to the event is termed ASR. If these symptoms are of sufficient severityand persist for beyond about 72 hours, the syndrome is termed acute stress disorder (ASD). If the symptoms persist for about 4 weeks or more, the disorder may evolve into PTSD. Methods for Treating or Preventing Acute Stress Reaction (ASR) or Acute Stress Disorder (ASD)

[0053] In one aspect, the present disclosure relates to a method for treating orpreventing acute stress reaction (ASR) or one or more associated symptoms thereof or for treating or preventing acute stress disorder (ASD) or one or more associated symptoms thereof in a subject who has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt of cyclobenzaprine and a pharmaceutically acceptable carrier.

[0054] In some embodiments, the subject has experienced or been exposed to atraumatic event within about 7 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within about 6 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within about 5 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within about 4 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within about 3 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within about 2 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within about 1 day (i.e., 24 hours) prior to the administration of a pharmaceutical composition of this disclosure.

[0055] In some embodiments, the subject has experienced or been exposed to atraumatic event within 7 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within 6 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within 5 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to atraumatic event within 4 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within 3 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within 2 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within 1 day (i.e., 24 hours) prior to the administration of a pharmaceutical composition of this disclosure.

[0056] In some embodiments, the traumatic event is a criterion A traumatic event. Insome embodiments, the criterion A traumatic event is selected from a motor vehicle collision, military combat, violent personal assault, being kidnapped, being taken hostage, terrorist attack, torture, incarceration as a prisoner of war or in a concentration camp, natural or manmade disasters, or being diagnosed with a life-threatening illness. In some embodiments, the criterion A traumatic event is a motor vehicle collision. In some embodiments, the criterion A traumatic event is military combat. In some embodiments, the criterion A traumatic event is a violent personal assault. In some embodiments, the criterion A traumatic event is being kidnapped. In some embodiments, the criterion A traumatic event is being taken hostage. In some embodiments, the criterion A traumatic event is a terrorist attack. In some embodiments, the criterion A traumatic event is torture. In some embodiments, the criterion A traumatic event is incarceration as a prisoner of war or in a concentration camp. In some embodiments, the criterion A traumatic event is a natural or manmade disaster. In some embodiments, the criterion A traumatic event is being diagnosed with a life-threatening illness.

[0057] In some embodiments, the pharmaceutical composition of this disclosure isadministered for about 14 days. In some embodiments, the pharmaceutical composition is administered for at least 14 days. In some embodiments, the pharmaceutical composition is administered for less than or equal to 14 days. In some embodiments, the pharmaceutical composition is administered for 14 days. In some embodiments, the pharmaceutical composition is administered for as long as necessary to have the desired effect on the ASR, ASD, PTSD, their associated symptoms, the stress occasioned by experiencing or being exposed to a traumatic event.

[0058] In some embodiments, the pharmaceutically acceptable salt of cyclobenzaprinein the pharmaceutical composition used in the methods of this disclosure is a cyclobenzaprine acid salt. In some embodiments, the cyclobenzaprine acid salt is cyclobenzaprine HCl.

[0059] In some embodiments, the cyclobenzaprine HCl used in the methods of thisdisclosure is in the form of a mannitol-eutectic. In some embodiments, the mannitol-eutectic used in the methods of this disclosure is selected from the group consisting of a 75% ± 2% by weight cyclobenzaprine HCl and 25% ± 2% by weight β-mannitol eutectic, a 65% ± 2% by weight cyclobenzaprine HCl and 35% ± 2% by weight δ-mannitol eutectic, a mixture of a 75% ± 2% by weight cyclobenzaprine HCl and 25% ± 2% by weight β-mannitol and a 65% ± 2% by weight cyclobenzaprine HCl and 35% ± 2% by weight δ-mannitol eutectic, and a granule comprising an outer layer of a 65% ± 2% by weight cyclobenzaprine HCl and 35% ± 2% by weight δ-mannitol eutectic and an inner layer of β-mannitol. In some embodiments, the mannitol-eutectic used in the methods of this disclosure is a 75% ± 2% by weight cyclobenzaprine HCl and 25% ± 2% by weight β-mannitol eutectic.

[0060] In some embodiments of this disclosure, the composition comprising thecyclobenzaprine HCl-mannitol eutectic used in the methods of this disclosure further comprises a basifying agent. In some embodiments, the basifying agent used in the methods of this disclosure is selected from a group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. In some embodiments, the basifying agent used in the methods of this disclosure is potassium dihydrogen phosphate. In some embodiments, the basifying agent used in the methods of this disclosure is dipotassium hydrogen phosphate. In some embodiments, the basifying agent used in the methods of this disclosure is tripotassium phosphate. In some embodiments, the basifying agent used in the methods of this disclosure is sodium carbonate. In some embodiments, the basifying agent used in the methods of this disclosure is sodium bicarbonate. In some embodiments, the basifying agent used in the methods of this disclosure is calcium carbonate. In some embodiments, the basifying agent used in the methods of this disclosure is calcium bicarbonate. In some embodiments, the basifying agent used in the methods of this disclosure is TRIS buffer. In some embodiments, the basifying agent used in the methods of this disclosure is sodium dihydrogen phosphate. In some embodiments, the basifying agent used in the methods of this disclosure is disodium hydrogen phosphate. In some embodiments, the basifying agent used in the methods of this disclosure is trisodium phosphate. In some embodiments, the basifying agent used in the methods of this disclosure is potassium carbonate. In some embodiments, the basifying agent used in the methods of thisdisclosure is potassium bicarbonate. In some embodiments, the basifying agent used in the methods of this disclosure is potassium acetate. In some embodiments, the basifying agent used in the methods of this disclosure is sodium acetate. In some embodiments, the basifying agent used in the methods of this disclosure is dipotassium citrate. In some embodiments, the basifying agent used in the methods of this disclosure is tripotassium citrate. In some embodiments, the basifying agent used in the methods of this disclosure is disodium citrate. In some embodiments, the basifying agent used in the methods of this disclosure is trisodium citrate.

