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Title:
NOVEL METHODS
Document Type and Number:
WIPO Patent Application WO/2017/066730
Kind Code:
A1
Abstract:
Provided are novel methods for the treatment or prophylaxis of pain in an equine in need thereof comprising administering to the equine an effective amount of 1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

Inventors:
MCKINNEY, Anthony (INC.43 Thorndike Street,Suite S1-, Cambridge MA, 02141, US)
BYMASTER, Franklin (INC.43 Thorndike Street,Suite S1-, Cambridge MA, 02141, US)
Application Number:
US2016/057253
Publication Date:
April 20, 2017
Filing Date:
October 16, 2016
Export Citation:
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Assignee:
EBI LIFE SCIENCES, INC. (43 Thorndike Street, Suite S1-3Cambridge, MA, 02141, US)
International Classes:
C07D401/12; A61P3/00; A61P25/04; A61P25/20; A61P25/28; A61P43/00
Foreign References:
US20050282859A12005-12-22
Attorney, Agent or Firm:
JONES, Marya K. (Hoxie & Associates LLC, 75 Main StreetSuite 20, Millburn NJ, 07041, US)
Download PDF:
Claims:
CLAIMS

WHAT IS CLAIMED IS:

1. A method for the treatment or prophylaxis of pain, depression, and/or anxiety in an equine in need thereof comprising administering to the equine an effective amount of 1- (4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

2. The method of claim 1 comprising administering 0.5 to 50 mg/kg/day, e.g., 1 to 50 mg/kg/day, e.g., 2 to 45 mg/kg/day, e.g., 5 to 40 mg/kg/day, e.g., 10 to 35 mg/kg/day, e.g., 15 to 30 mg/kg/day, e.g., 15 to 25 mg/kg/day, of l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

3. The method of claim 1 or 2 comprising administering l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, once or twice daily.

4. The method of any one of claims 1-3, wherein l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is crystalline.

5. The method of any one of claims 1-4, wherein l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane is in pharmaceutically acceptable salt form.

6. The method of any one of claims 1-5, wherein l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane in pharmaceutically acceptable salt form is an acid addition salt.

7. The method of any one of claims 1-6, wherein l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane in pharmaceutically acceptable salt form is l-(4-methylphenyl)-3- azabicyclo[3.1.OJhexane hydrochloride.

8. The method of claim 7, wherein l-(4-methylphenyl)-3- azabicyclo[3.1. OJhexane hydrochloride is l-(4-methylphenyl)-3-azabicyclo[3.1. OJhexane hydrochloride polymorph form B.

9. The method of claim 8, wherein l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane hydrochloride polymorph form B is substantially free of other polymorphic forms.

10. The method of claim 7, wherein l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane hydrochloride is l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride polymorph form A.

11. The method of claim 10, wherein l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane hydrochloride polymorph form A is substantially free of other polymorphic forms.

12. The method of any one of claims 1-7 comprising administering an effective amount of (+)-l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

13. The method of any one of claims 1-7 comprising administering an effective amount of (-)-l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

14. The method of any one of claims 1-13 further comprising administering one or more of a local anesthetic, an opioid, an alpha-2 agonist, a non-steroidal anti-inflammatory drug (NSAID), a corticosteroid, a N-methyl-D-aspartate (NMD A) receptor antagonist, a NKl receptor antagonist, a calcium channel blocker, a muscle relaxant, and a bisphosphonate.

15. The method of claim 14, wherein the administration with l-(4-methylphenyl)- 3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is concurrent.

16. The method of claim 14, wherein the administration with l-(4-methylphenyl)- 3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is sequential. The method of any one of claims 1-16, wherein the pain is acute pain.

The method of any one of claims 1-16, wherein the pain is chronic pain.

The method of any one of claims 1-18, wherein the pain is neuropathic pain.

The method of any one of claims 1-19, wherein the equine is a horse.

The method of claim 20, wherein the horse is a racehorse (e.g., a thoroughbred

The method of claim 20, wherein the horse is a polo pony.

