WO2018217937A1 - Promédicaments à base d'agonistes de trpv1 phénoliques en combinaison avec des anesthésiques locaux et des vasoconstricteurs pour améliorer une anesthésie locale - Google Patents

Promédicaments à base d'agonistes de trpv1 phénoliques en combinaison avec des anesthésiques locaux et des vasoconstricteurs pour améliorer une anesthésie locale Download PDF

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Publication number
WO2018217937A1
WO2018217937A1 PCT/US2018/034206 US2018034206W WO2018217937A1 WO 2018217937 A1 WO2018217937 A1 WO 2018217937A1 US 2018034206 W US2018034206 W US 2018034206W WO 2018217937 A1 WO2018217937 A1 WO 2018217937A1
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pain
effective dose
compound
pharmaceutical composition
local anesthetic
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PCT/US2018/034206
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English (en)
Inventor
John F. Donovan
Craig Husfeld
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Concentric Analgesics, Inc.
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Publication of WO2018217937A1 publication Critical patent/WO2018217937A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine

Definitions

  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 2 hexahydroimidazo[l,5-a]pyridin-3(2H)-one is a metabolite of Compound 1.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1) and a local anesthetic, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg, and the effective dose of the
  • vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg. In some embodiments of the methods described herein, the effective dose of the local anesthetic is from about 1 mg to about 150 mg. In some embodiments of the methods described herein, the effective dose of the local anesthetic is from about 1 mg to about 75 mg. In some embodiments of the methods described herein, the effective dose of the local anesthetic is from about 1 mg to about 25 mg. In some embodiments of the methods described herein, the effective dose of the local anesthetic is from about 10 mg to about 75 mg.
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 125 ⁇ g. In some embodiments of the methods described herein, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g. In some embodiments of the methods described herein, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g. In some embodiments of the methods described herein, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 25 ⁇ g. In some embodiments of the methods described herein, the effective dose of the vasoconstrictor is from about 5 ⁇ g to about 25 ⁇ g.
  • the vasoconstrictor is epinephrine. In some embodiments of the methods described herein, the vasoconstrictor is phenylephrine. In some embodiments of the methods described herein, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine. In some embodiments of the methods described herein, the local anesthetic is bupivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 1% (10 mg/mL). In some embodiments of the methods described herein, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.75% (7.5 mg/mL). In some embodiments of the methods described herein, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL). In some embodiments of the methods described herein, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL).
  • the vasoconstrictor is in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL. In some embodiments of the methods described herein, the vasoconstrictor is in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL. In some embodiments of the methods described herein, the vasoconstrictor is epinephrine. In some embodiments of the methods described herein, the vasoconstrictor is phenylephrine.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine. In some embodiments of the methods described herein, the local anesthetic is bupivacaine. In some embodiments of the methods described herein, the effective dose of Compound 1 is from about 0.01 mg to about 15 mg. In some embodiments of the methods described herein, the effective dose of Compound 1 is from about 0.1 mg to about 10 mg. In some embodiments of the methods described herein, the effective dose of Compound 1 is from about 0.5 mg to about 10 mg.
  • the effective dose of Compound 1 is from about 0.5 mg to about 5 mg.
  • the pain is post-surgical pain, post amputation pain, chronic postsurgical pain, and traumatic injury pain.
  • the pain is post-surgical pain.
  • the postsurgical pain is pain from a laparotomy, thoracotomy, thoraco-abdominal incision, flank incision, total hip replacement, total knee replacement, ACL reconstruction, rotator cuff repair, bunionectomy, laparoscopy, dental extraction, or open reduction internal fixation of fractures.
  • the pain is traumatic injury pain. In some embodiments of the methods described herein, the traumatic injury pain is pain from a long bone, short bone, flat bone, or irregular bone fracture. In some embodiments of the methods described herein, the traumatic injury pain is pain from a hip or rib fracture. In some embodiments of the methods described herein, the pain is chronic post-surgical pain. In some embodiments of the methods described herein, the pain is chronic post-surgical pain after mastectomy or
  • the pain is chronic postsurgical pain after thoractomy. In some embodiments of the methods described herein, the pain is chronic post-surgical pain after amputation. In some embodiments of the methods described herein, the pain is chronic pain. In some embodiments of the methods described herein, the chronic pain is chronic pain associated with osteoarthritis. In some embodiments of the methods described herein, the chronic pain is chronic pain associated with osteoarthritis of the knee. In some embodiments of the methods described herein, the chronic pain is chronic musculoskeletal pain. In some embodiments of the methods described herein, the chronic pain is chronic musculoskeletal pain of the lower back.