[0061] In some embodiments, the pharmaceutical compositions used in the methods ofthis disclosure comprise between 0.1 mg and 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure comprise between 1 mg and 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure comprise less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure comprise less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure comprise about 5.6 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical composition used in the methods of this disclosure comprises 5.6 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure comprise about 2.8 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure comprise 2.8 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure comprise between about 2.8 mg and about 5.6 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure comprise between 2.8 mg and 5.6 mg of cyclobenzaprine HCl.

[0062] In some embodiments, the pharmaceutical compositions used in the methods ofthis disclosure comprise a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt of cyclobenzaprine in the form of a cyclobenzaprine HCl- mannitol eutectic, and optionally a basifying agent, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is administered simultaneously or sequentially in two dosage units, wherein the combined amount of the cyclobenzaprine HCl in the two dosage units is about 5.6 mg. In some embodiments, the pharmaceutical composition used in the methodsof this disclosure comprises a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt of cyclobenzaprine in the form of a cyclobenzaprine HCl- mannitol eutectic, and optionally a basifying agent, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is administered simultaneously or sequentially in two dosage units, wherein the combined amount of the cyclobenzaprine HCl in the two dosage units is 5.6 mg. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are administered simultaneously in two dosage units, wherein each dosage unit comprises about 2.8 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are administered simultaneously in two dosage units, wherein each dosage unit comprises 2.8 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are administered in a single dosage unit comprising about 2.8 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are administered in a single dosage unit comprising 2.8 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are administered daily. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are administered once daily. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are administered at bedtime.

[0063] In some embodiments, the pharmaceutical compositions used in the methods ofthis disclosure are formulated for parenteral administration (e.g., intravenous administration, intramuscular administration, subcutaneous administration, inhalational administration, or intranasal administration), transmucosal administration (e.g., sublingual administration or buccal administration), oral administration, rectal administration, vaginal administration or transdermal administration. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated for parenteral administration. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated for intravenous administration. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated for intramuscular administration. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated for subcutaneous administration. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated for inhalational administration. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated for intranasal administration. In someembodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated for transmucosal administration. In some embodiments, pharmaceutical compositions used in the methods of this disclosure are formulated for sublingual administration. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated for buccal administration. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated for oral administration. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated for rectal administration. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated for vaginal administration. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated for transdermal administration. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated for palatal administration.

[0064] In some embodiments, the pharmaceutical compositions used in the methods ofthis disclosure are formulated as a tablet, a thin film, a liquid, a powder, a spray or a suppository. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated as a tablet. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated as a sublingual tablet. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated as a thin film. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated as a sublingual film. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated as a liquid. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated as a powder. In some embodiments, the pharmaceutical composition used in the methods of this disclosure is formulated as a sublingual powder. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated as a spray. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated as an oral spray. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated as a sublingual spray. In some embodiments, the pharmaceutical compositions used in the methods of this disclosure are formulated as a suppository.

[0065] In another aspect, the present disclosure relates to a method for preventing theonset of post-traumatic stress disorder (PTSD) or one or more associated symptoms thereof, reducing the likelihood of developing PTSD or its associated symptoms, or reducing thefrequency or severity of stress related symptoms of PTSD that may evolve from the ASR or ASD in a subject suffering from or at risk of ASR or ASD as the result of experiencing or being exposed to a traumatic event, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof (in some embodiments the pharmaceutical compositions of this disclosure comprise a cyclobenzaprine HCl mannitol eutectic and optionally a basifying agent) and a pharmaceutically acceptable carrier, wherein the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of the pharmaceutical composition.

[0066] In another aspect, the present disclosure relates to a method for preventing theevolution of acute stress reaction (ASR) or one or more associated symptoms thereof or acute stress disorder (ASD) or one or more associated symptoms thereof to post-traumatic stress disorder (PTSD) or one or more associated symptoms thereof in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of the pharmaceutical composition.

[0067] In another aspect, the present disclosure relates to a method for reducing theseverity or frequency of one or more post-traumatic stress disorder (PTSD)-associated symptoms in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of the pharmaceutical composition wherein the subject is suffering from or at risk of acute stress reaction (ASR) or one or more associated symptoms thereof or acute stress disorder (ASD) or one or more associated symptoms thereof.

[0068] In another aspect, the present disclosure relates to a method for improving stressrecovery in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of the pharmaceutical composition.

[0069] In some embodiments, the subject has experienced or been exposed to atraumatic event within about 7 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within about 6 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within about 5 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within about 4 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within about 3 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within about 2 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within about 1 day (i.e., 24 hours) prior to the administration of a pharmaceutical composition of this disclosure.