The method of any one of claims 1-22, wherein the equine is a foal (e.g., a foal

Description:
NOVEL METHODS

[0001] This application claims the benefit of U.S. Provisional Application No. 62/242,959 filed October 16, 2015, which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

[0002] The present disclosure relates to novel methods for the treatment or prophylaxis of pain, depression, and/or anxiety in an equine in need thereof comprising administering to the equine an effective amount of l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

BACKGROUND

[0003] Colic and lameness are important medical problems facing horses and their owners. It has been reported that each year approximately 2.4% of horses in the United States experience at least one episode of colic and 2.8% of horses become lame. The costs to owners in veterinary care, lost training time, loss of use, or death of the horse as a result of those conditions exceeds $500 million dollars. Management of pain is a major part of the treatment for both of those conditions.

[0004] Pain and anxiety management may be especially important with orthopedic injuries in horses because if the horse is agitated the injury can easily be aggravated, potentially leading to permanent disability and even death.

[0005] Currently, pain in horses is most frequently managed with NSAIDs (non-steroidal anti-inflammatory drugs). NSAIDs work by inhibiting cyclooxygenase (COX), which metabolizes arachidonic acid to prostaglandins. Certain prostaglandins activate prostaglandin receptors throughout the body, producing pain, inflammation, and fever. However, other prostaglandins are responsible for protecting the stomach and intestinal lining from acid and digestive enzymes and for regulating renal blood flow and maintaining normal renal tubular function. NSAIDs can decrease production of prostaglandins involved in inflammation, but can also decrease production of prostaglandins that protect organs. Accordingly, gastric ulcers can result from NSAID use. NSAIDs also have a number of other disadvantages for use in equines, particularly with long-term use. For instance, problems with NSAIDs include reduction in bone remodeling, colic, kidney damage, particularly in horses that are dehydrated and young and old horses, and diarrhea. NSAIDs are particularly dangerous in foals because their kidney function is not fully developed and because they are especially sensitive to the intestinal side effects.

[0006] Opioids may also be used to manage pain in horses, however, opioids have a number of disadvantages in this species as well. Problems with opioids include the special licensing and record keeping required; predisposition to ileus, constipation, and colic; and production of excitement (increased locomotor activity), agitation, disorientation, and ataxia. In addition, opioids may cause disorientation which may aggravate an injury, with potentially catastrophic consequences. Urine retention may result from large or repeated dosages of opioids which is an important postsurgical consideration in some horses.

[0007] Thus, there is a need for novel methods that may be used to treat pain in equines.

BRIEF SUMMARY

[0008] Provided is a method of treating pain in an equine in need thereof comprising administering to the equine an effective amount of l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane (bicifadine), in free or pharmaceutically acceptable salt form.

[0009] Also provided is a method of treating depression in an equine in need thereof comprising administering to the equine an effective amount of l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane (bicifadine), in free or pharmaceutically acceptable salt form.

[0010] Also provided is a method of treating anxiety (e.g., separation anxiety and/or generalized anxiety disorder) in an equine in need thereof comprising administering to the equine an effective amount of l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane (bicifadine), in free or pharmaceutically acceptable salt form.

[0011] Further areas of applicability of the present disclosure will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating preferred embodiments, are intended for purposes of illustration only and are not intended to limit the scope of the disclosure. DETAILED DESCRIPTION

[0012] As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range.

[0013] All references cited herein are hereby incorporated by reference in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.

[0014] l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, bicifadine, of Formula I below, is described in U.S. Patent Nos. 4,131,611 and 4,435,419 and U.S. Patent Publication No.

2013/0345280, all of which are h rence in their entireties.

Formula I

[0015] U.S. Patent No. 7,094,799 describes l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride as a non-narcotic analgesic. However, the use of l-(4-methylphenyl)-3- azabicyclo[3.1.OJhexane to treat pain in an equine in need thereof has not been previously disclosed.