  • the pain is cancer pain, phantom limb pain, pain associated with spinal cord injury, complex regional pain syndrome, visceral pain, or peripheral neuropathy.
  • the pain is cancer pain.
  • the pain is phantom limb pain.
  • the pain is pain associated with spinal cord injury.
  • the pain is complex regional pain syndrome.
  • the pain is visceral pain.
  • the pain is peripheral neuropathy.
  • the effective dose is administered to the subject is in a dosing volume from about 1 mL to about 120 mL. In some embodiments of the methods described herein, the effective dose is administered to the subject is in a dosing volume from about 10 mL to about 30 mL. In some embodiments of the methods described herein, the effective dose is administered to the subject is in a dosing volume from about 30 mL to about 120 mL. In some embodiments of the methods described herein, the effective dose is administered to the subject is in a dosing volume from about 1 mL to about 10 mL. In some embodiments of the methods described herein, the subject is awake. In some embodiments of the methods described herein, the subject is sedated.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g, and the vasoconstrictor is epinephrine.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g
  • the vasoconstrictor is epinephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g, and the vasoconstrictor is phenylephrine.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g
  • the vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 75 ⁇ g.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • Compound 1 a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL)
  • a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine,
  • dimethisoquien in some embodiments is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.75% (7.5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1- carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine,
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.75% (7.5 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine,
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine, and the vasoconstrictor is epinephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is bupivacaine, and the vasoconstrictor is epinephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine,
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine, and the vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is bupivacaine, and the vasoconstrictor is phenylephrine.
  • the effective dose of Compound 1 is from about 0.01 mg to about 15 mg. In some embodiments of the
  • the effective dose of Compound 1 is from about 0.1 mg to about 10 mg. In some embodiments of the aforementioned embodiments, the effective dose of Compound 1 is from about 0.5 mg to about 10 mg. In some embodiments of the aforementioned embodiments, the effective dose of Compound 1 is from about 0.5 mg to about 5 mg. In some embodiments of the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the pain is post-surgical pain, post amputation pain, chronic post-surgical pain, and traumatic injury pain. In some embodiments of the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the pain is post-surgical pain.
  • the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the post-surgical pain is pain from a laparotomy, thoracotomy, thoraco-abdominal incision, flank incision, total hip replacement, total knee replacement, ACL reconstruction, rotator cuff repair, bunionectomy, laparoscopy, dental extraction, or open reduction internal fixation of fractures.
  • the pain is traumatic injury pain.
  • the traumatic injury pain is pain from a hip or rib fracture.
  • embodiments of the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the pain is chronic post-surgical pain. In some embodiments of the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the pain is chronic post-surgical pain after mastectomy or lumpectomy. In some embodiments of the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the pain is chronic post-surgical pain after thoractomy. In some embodiments of the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the pain is chronic post-surgical pain after amputation. In some embodiments of the methods described herein, the pain is chronic pain.
  • the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the chronic pain is chronic pain associated with osteoarthritis. In some embodiments of the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the chronic pain is chronic pain associated with osteoarthritis of the knee. In some embodiments of the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the chronic pain is chronic musculoskeletal pain. In some embodiments of the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the chronic pain is chronic musculoskeletal pain of the lower back.
  • the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the pain is cancer pain, phantom limb pain, pain associated with spinal cord injury, complex regional pain syndrome, visceral pain, or peripheral neuropathy.
  • the pain is cancer pain, phantom limb pain, pain associated with spinal cord injury, complex regional pain syndrome, visceral pain, or peripheral neuropathy.
  • embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the pain is cancer pain. In some embodiments of the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the pain is phantom limb pain. In some embodiments of the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the pain is pain associated with spinal cord injury. In some embodiments of the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the pain is complex regional pain syndrome. In some embodiments of the aforementioned embodiments is a method of treating or preventing pain in a subject in need thereof, wherein the pain is visceral pain.