[0070] In some embodiments, the subject has experienced or been exposed to atraumatic event within 7 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within 6 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within 5 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within 4 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within 3 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within 2 days prior to the administration of a pharmaceutical composition of this disclosure. In some embodiments, the subject has experienced or been exposed to a traumatic event within 1 day (i.e., 24 hours) prior to the administration of a pharmaceutical composition of this disclosure.

[0071] The initiation of ASR symptoms generally occurs immediately (for examplebetween 30 minutes and 72 hours) following an ASR-causing traumatic event. Symptoms persisting for more than about 72 hours after the traumatic event, are classified as ASD symptoms. The symptoms then may become increasingly severe. If the severity or frequencyof the symptoms persists for more than about 4 weeks, the disorder may be termed PTSD. ASR and ASD share many of the same symptoms as PTSD, however ASD is generally more associated with dissociative symptoms, such as emotional disconnection, difficulty experiencing pleasure, temporary amnesia, depersonalization and derealization. It is thought that these dissociative symptoms may play a role in preventing the subject from processing the traumatic event fully, and may hinder the subject’s stress recovery process. Without wishing to be bound by theory, interventions as early as possible after a traumatic event may prevent some subjects from developing ASR or ASD and may prevent some subjects suffering from ASR or ASD from developing PTSD or at least reduce the severity or frequency of one or more symptoms associated with PTSD. By decreasing the amount of time between the traumatic event and the commencement of treatment, the efficacy of the treatment can be enhanced. In some embodiments, the treatment is commenced within 1 week of the traumatic event. In some embodiments, the treatment is begun the same day as the traumatic event. In other embodiments, the treatment is begun within about 2, 3 ,4, 5, 6, or 7 days of the event. In some embodiments, the traumatic event is classified as a criterion A traumatic event (e.g., a motor vehicle collision, military combat, violent personal assault, being kidnapped, being taken hostage, terrorist attack, torture, incarceration as a prisoner of war or in a concentration camp, natural or manmade disasters, or being diagnosed with a life-threatening illness). EXAMPLES Example 1: Cyclobenzaprine HCl Sublingual Formulation

[0072] The cyclobenzaprine HCl sublingual formulation used in some of the methodembodiments of this disclosure comprises a eutectic of cyclobenzaprine HCl and β-mannitol and a potassium phosphate, dibasic basifying agent. Table 1 shows the specific composition of a cyclobenzaprine HCl sublingual tablet useful in the methods of this disclosure.Table 1: Cyclobenzaprine HCl Sublingual Tablet CompositionaMannitol: about 0.7 mg of the 2.5 mg total amount is a component of the eutectic and the rest is diluent.bPearlitol®Flash is the trade name for an excipient containing about 80% mannitol and 20% corn starch.cCalculated as the HCl salt Example 2: Efficacy of Cyclobenzaprine HCl Sublingual Tablet in Treating Military- Related PTSD

[0073] A 12-week clinical trial of the cyclobenzaprine HCl sublingual tablet of Table1 was conducted in 24 outpatient psychiatric research clinics in the US, including two Veterans Administration centers and two academic medical centers (“trial P201”). The modified intent- to-treat (mITT) population totaled 231 subjects, 225 (97.4%) of whom were in military service during the time of the trauma. A total of 197 (85.2%) subjects were assessed as having an index trauma that was of the combat trauma-type. The study was powered to test the effects of the cyclobenzaprine HCl sublingual formulation 2.8 mg (N=90) versus placebo (N=92), with an underpowered cyclobenzaprine HCl sublingual formulation 5.6 mg group (N=49) to assess dose-response as well as tolerability of the higher dose.

[0074] As illustrated in Figure 1, on the primary outcome measure, change frombaseline in total Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score, the 2.8 mg group showed an early advantage at the Week 2 timepoint with a least-squares meandifference (LSMD) (+ / - standard error) (SE) over placebo of -3.2 (1.55), p=0.04, and the Week 4 timepoint with a LSMD -3.8 (1.76), p=0.03. That difference from placebo diminished and was not significant at the Week 8 (p=0.17) and Week 12 (p=0.25) timepoints. In contrast, the underpowered 5.6 mg group demonstrated a substantial signal over placebo at Weeks 2, 4 and 8, and which was on the cusp of significance at Week 12 (LSMD of -4.5 (2.31), p=0.053) by the mixed-effects model repeated measures (MMRM) primary analytic approach. A sensitivity analysis using MMRM with multiple imputation (MI) showed the 5.6 mg group was significantly more improved than placebo at Week 12 with LSMD of -5.0 (2.33), p=0.031. Thus, trial P201 provided preliminary evidence that the sublingual cyclobenzaprine HCl formulation 5.6 mg group substantially improved CAPS-5 total score over placebo as early as Week 2, with progressively greater separation at the Weeks 4, 8 and 12 timepoints, with this group on the cusp of significance at Week 12.

[0075] Retrospective analyses were performed to examine the effects of potentialconfounders on treatment response. Subgroups with either high or low treatment response were identified from trial P201 and from trial P301 (a separate 12-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose trial (5.6 mg of the cyclobenzaprine HCl sublingual formulation given at about the same time in two 2.8 mg doses) conducted to investigate the efficacy and safety of the sublingual cyclobenzaprine HCl formulation). Older patients with military-related PTSD from very distant traumas have traditionally been reported to be less responsive to treatment, so the effects of combat versus non-combat trauma, age and the time since index trauma (TST) were explored. Continuous variables were dichotomized by their approximate baseline median to create subgroups. For each subgroup analysis, the LS mean difference in Figure 2 is represented by a circle and horizontal line, representing the point estimate and 95% Confidence Interval (CI), respectively. Analysis outcome with p < 0.05 is represented by a square.