[0016] l-(4-methylphenyl)-3-azabicyclo[3.1. OJhexane is a serotonin-norepinephrine- dopamine reuptake inhibitor. In equines, l-(4-methylphenyl)-3-azabicyclo[3.1. OJhexane is believed to be metabolized with a dual extrahepatic (MAO) and hepatic (cytochrome) metabolism. This dual non-renal mechanism of metabolism may relieve stress on the kidneys, especially in a horse with other causes of renal dysfunction (e.g., exertional rhabdomyolysis). In addition, because l-(4-methylphenyl)-3-azabicyclo[3.1. OJhexane may not significantly inhibit cyclooxygenase in equines, use of l-(4-methylphenyl)-3-azabicyclo[3.1. OJhexane may be less detrimental to the stomach and colon compared to NSAIDs. Long-term use of NSAIDs, for example with a soft tissue injury, can result in ulcers.

[0017] Further, anti-inflammatory activity is not necessarily desired with an orthopedic injury in a horse, because the anti-inflammatory activity may give the practitioner false belief that the injury has been cured leading an owner to push the horse and causing the horse further injury, potentially leading to a catastrophic outcome. Similar masking may also occur with colic. l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane has analgesic properties without classic anti-inflammatory activity. And, l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane's E

(norepinephrine) and 5-HT (serotonin) reuptake activity may benefit equines that are anxious or depressed due to an injury, pain, or other disease, for example, because of restricted activity.

[0018] It is well established that NSAIDS inhibit bone healing, however, l-(4-methylphenyl)- 3-azabicyclo[3.1.0]hexane may not inhibit bone healing.

[0019] Provided herein is a method of treating pain in an equine in need thereof comprising administering to the equine an effective amount of l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

[0020] l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane may be synthesized as described in U.S. Patent Nos. 4, 131,611 and 4,435,419.

[0021] As used herein, the singular forms "a," "an," and "the" include the plural reference unless the context clearly indicates otherwise.

[0022] As used herein, "l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane" is to be understood as embracing the compound in any form, for example, free or pharmaceutically acceptable salt form, e.g., as a pharmaceutically acceptable acid addition salt. Pharmaceutically acceptable salts are known in the art and include salts that are physiologically acceptable at the dosage amount and form to be administered, for example, hydrochloride salts.

[0023] "l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane" is also to be understood as embracing its enantiomers, crystalline and amorphous forms, and mixtures thereof.

"Crystalline form" and "polymorph" may be used interchangeably herein, and are meant to include all crystalline forms of l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, including, for example, solvates (including hydrates).

[0024] The (+) and (-) enantiomers of l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane are described by Epstein et al., Journal of Medicinal Chemistry, 1981, 24 (5), 481. See also U.S. Patent Nos. 4, 131,611, 4,231,935, and 4,435,419. In some embodiments, an effective amount of (+)-l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is used. In some embodiments, an effective amount of (-)-l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is used. In some embodiments, a mixture of (+)-l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, and (-)-l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is used (e.g., a racemic mixture, a mixture comprising > 50% (+)-l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or

pharmaceutically acceptable salt form, or a mixture comprising > 50% (-)-l-(4- methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form).

[0025] In some embodiments, an effective amount comprises essentially pure (+)-l-(4- methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form (e.g., having 90-95%) of (+)-l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, by weight of total l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, present), essentially pure (-)-l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or

pharmaceutically acceptable salt form, or any mixture of (+)-l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, and (-)-l-(4- methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

[0026] l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride exists in at least two polymorphic forms, labeled polymorphs A and B as disclosed in U.S. Patent No. 7,094,799, which is hereby incorporated by reference in its entirety. Crystalline and amorphous forms of l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, may be used in any combination or in forms that are substantially free of one or more of the other crystalline forms or free of the amorphous form.

[0027] Thus, useful forms of l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane within the methods, uses, and compositions described herein include l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, as well as enantiomers, polymorphs, solvates, hydrates, prodrugs, and combinations thereof.