  • the effective dose administered to the subject is in a dosing volume from about 1 mL to about 120 mL. In some embodiments of the aforementioned embodiments, the effective dose administered to the subject is in a dosing volume from about 10 mL to about 30 mL. In some embodiments of the aforementioned embodiments, the effective dose administered to the subject is in a dosing volume from about 30 mL to about 120 mL.
  • the effective dose administered to the subject is in a dosing volume less than about 10 mL. In some embodiments of the aforementioned embodiments, the subject is awake. In some embodiments of the aforementioned embodiments, the subject is sedated.
  • a pharmaceutical composition for the treatment or prevention of pain comprising an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l- carboxylate hydrochloride (Compound 1), and a pharmaceutically acceptable carrier, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain comprising an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l- carboxylate hydrochloride (Compound 1), a local anesthetic, and a pharmaceutically acceptable carrier, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg.
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of
  • Compound 1 ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l- carboxylate hydrochloride (Compound 1), a vasoconstrictor, and a pharmaceutically acceptable carrier, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of
  • the effective dose of the local anesthetic is from about 0.5 mg to about
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg. In some embodiments of the pharmaceutical compositions described herein, the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg. In some embodiments of the pharmaceutical compositions described herein, the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg. In some
  • the effective dose of the local anesthetic is from about 1 mg to about 150 mg. In some embodiments of the pharmaceutical compositions described herein, the effective dose of the local anesthetic is from about 1 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the effective dose of the local anesthetic is from about 1 mg to about 25 mg. In some embodiments of the pharmaceutical compositions described herein, the effective dose of the local anesthetic is from about 10 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 125 ⁇ g. In some embodiments of the pharmaceutical compositions described herein, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g. In some embodiments of the
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g. In some embodiments of the pharmaceutical compositions described herein, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 25 ⁇ g. In some embodiments of the pharmaceutical compositions described herein, the effective dose of the vasoconstrictor is from about 5 ⁇ g to about 25 ⁇ g. In some embodiments of the pharmaceutical compositions described herein, the vasoconstrictor is epinephrine. In some embodiments of the pharmaceutical compositions described herein, the vasoconstrictor is phenylephrine.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine. In some embodiments of the pharmaceutical compositions described herein, the local anesthetic is bupivacaine.
  • a pharmaceutical composition for the treatment or prevention of pain comprising an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l- carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a pharmaceutically acceptable carrier, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain comprising an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l- carboxylate hydrochloride (Compound 1), a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, and a pharmaceutically acceptable carrier, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain comprising an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l- carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, and a pharmaceutically acceptable carrier, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 1% (10 mg/mL). In some embodiments of the pharmaceutical compositions described herein, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.75% (7.5 mg/mL). In some embodiments of the pharmaceutical compositions described herein, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL).
  • the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL).
  • the vasoconstrictor is in a concentration range from about 2 ⁇ / ⁇ . to about 10
  • the vasoconstrictor is in a concentration range from about 2 ⁇ / ⁇ . to about 5 ⁇ / ⁇ .. In some embodiments of the pharmaceutical
  • the vasoconstrictor is epinephrine. In some embodiments of the pharmaceutical compositions described herein, the vasoconstrictor is phenylephrine. In some embodiments of the pharmaceutical compositions described herein, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine. In some embodiments of the pharmaceutical compositions described herein, the local anesthetic is bupivacaine. In some embodiments of the pharmaceutical compositions described herein, the effective dose of
  • Compound 1 is from about 0.01 mg to about 15 mg. In some embodiments of the pharmaceutical compositions described herein, the effective dose of Compound 1 is from about 0.1 mg to about 10 mg. In some embodiments of the pharmaceutical compositions described herein, the effective dose of Compound 1 is from about 0.5 mg to about 10 mg. In some embodiments of the pharmaceutical compositions described herein, the effective dose of Compound 1 is from about 0.5 mg to about 5 mg. In some embodiments of the pharmaceutical compositions described herein, the pain is post-surgical pain, post amputation pain, chronic post-surgical pain, and traumatic injury pain. In some embodiments of the pharmaceutical compositions described herein, the pain is post-surgical pain. In some embodiments of the pharmaceutical compositions described herein, the post-surgical pain is pain from a laparotomy, thoracotomy, thoracoabdominal incision, flank incision, total hip replacement, total knee replacement, ACL
  • the pain is traumatic injury pain.