[0076] As seen in Figure 2A, there is a differential response to the sublingualcyclobenzaprine HCl formulation on the CAPS-5 total score based on TST at Week 4. The ≤ 9 years TST subgroup had clinically meaningful separation, with a mean difference from placebo in the total CAPS-5 of -6.6 points, whereas the > 9 years TST subgroup had a mean difference of -2.4 points. The subgroups of age and trauma type (combat versus non-combat) had little impact on treatment response. At Week 12 (Figure 2B), the single best discriminator of treatment response to the sublingual cyclobenzaprine HCl formulation was TST, where the subgroup ≤ 9 years TST separated by 6.7 points (p = 0.016, MMRM). The TST > 9 years subgroup failed to demonstrate any treatment effect with 5.6 mg of the sublingualcyclobenzaprine HCl formulation (difference from placebo = +0.2). Similar to Week 4, analysis of subgroups by age or trauma type indicated little impact on treatment response. These data suggest a clinically meaningful treatment response in those ≤ 9 years TST, and a dramatically greater response in those within 6 years TST. Example 3: Efficacy of Cyclobenzaprine HCl Sublingual Tablet in Treating and Managing Fibromyalgia

[0077] A randomized, double-blind placebo-controlled study in subjects withfibromyalgia (F304) was performed in 39 U.S. sites with a total of 503 subjects to study the effects of the sublingual cyclobenzaprine HCl formulation 5.6 mg, taken once daily at bedtime, on pain reduction. F304, met the primary efficacy endpoint, a reduction from baseline in the weekly average of daily diary pain scores at Week 14. The treatment group difference (sublingual cyclobenzaprine HCl formulation 5.6 mg minus placebo) in pain reduction was statistically significant (p = 0.010) in favor of the sublingual cyclobenzaprine HCl formulation. Because the analysis of the first key secondary efficacy endpoint, the proportion of subjects with a PGIC rating of “very much improved” or “much improved” at Week 14, did not meet statistical significance (p = 0.058), the results from the analyses of the remaining key secondary endpoints were considered descriptive. Nonetheless, each of the other 5 key secondary endpoints in the hierarchy showed favorable outcomes for the sublingual cyclobenzaprine HCl formulation versus placebo, including the changes from baseline at Week 14 in the following variables: Fibromyalgia Impact Questionnaire-Revised (FIQ-R) symptom domain scores (p = 0.007), FIQ-R function domain scores (p = 0.009), PROMIS Sleep Disturbance T-scores (p < 0.001), PROMIS Fatigue T-scores (p = 0.018), and weekly average of daily diary assessment of sleep quality (p < 0.001) (Table 2).Table 2. Results of F304 Primary and Secondary EndpointsExample 4: The Use of Cyclobenzaprine HCl sublingual tablet in reducing Acute Stress Reaction (ASR) and in preventing or reducing post-traumatic stress (PTS) symptoms following Motor Vehicle Collision (MVC)

[0078] A double-blind, placebo-controlled, randomized clinical trial to examine thesafety and efficacy of the sublingual cyclobenzaprine HCl formulations in reducing acute stressreaction (ASR) or acute stress disorder (ASD) symptoms and behavioral changes among patients presenting to the emergency department (ED) after a motor vehicle collision (MVC) is conducted as authorized to proceed by FDA. The clinical trial evaluates the efficacy of the sublingual cyclobenzaprine HCl formulation of Table 1 in improving neurocognitive function and in preventing post-traumatic stress (PTS) symptoms after an MVC or in reducing the severity or frequency of those symptoms. Enrollment Procedures and Eligibility

[0079] A total of 180 subjects are enrolled in this study. Eligible subjects meet thefollowing criteria: 1. Between the ages of 18 and 55 years;2. Admitted to the emergency department (ED) within 24 hours of MVC;3. Anticipated to be discharged home from the ED;4. Post-traumatic stress (PTS) prediction tool risk score ≥ 16 in the ED;5. Pain severity in the ED ≥ 4 (0-10 numeric rating scale);

[0080] Subjects meeting any of the following criteria are excluded from the study:1. Chronic daily opioid use prior to MVC (>20 mg oral daily morphineequivalents); 2. Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 daysafter their discontinuation due to risk of potential fatal drug-drug interactions; 3. Current or planned use of the following prohibited concomitant medicationsduring study participation: anticholinergic medications, guanethidine, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, mirtazapine, trazodone, nefazodone, MAO inhibitors, anticholinergic medications, guanethidine, potent cytochrome P450 subtype 3A4 inhibitor, St. John’s wort, or other prohibited concomitant medications;