[0028] "l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane" also encompasses its stable and unstable isotopes. Stable isotopes are nonradioactive isotopes that contain one additional neutron compared to the abundant nuclides of the same species (i.e., element). For example, the hydrogen atom at a certain position on l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane may be replaced with deuterium (a stable isotope which is non-radioactive). Alternatively, unstable isotopes, which are radioactive isotopes that contain additional neutrons compared to the abundant nuclides of the same species (i.e., element), e.g., C, may replace the corresponding abundant species.

[0029] In some embodiments, an effective amount comprises at least 10% to 10-20%, 20- 35%, 35-50%, 50-70%, 70-85%, 85-95%, and up to 95-99% or greater (by weight) polymorph B.

[0030] As used herein, "substantially free of other polymorphic forms" means that the crystalline material, e.g., polymorph A or polymorph B, contains 10% w/w or less of any other crystalline form. For example a crystalline material, e.g., polymorph A or polymorph B, contains 5% w/w or less of any other crystalline form, e.g., 1% w/w or less of any other crystalline form.

[0031] As used herein, "treatment" and "treating" include minimizing or eliminating pain in an equine.

[0032] As used herein, "effective amount" is intended to encompass a therapeutically effective amount to treat a specific disease or disorder.

[0033] As used herein, "equine" refers to animals belonging to the family Equidae including, for example, horses, ponies, miniature horses, miniature ponies, donkeys, mules, and zebras.

[0034] As used herein, "pain" includes pain of varying severity, i.e. mild, moderate, and severe pain, as well as acute and chronic pain.

[0035] In some embodiments, pain occurs because of an injury (e.g., an orthopedic injury, e.g., a bone fracture or contusion), degenerative issues in the animal's tissues, blunt trauma, or following surgery or medical treatment. In some embodiments, pain occurs because of a soft tissue injury, such as an injury to a ligament or tendon. In some embodiments, the pain is associated with colic in the equine. As used herein, "colic" encompasses all forms of gastrointestinal conditions which cause pain as well as other causes of abdominal pain not involving the gastrointestinal tract. Colic may include a visceral component. In some embodiments, the pain is associated with laminitis in the equine, e.g., acute laminitis or chronic laminitis. In some embodiments, the pain is due to arthritis, for example osteoarthritis (also known as degenerative joint disease).

[0036] As used herein, "acute pain" refers to either an initial phase of a painful condition that either largely resolves within several hours, days, or months (typically lasting no more than 3 months) or progresses on to a subacute pain (e.g., lasting 3-6 months) or chronic pain (e.g., persisting, in some cases intermittently, for more than 3 months, and often more than 6 months). Acute pain also refers to a transient exacerbation or flare up of a chronic pain condition in which pain intensity worsens substantially, whereby supplemental treatment and/or upwards dose adjustment is indicated, provided that such treatment would be tolerated adequately.

[0037] Acute pain may occur with or after colic, fracture, trauma, surgery, infection, or inflammatory disease.

[0038] As used herein, "chronic pain" refers to pain that lasts more than 3 months, for example more than 6 months, and/or extends beyond the expected period of healing. Chronic pain may be considered pathologic, or having the characteristics of a diseased state. It may be unrelenting, have no identifiable cause, spread beyond the original site of an injury or insult, and serve no biological function.

[0039] Chronic pain may occur with musculoskeletal injury or disease (e.g., chronic pain may occur with laminitis, osteoarthritis, stomatitis, and intervertebral disk disease). Chronic pain may also include pain consequent to cancer, diabetes, and chronic low back pain.

[0040] As used herein, "neuropathic pain" refers to pain caused by injury or damage to either the peripheral and/or the central nervous system.

[0041] Equines with injuries that involve nerve damage, equines that have had neurectomies, and equines with back pain may suffer from neuropathic pain.

[0042] As used herein, "concurrently" means the compounds are administered simultaneously or within the same composition. In some embodiments, the compounds are administered simultaneously. In some embodiments, the compounds are administered within the same composition.

[0043] As used herein, a foal is a young equine (e.g., horse), for example, an equine (e.g., horse) that is one year old or younger.