  • the traumatic injury pain is pain from a long bone, short bone, flat bone, or irregular bone fracture.
  • the traumatic injury pain is pain from a hip or rib fracture.
  • the pain is chronic post-surgical pain.
  • the pain is chronic post-surgical pain after mastectomy or lumpectomy.
  • the pain is chronic postsurgical pain after thoractomy.
  • the pain is chronic post-surgical pain after amputation.
  • the pain is chronic pain.
  • the chronic pain is chronic pain associated with osteoarthritis.
  • the chronic pain is chronic pain associated with osteoarthritis of the knee. In some embodiments of the pharmaceutical compositions described herein, the chronic pain is chronic musculoskeletal pain. In some embodiments of the pharmaceutical compositions described herein, the chronic pain is chronic musculoskeletal pain of the lower back. In some embodiments of the pharmaceutical compositions described herein, the pain is cancer pain, phantom limb pain, pain associated with spinal cord injury, complex regional pain syndrome, visceral pain, or peripheral neuropathy. In some embodiments of the pharmaceutical
  • the pain is cancer pain.
  • the pain is cancer pain.
  • the pain is phantom limb pain. In some embodiments of the pharmaceutical compositions described herein, the pain is pain associated with spinal cord injury. In some embodiments of the pharmaceutical compositions described herein, the pain is complex regional pain syndrome. In some embodiments of the pharmaceutical compositions described herein, the pain is visceral pain. In some embodiments of the
  • the pain is peripheral neuropathy.
  • the carrier is sterile water.
  • the carrier is sterile saline.
  • the effective dose is administered to the subject is in a dosing volume from about 1 mL to about 120 mL.
  • the effective dose is administered to the subject is in a dosing volume from about 10 mL to about 30 mL.
  • the effective dose is administered to the subject is in a dosing volume from about 30 mL to about 120 mL.
  • the effective dose is administered to the subject is in a dosing volume from about 1 mL to about 10 mL.
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy- 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate
  • Compound 1 hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • Compound 1 an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride
  • a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1)
  • a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1)
  • a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy- 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 2 ⁇ / ⁇ . to about 10 ⁇ / ⁇ ., wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy- 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • Compound 1 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride
  • a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • Compound 1 an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1)
  • a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.75% (7.5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l -carboxylate hydrochloride
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1)
  • a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride
  • Compound 1 and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain comprises an effective dose of (£)-2-methoxy- 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexyl
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, te
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.75% (7.5 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy- 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexyl
  • vasoconstrictor is epinephrine. In some embodiments is a
  • compositions for the treatment or prevention of pain comprising an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine, and the vasoconstrictor is epinephrine.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the local anesthetic is selected from the group consisting of bupivac
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is bupivacaine, and the vasoconstrictor is epinephrine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy- 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexyl
  • vasoconstrictor is phenylephrine. In some embodiments is a
  • compositions for the treatment or prevention of pain comprising an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine, and the vasoconstrictor is phenylephrine.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the local anesthetic is selected from the group consisting of bupivac
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is bupivacaine, and the vasoconstrictor is phenylephrine.
  • the effective dose of Compound 1 is from about 0.01 mg to about 15 mg. In some embodiments of the
  • the effective dose of Compound 1 is from about 0.1 mg to about 10 mg. In some embodiments of the aforementioned embodiments, the effective dose of Compound 1 is from about 0.5 mg to about 10 mg. In some embodiments of the aforementioned embodiments, the effective dose of Compound 1 is from about 0.5 mg to about 5 mg. In some embodiments of the aforementioned embodiments is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is post-surgical pain, post amputation pain, chronic post-surgical pain, and traumatic injury pain. In some embodiments of the
  • aforementioned embodiments is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is post-surgical pain.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the post-surgical pain is pain from a laparotomy, thoracotomy, thoraco-abdominal incision, flank incision, total hip replacement, total knee replacement, ACL reconstruction, rotator cuff repair, bunionectomy, laparoscopy, dental extraction, or open reduction internal fixation of fractures.
  • the pain is traumatic injury pain.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the traumatic injury pain is pain from a hip or rib fracture.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is chronic post-surgical pain.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is chronic post-surgical pain after mastectomy or lumpectomy.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is chronic post-surgical pain after thoractomy.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is chronic post-surgical pain after amputation.