[0081] Eligible subjects who consent to participate in the study receive a blood draw tocollect approximately 15 mL of blood to confirm eligibility and determine baseline blood values. The subjects are randomized in the ED and receive one sublingual tablet comprising 2.8 mg of the sublingual cyclobenzaprine HCl formulation (see Table 1) or placebo (1 tablet) in the ED as part of enrollment procedures. Subjects are discharged from the ED with a fourteen-day supply of the sublingual cyclobenzaprine HCl formulation of Table 1 or placebo. If the time between taking the first 2.8.mg tablet and the planned bedtime of the subject is lessthan 6 hours, subjects are instructed to take 1 additional tablet (2.8 mg of the sublingual cyclobenzaprine HCl formulation) the first night at bedtime, and 2 tablets (2.8 mg each) (in total 5.6 mg of the sublingual cyclobenzaprine HCl formulation) on subsequent nights at bedtime. If the time between taking the first 2.8 mg tablet and planned bedtime of the subject is greater than or equal to 6 hours, then subjects are instructed to take 2 tablets (2.8 mg each) (in total 5.6 mg of the sublingual cyclobenzaprine HCl formulation) the first night at bedtime and on subsequent nights at bedtime. Over the following 13 days, all subjects are instructed to take two 2.8 mg tablets (in total 5.6 mg of the sublingual cyclobenzaprine HCl formulation) at bedtime, ensuring consistent adherence to the prescribed dosage regimen. Study Assessments

[0082] Prior to initial administration of the sublingual cyclobenzaprine HClformulation (2.8 mg), and during the hours, days, and weeks after, subjects are given serial longitudinal assessments of psychological and somatic symptoms, neurocognitive function, and adverse events. All data are collected using FDA Title 21 CFR Part 11-compliant, web- based REDCap software. Domains assessed in the study are summarized in Table 3. ED and follow-up assessments are administered as self-report surveys. With the exception of neurocognitive tests, if subjects are unable to complete baseline or follow-up surveys via self- report, those surveys are completed via phone interviews. Assessments Prior To Study Medication Administration

[0083] The following assessments are conducted prior to initial administration of thesublingual cyclobenzaprine HCl formulation (2.8 mg) in the ED (Table 3).

[0084] Pre-MVC Characteristics: Available past medical history is obtained from theED nursing and physician records. Pre-MVC medication use is obtained as part of the ED evaluation, including specific questions addressing the quantity and frequency of pain medications used during the week prior to their ED visit. Demographics, contact information, pre-MVC trauma history (via the Life Events Checklist), and reported pre-MVC psychological characteristics (via PTSD Checklist for DSM-5, PCL-5), anxiety (via the PROMIS 4a, depressive (via the PROMIS 8b) are assessed. In addition, reported pre-MVC pain symptoms (location via modified regional pain scale, severity in each area with pain via 0-10 NRS) and somatic symptoms (20 common somatic symptoms, including “post-concussive” symptoms, each assessed via 0-10 NRS) are evaluated. Pre-MVC sleep (via Insomnia Severity Index) and general mental and physical health (via SF- 12) are also assessed.Table 3: Domains Assessed* Domains assessed via short (6 minutes) and long (24 minutes) neurocognitive assessments † Domains that assess Acute Stress Reaction (ASR) symptoms which are experienced prior to meeting criteria for ASD. Using the DSM-5 Criteria for ASD, symptoms can only be evaluated if they have persisted for at least 3 days and up to 1 month post-trauma. Symptoms of ASD (intrusion, negative mood, dissociation, avoidance, and arousal) are experienced prior to meeting criteria for ASD and are referred to as ASR symptoms.

[0085] MVC Characteristics: Information about the MVC is obtained from the subjectas part of the survey that enrolled subjects complete in the ED. The description of the event as well as the location, date, estimated time, and type of vehicle(s) involved in collision are reported. Location and severity of damage to vehicle are evaluated on a scale of no damage to severe damage. The situation of the subject is reported as a rider, occupant, or non-occupant. Any contact made to the subject’s body is assessed. In addition, the number and status(es) of other passengers are documented.

[0086] Peritraumatic Characteristics: Current distress is assessed using thePeritraumatic Distress Inventory. Sense of life threat during the MVC is assessed using a 0-10 numeric rating scale. Current pain and somatic symptoms, and expectations of mental and physical recovery, are also assessed via the AURORA 0-10 numeric rating scales. Treatment credibility and expectancy are assessed using the Credibility / Expectancy Questionnaire. In addition, twenty-two 0-10 numeric rating scale questions will be used to assess the severity of key ASR / ASD / PTSD symptoms: anxiety, hyperarousal, dissociation, sadness, re-experiencing, avoidance, numbing, somatic, (cognitive, general), and pain. Each domain is assessed via two survey items, so that in addition to repeated measures analyses of these responses according to treatment group, in secondary analyses latent variables can be developed for each construct, and fine-grain comparisons of symptom trajectories of different treatment groups can be performed.

[0087] Brief Neurocognitive Assessment: Psychomotor vigilance and responseinhibition (inhibitory control) are assessed using the Test My Brain Gradual Onset Continuous Performance Test one-minute task. Procedural reaction is assessed using the Test My Brain Choice Reaction Time Test one-minute task. Visual search and visual change detection are assessed via the Test My Brain Flicker Change Detection test one-minute task. Shooting / multiple object tracking test is performed using the Test My Brain Multiple ObjectTracking Test one-minute task. N-back / working memory test is performed using the Test MyBrain N-back test one-minute task. The total evaluation time of this assessment is 6 minutes.

[0088] Blood Draw: A blood sample of approximately 15 mL (equivalent to about 1tablespoon) is obtained to assess study eligibility: (1) general chemistries, including creatinine, blood urea nitrogen (BUN), carbon dioxide, glucose, sodium, chloride, and potassium; (2) liver function tests, including alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), serum bilirubin, total protein, and albumin; and (3) complete blood count, including white blood cell count, hemoglobin, and platelet count.