[0044] Provided herein is a method (Method 1) for the treatment or prophylaxis of pain in an equine in need thereof comprising administering to the equine an effective amount of l-(4- methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

[0045] Also provided herein is a method (Method 2) for the treatment or prophylaxis of depression in an equine in need thereof comprising administering to the equine an effective amount of l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

[0046] Also provided herein is a method (Method 3) for the treatment or prophylaxis of anxiety (e.g., separation anxiety and/or generalized anxiety disorder) in an equine in need thereof comprising administering to the equine an effective amount of l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

[0047] Further provided is any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, as follows:

1.1 Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3,

comprising administering 0.5 to 50 mg/kg/day, e.g., 1 to 50 mg/kg/day, e.g., 2 to 45 mg/kg/day, e.g., 5 to 40 mg/kg/day, e.g., 10 to 35 mg/kg/day, e.g., 15 to 30 mg/kg/day, e.g., 15 to 25 mg/kg/day, of l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

1.2 Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1 comprising administering l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, once or twice daily.

1.3 Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1 or 1.2 wherein l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or

pharmaceutically acceptable salt form, is crystalline.

1.4 Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1-

1.3 wherein l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane is in pharmaceutically acceptable salt form.

1.5 Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1-

1.4 wherein l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane in pharmaceutically acceptable salt form is an acid addition salt.

1.6 Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1-

1.5 wherein l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane in pharmaceutically acceptable salt form is l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride.

1.7 Method 1.6 wherein l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride is l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride polymorph form B. Method 1.7 wherein l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride polymorph form B is substantially free of other polymorphic forms.

Method 1.6 wherein l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride is l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride polymorph form A. Method 1.9 wherein l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride polymorph form A is substantially free of other polymorphic forms.

Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1- 1.6 comprising administering an effective amount of (+)-l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1- 1.6 comprising administering an effective amount of (-)-l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.

Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1-

1.12 further comprising administering one or more of a local anesthetic, an opioid, an alpha-2 agonist, a non-steroidal anti-inflammatory drug (NSAID), a corticosteroid, a N-methyl-D-aspartate (NMD A) receptor antagonist, a NK1 receptor antagonist, a calcium channel blocker, a muscle relaxant, and a bisphosphonate.

Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1-

1.13 further comprising administering one or more of procaine, chloroprocaine, mepivacaine, prilocaine, lidocaine, articaine, tetracaine, bupivacaine (with or without epinephrine), levobupivacaine, ropivacaine, capsaicin, resiniferatoxin, morphine, oxymorphone, meperidine, methadone, hydromorphone, fentanyl, butorphanol, codeine (e.g., codeine/acetaminophen), hydrocodone, tramadol, buprenorphine, alfentanil, sufentanil, pentazocine, nalbuphine, naloxone, nalmefene, xylazine, detomidine, medetomidine, dexmedetomidine, romifidine, aspirin, acetaminophen, phenylbutazone, flunixin (e.g., flunixin meglumine), ketoprofen, firocoxib, diclofenac, meloxicam, piroxicam, carprofen, naproxen, etodolac, vedaprofen, deracoxib, robenacoxib, mavacoxib, tepoxalin, tolfenamic acid, ketorolac, prednisone, prednisolone, hydrocortisone, triamcinolone (e.g., triamcinolone acetonide and triamcinolone diacetate), methylprednisolone, dexamethasone, fludrocortisone, isoflupredone, flumethasone, betamethasone, ketamine, amantadine, tiletamine, maropitant, gabapentin, methocarbamol, imipramine, amitriptyline, duloxetine, sarapin, atropine, hyoscine N-butylbromide, dipyrone, hyoscine, and pamidronate. Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1-

1.14 comprising administering one or more of another anti-depressant or anxiolytic. Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1-

1.15 further comprising performing one or more of acupuncture, rehabilitation, low- level laser, transcutaneous electric nerve stimulation, hydrotherapy, massage, prolotherapy, neural therapy, and reflexology.

Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1-

1.16 further comprising administering one or more of a nutraceutical and an herbal supplement.

Any one of Methods 1.13, 1.14, 1.15, or 1.17 wherein the administration with l-(4- methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is concurrent.

Any one of Methods 1.13, 1.14, 1.15, or 1.17 wherein the administration with l-(4- methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is sequential.

Any one of Methods 1 or 1.1-1.19 wherein the pain is acute pain.

Any one of Methods 1 or 1.1-1.19 wherein the pain is chronic pain.

Any one of Methods 1 or 1.1-1.21 wherein the pain is neuropathic pain.

Any one of Methods 1 or 1.1-1.22 wherein the pain is co-morbid with depression. Any one of Methods 1 or 1.1-1.23 wherein the pain is co-morbid with anxiety.

Any one of Methods 3 or 1.1-1.19 or 1.24 wherein the anxiety is separation anxiety. Any one of Methods 3 or 1.1-1.19 or 1.24 wherein the anxiety is generalized anxiety disorder.

Any one of Methods 3 or 1.1-1.19, 1.25, or 1.26 wherein the anxiety is co-morbid with pain.

Method 1.27 wherein the pain is acute pain.

Method 1.27 wherein the pain is chronic pain.

Any one of Methods 1.27-1.29 wherein the pain is neuropathic pain.

Any one of Methods 2 or 1.1-1.19 wherein the depression is co-morbid with pain. 1.32 Method 1.31 wherein the pain is acute pain.

1.33 Method 1.31 wherein the pain is chronic pain.

1.34 Any one of Methods 1.31-1.33 wherein the pain is neuropathic pain.

1.35 Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1- 1.34 wherein the equine is a horse.

1.36 Method 1.35 wherein the horse is a racehorse (e.g., a thoroughbred racehorse).

1.37 Method 1.35 wherein the horse is a polo pony.

1.38 Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1- 1.37 wherein the equine is a foal (e.g., a foal horse).

1.39 Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1-

1.38, wherein the l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is administered as a pharmaceutical

composition comprising an effective amount of l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in combination with a pharmaceutically acceptable diluent or carrier.

1.40 Any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, or 1.1-

1.39, wherein the l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is administered as a pharmaceutical

composition consisting essentially of an effective amount of l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in combination with a pharmaceutically acceptable diluent or carrier.

[0048] Where one or more active agents and l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, are administered, the active agent(s) and 1- (4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, may be administered concurrently or sequentially in any order.

[0049] Also provided herein is use of l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, for the treatment or prophylaxis of pain, depression, and/or anxiety in an equine in need thereof, for example, for use in any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, e.g., any one of Methods 1.1-1.40.

[0050] Also provided herein is use of l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for the treatment or prophylaxis of pain, depression, and/or anxiety in an equine in need thereof, for example, for use in any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, e.g., any one of Methods 1.1-1.40.

[0051] Also provided is a pharmaceutical composition comprising an effective amount of 1- (4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in combination with a pharmaceutically acceptable diluent or carrier, for use in the treatment or prophylaxis of pain, depression, and/or anxiety in an equine in need thereof, for example, for use in any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, e.g., any one of Methods 1.1-1.40.

[0052] Also provided is a pharmaceutical composition consisting essentially of an effective amount of l-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in combination with a pharmaceutically acceptable diluent or carrier, for use in the treatment or prophylaxis of pain, depression, and/or anxiety in an equine in need thereof, for example, for use in any one of Methods 1, 2, or 3, e.g., Method 1, e.g., Method 2, e.g., Method 3, e.g., any one of Methods 1.1-1.40.

[0053] A dose or method of administration of the dose of the present disclosure is not particularly limited. Dosages employed will vary depending, e.g., on the particular disease or condition to be treated, the mode of administration, and the therapy desired. l-(4- methylphenyl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, although various other known delivery routes, devices and methods can likewise be employed.

[0054] Pharmaceutical compositions comprising l-(4-methylphenyl)-3- azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus, dosage forms may include tablets, capsules, solutions, suspensions, pastes, and the like.