[0089] Urine Pregnancy Test: As described above, a pregnancy test is taken by womenwith childbearing potential, either as part of usual care or for the study. Assessments After Study Medication Administration and Prior to ED Discharge

[0090] The following assessments are carried out about 30 minutes and about 1 hourafter initial administration of the sublingual cyclobenzaprine HCl formulation (2.8 mg) and prior to the participants’ discharge from the ED (Table 3).

[0091] Adverse Event Assessment: Subjects are observed for adverse events throughouttheir ED evaluation period. Subjects are asked, “have you had any changes in your health that the study team should know about?” Subjects who report a change in their health status are asked follow-up questions, and the study site care team and study investigators are involved as necessary depending on the nature and severity of the reported event.

[0092] Brief “Flash Survey”: This brief, 22-question, 0-10 numeric rating scaleassessment measures anxiety, hyperarousal, dissociation, sadness, re-experiencing, avoidance, numbing, pain and somatic (cognitive, general) symptoms.

[0093] Brief Neurocognitive Assessment: The neurocognitive assessment describedabove is repeated 30 minutes and 1 hour after initial study drug administration.

[0094] Medication Use: Via self-report surveys, medication use is collected 1 week, 3weeks, 6 weeks, 12 weeks after initial study drug administration. Assessments After Study Medication Administration and After ED Discharge

[0095] The following assessments are conducted after the sublingual cyclobenzaprineHCl formulation (2.8 mg) is administered and after the participant’s discharge from the ED (Table 3).

[0096] Medication Use: Via self-report surveys, medication use is collected 1 week, 3weeks, 6 weeks, 12 weeks after initial administration of the sublingual cyclobenzaprine HCl formulation (2.8 mg).

[0097] Adverse Event Assessment: Via self-report surveys, subjects are asked, “haveyou had any changes in your health that the study team should know about?” Subjects who report a change in health status, or who do not respond to the survey, receive a phone call to determine if they have had a change in health status or to assess the details of their reported health status change. Such phone assessments are used to evaluate the details of any adverse events because conversation and the ability to ask follow-up questions is important. Adverse events are performed by study day, including on weekends, weekdays, and holidays. The study staff follows an on-call schedule to determine which staff member performs follow-upassessments on a specific day. Monitoring is designed to be performed most frequently during the administration of the sublingual cyclobenzaprine HCl formulation and immediately after, because these are the time periods when side effects are most likely. In addition to receiving regular adverse effect assessments, patients are given a toll-free number and a study email that they can use to contact the study team if they have questions, are experiencing any medication side effects, or wish to discuss any other study-related matters. Female subjects of childbearing potential are reminded to continue using a form of medically acceptable birth control while taking study medication.

[0098] In the event that a subject does report a change in health during a follow-uptelephone call, the study investigator on call can be contacted. The study team has extensive experience assessing adverse events and adjusting study drug dosing in response to adverse events as necessary. Any decision to stop the study medication is based on the severity of the adverse event and whether or not it is thought to be possibly or probably related to the sublingual cyclobenzaprine HCl formulation; this will ultimately be at the discretion of the principal investigator (PI) or study investigator on call. After any decision regarding study medication, the PI emails the investigative team and the coordinator, with the subject’s subject ID number (no patient health information (PHI)) and a description of the event and decision. This information is also entered into the study database. This PI email system, and twice weekly calls discussing study events, ensures consistent and shared decision-making between PIs.

[0099] In addition to subject-reported adverse events which can occur at any timeduring their participation, adverse event assessments are repeated 6 hours, 12 hours, 1 day, 2 days, 3 days, 2 weeks, 5 weeks, 8 weeks, 11 weeks, and 12 weeks after initial administration of the sublingual cyclobenzaprine HCl formulation.

[0100] Brief "Flash Survey": The brief flash survey described above is repeated 6hours, 12 hours, 1 day, 2 days, 3 days, 2 weeks, 5 weeks, 8 weeks, and 11 weeks after initial administration of the sublingual cyclobenzaprine HCl formulation.

[0101] Brief Neurocognitive Assessment: The neurocognitive assessment describedabove is repeated 6 hours, 12 hours, 1 day, 2 days, 3 days, 2 weeks, 5 weeks, 8 weeks, and 11 weeks after initial administration of the sublingual cyclobenzaprine HCl formulation.

[0102] Long Neurocognitive Assessment: The long version of the Brief NeurocognitiveAssessment is performed: Psychomotor vigilance and response inhibition (inhibitory control) (six-minute task), Procedural reaction (three-minute task), visual search and visual change detection (four-minute task), shooting / multiple object tracking test (six-minute test), and N- back / working memory test (five-minute test). This long neurocognitive assessment has a totalevaluation time of 24 minutes and is completed 1 week, 3 weeks, 6 weeks, and 12 weeks after initial administration of the sublingual cyclobenzaprine HCl formulation.

[0103] Standardized survey assessment of ASD symptoms: ASD symptom severity isassessed 1 and 3 weeks after trauma with the most widely used ASD measure, the ASD Scale.

[0104] Standardized survey assessments of post-traumatic stress disorder symptoms:PTSD symptom severity is assessed 6 weeks and 12 weeks after trauma using the PTSD Checklist for DSM-5 (PCL-5).

[0105] Standardized survey assessments of key outcome domains: To assess keyoutcome domains, 1, 3, 6, and 12 weeks after trauma, standardized survey assessments of sleep (Insomnia Severity Index), depression (PROMIS 8b), anxiety (PROMIS 4a), general mental and physical health (SF- 12), and global improvement (Clinical Global Impression) are performed. Pain location and severity are evaluated using the modified regional pain scale described above, in which pain severity in each area is assessed using a 0-10 NRS. Somatic symptoms, including “post-concussive” symptoms, are also assessed at these timepoints as described above. Health services utilization and medication use are also assessed using the AURORA Health Services and Medication Use Questionnaire. In addition, at the time of consent, permission from the subject is requested to review their medical records and records of their state’s prescription monitoring program (PDMP) at the end of the study. Study Stopping Criteria

[0106] The study is stopped for evaluation by the DSMB if 3 or more participants havesevere adverse events of grade 3 (severe) or higher severity per the CTCAE scale (see Appendix 1) that are possibly related to study drug, or any investigator judges it necessary for medical, safety, regulatory, or other reasons. The Principal Investigator (PI), the Data Safety Monitoring Board (DSMB), and the Institutional Review Board (IRB) have the ability to stop the trial if safety concerns arise. Individual Participant Stopping Criteria

[0107] If a participant develops a grade 3 or higher severity adverse event (per theCTCAE grading scale) or an SAE that is considered possibly related to study drug, the intervention is stopped in that participant. Study Analyses (i) Analyses for Primary Outcome Measure

[0108] To compare ASD symptom severity between intervention groups, patient-reported Acute Stress Disorder Scale (ASD Scale) scores are collected 7 and 21 days after MVC (primary outcome) are used. Changes in ASD scale scores over time are evaluated using mixed effects models (primary endpoint). A moderate effect size of 0.5 greater reduction in ASD every week compared to placebo is considered the minimal clinically important difference to achieve the primary outcome. ASD symptom severity is assessed 1 week and 3 weeks after trauma with the most widely used ASD measure, the ASD Scale. (ii) Analyses for Secondary Outcome Measure

[0109] To assess neurocognitive function between treatment groups, group differencesover time for each neurocognitive domain: psychomotor vigilance, procedural reaction, response inhibition / control, visual search and change detection, shooting task, and N- back / working memory, are separately evaluated. (iii) Exploratory Analysis

[0110] In addition to the neurocognitive secondary outcomes, a number of exploratoryadverse post-traumatic outcomes over time including pain and posttraumatic stress symptoms are evaluated. Post-traumatic symptomatology is examined using traditional survey assessments and a battery of flash surveys on the subject’s mobile phone. The proportion of individuals developing clinically significant chronic symptoms (as measured at the 3-month assessment), particularly moderate to severe chronic pain and PTSD symptoms, is also examined.

Claims

CLAIMS What is claimed is:

1. A method for treating or preventing (1) acute stress reaction (ASR) or one or moreassociated symptoms thereof or (2) acute stress disorder (ASD) or one or more associated symptoms thereof in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of the pharmaceutical composition.

2. The method according to claim 1, wherein the subject has experienced or beenexposed to the traumatic event within about 1, 2, or 3 days prior to the administration of the pharmaceutical composition.

3. The method according to claim 1 or 2, wherein the subject has experienced or beenexposed to the traumatic event within about 1 day prior to the administration of the pharmaceutical composition.

4. The method according to any one of claims 1-3, wherein the traumatic event is acriterion A traumatic event.

5. The method according to claim 4, wherein the criterion A traumatic event is selectedfrom a motor vehicle collision, military combat, violent personal assault, being kidnapped, being taken hostage, terrorist attack, torture, incarceration as a prisoner of war or in a concentration camp, natural or manmade disasters, or being diagnosed with a life-threatening illness.

6. The method according to any one of claims 1-5, wherein the pharmaceuticallyacceptable salt of cyclobenzaprine in the pharmaceutical composition is a cyclobenzaprine acid salt.

7. The method according to claim 6, wherein the cyclobenzaprine acid salt iscyclobenzaprine HCl.

8. The method according to claim 7, wherein the cyclobenzaprine HCl is in the form ofa mannitol-eutectic.

9. The method according to claim 8, wherein the mannitol-eutectic is selected from thegroup consisting of a 75% ± 2% by weight cyclobenzaprine HCl and 25% ± 2% by weight β-mannitol eutectic, a 65% ± 2% by weight cyclobenzaprine HCl and 35% ± 2% by weight δ-mannitol eutectic, a mixture of a 75% ± 2% by weight cyclobenzaprine HCl and 25% ± 2% by weight β-mannitol and a 65% ± 2% by weight cyclobenzaprine HCl and 35% ± 2% by weight δ-mannitol eutectic, and a granule comprising an outer layer of a 65% ± 2% by weight cyclobenzaprine HCl and 35% ± 2% by weight δ-mannitol eutectic and an inner layer of β-mannitol.

10. The method according to any one of claims 1-9, wherein the pharmaceuticalcomposition further comprises a basifying agent.

11. The method according to claim 10, wherein the basifying agent is selected from agroup consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

12. The method according to claim 11, wherein the basifying agent is dipotassiumhydrogen phosphate.

13. The method according to any one of claims 1-12, wherein the pharmaceuticalcomposition comprises between 0.1 mg and 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

14. The method according to claim 13, wherein the pharmaceutical compositioncomprises between 1 mg and 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

15. The method according to claim 14, wherein the pharmaceutical compositioncomprises less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

16. The method according to claim 15, wherein the pharmaceutical compositioncomprises less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

17. The method according to claim 15, wherein the pharmaceutical compositioncomprises about 5.6 mg of cyclobenzaprine HCl.

18. The method according to claim 15 or 16, wherein the pharmaceutical compositioncomprises about 2.8 mg of cyclobenzaprine HCl.

19. The method according to claim 17, wherein the pharmaceutical composition isadministered simultaneously or sequentially in two dosage units, and wherein each dosage unit comprises 2.8 mg of cyclobenzaprine HCl.

20. The method according to claim 17, wherein the pharmaceutical composition isadministered simultaneously or sequentially in two dosage units, and wherein the combined amount of the cyclobenzaprine HCl in the two dosage units is 5.6 mg.

21. The method according to any one of claims 1-20, wherein the pharmaceuticalcomposition is administered daily.

22. The method according to claim 21, wherein the pharmaceutical composition isadministered once daily.

23. The method according to claim 21 or 22, wherein the pharmaceutical composition isadministered at bedtime.

24. The method according to any one of claims 1-23, wherein the pharmaceuticalcomposition is formulated for sublingual, buccal, intranasal, oral, intravenous, intramuscular, subcutaneous, inhalational, transdermal, rectal, vaginal, or palatal administration.

25. The method according to claim 24, wherein the pharmaceutical composition isformulated as a tablet, a thin film, a liquid, a powder, a spray or a suppository.

26. The method according to claim 24, wherein the pharmaceutical composition isformulated for sublingual administration.

27. The method according to claim 26, wherein the pharmaceutical composition isformulated as a sublingual tablet, a sublingual film, a sublingual powder, or a sublingual spray.

28. The method according to any one of claims 1-27, wherein the symptoms of ASD areselected from the group consisting of reexperiencing symptoms, avoidance symptoms, arousal symptoms, difficulty with sleep, nightmares, irritability, difficulty concentrating, hypervigilance, persistent exaggerated startle response, feelings such as not knowing where you are, and feeling as if you are outside of your body.

29. The method according to any one of claims 1-27, wherein the symptoms of ASR areselected from the group consisting of intrusion, avoidance, hyperarousal symptoms, severe anxiety, negative mood, dissociative symptoms, pain, cognitive impairment symptoms, and somatic symptoms.

30. A method for preventing the onset of post-traumatic stress disorder (PTSD) or oneor more associated symptoms thereof in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of the pharmaceutical composition, wherein the subject is suffering from or at risk of developing acute stress reaction (ASR) or one or more associated symptoms thereof or acute stress disorder (ASD) or one or more associated symptoms thereof.

31. A method for preventing the evolution of acute stress reaction (ASR) or one or moreassociated symptoms thereof or acute stress disorder (ASD) or one or more associated symptoms thereof to post-traumatic stress disorder (PTSD) or one or more associated symptoms thereof in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject has experienced or beenexposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of the pharmaceutical composition.

32. A method for reducing the severity or frequency of one or more post-traumaticstress disorder (PTSD)-associated symptoms in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of the pharmaceutical composition wherein the subject is suffering from or at risk of acute stress reaction (ASR) or one or more associated symptoms thereof or acute stress disorder (ASD) or one or more associated symptoms thereof.

33. A method for improving stress recovery in a subject, comprising administering tothe subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject has experienced or been exposed to a traumatic event within about 1, 2, 3, 4, 5, 6, or 7 days prior to the administration of the pharmaceutical composition.

34. The method according to any one of claims 30-33, wherein the subject hasexperienced or been exposed to the traumatic event within about 1, 2 or 3 days prior to the administration of the pharmaceutical composition.

35. The method according to any one of claims 30-34, wherein the subject hasexperienced or been exposed to the traumatic event less than or equal to about 24 hours prior to the administration of the pharmaceutical composition.

36. The method according to any one of claims 30-35, wherein the traumatic event is acriterion A traumatic event.

37. The method according to claim 36, wherein the criterion A traumatic event isselected from a motor vehicle collision, military combat, violent personal assault, being kidnapped, being taken hostage, terrorist attack, torture, incarceration as a prisoner of war or in a concentration camp, natural or manmade disasters, or being diagnosed with a life-threatening illness.

38. The method according to any one of claims 30-32 and 34-37, wherein the associatedsymptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognition and mood symptoms, arousal and reactivity symptoms, difficulty falling sleep, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle response.

39. The method according to any one of claims 30-32 and 34-37, wherein the associatedsymptoms of ASD are selected from the group consisting of reexperiencing symptoms, avoidance symptoms, arousal symptoms, difficulty with sleep, nightmares, irritability, difficulty concentrating, hypervigilance, persistent exaggerated startle response, feelings such as not knowing where you are, and feeling as if you are outside of your body.

40. The method according to any one of claims 30-32 and 34-37, wherein the associatedsymptoms of ASR are selected from the group consisting of intrusion, avoidance, hyperarousal symptoms, severe anxiety, negative mood, dissociative symptoms, pain, cognitive impairment symptoms, and somatic symptoms.

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