  • a pharmaceutical composition for the treatment or prevention of pain the pain is chronic pain.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the chronic pain is chronic pain associated with osteoarthritis.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the chronic pain is chronic pain associated with osteoarthritis of the knee.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is cancer pain, phantom limb pain, pain associated with spinal cord injury, complex regional pain syndrome, visceral pain, or peripheral neuropathy.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is cancer pain.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is phantom limb pain.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is phantom limb pain.
  • compositions for the treatment or prevention of pain wherein the pain is pain associated with spinal cord injury.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is complex regional pain syndrome.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is visceral pain.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is visceral pain.
  • the carrier is sterile water. In some embodiments of the aforementioned embodiments, the carrier is sterile saline. In some embodiments of the aforementioned embodiments, the effective dose is in a dosing volume from about 1 mL to about 120 mL. In some embodiments of the aforementioned embodiments, the effective dose is in a dosing volume from about 10 mL to about 30 mL. In some embodiments of the aforementioned embodiments, the effective dose is in a dosing volume from about 30 mL to about 120 mL. In some embodiments of the aforementioned embodiments, the effective dose is in a dosing volume less than about 10 mL.
  • Fig. 1 and Fig. 2 show the measurable plasma concentrations of capsaicin vs. time following subcutaneous (SC) dosing in rats (linear plot).
  • Group 1 ( ⁇ ) represents the plasma concentration of capsaicin following SC dosing of Compound 1 HC1 (1.57 mg/kg) in sterile water.
  • Group 2 (A) represents the plasma concentration of capsaicin following SC dosing of Compound 1 HC1 (at 1.57 mg/kg) in 0.5% bupivacaine hydrochloride solution.
  • Group 3 (+) represents the plasma concentration of capsaicin following SC dosing of Compound 1 HC1 (at 1.57 mg/kg) in 0.5% bupivacaine hydrochloride solution plus epinephrine (1 :200,000) solution).
  • Group 4 (T) represents the plasma concentration of capsaicin following SC dosing of Compound 1 HC1 (at 1.57 mg/kg) in 2.0%> lidocaine hydrochloride solution.
  • Group 5 (O) represents the plasma concentration of capsaicin following SC dosing of Compound 1 HC1 (at 1.62 mg/kg) in
  • Fig. 3 and Fig. 4 show the measurable plasma concentrations of Compound 2 (cyclic urea metabolite of compound 1) vs. time following subcutaneous (SC) dosing in rats (linear plot).
  • Group 1 ( ⁇ ) represents the plasma concentration of Compound 2 following SC dosing of
  • Group 2 (A) represents the plasma concentration of Compound 2 following SC dosing of Compound 1 HC1 (at 1.57 mg/kg) in 0.5% bupivacaine hydrochloride solution.
  • Group 3 (+) represents the plasma concentration of Compound 2 following SC dosing of Compound 1 HC1 (at 1.57 mg/kg) in 0.5% bupivacaine hydrochloride solution plus epinephrine (1 :200,000) solution).
  • Group 4 (T) represents the plasma concentration of Compound 2 following SC dosing of Compound 1 HC1 (at 1.57 mg/kg) in 2.0% lidocaine hydrochloride solution.
  • Group 5 (O) represents the plasma concentration of capsaicin following
  • Pain management in patients after surgery remains insufficient (Pogatzki-Zahn et al., 2012), and there is no ideal way to provide continuous, effective pain relief beyond 12 -18 hours after surgery.
  • Systemic pharmacological therapies remain the mainstay of postoperative pain relief, with opioids a key component, especially for moderate-to-severe pain.
  • Systemic opioids are effective, but increase cost and morbidity, especially due to known safety issues such as respiratory depression, gastrointestinal dysfunction, and abuse.
  • Non-opioid analgesics including acetaminophen, nonselective NSAIDs, and selective COX-2 inhibitors are useful for the treatment of light-to-moderate pain and are part of a balanced multimodal pain treatment
  • peripheral regional anesthetic techniques have been shown to be effective as a component of multimodal analgesia for management of postoperative pain associated with a number of surgical procedures, including thoracotomy, lower extremity joint surgery, shoulder surgery, cesarean section, hemorrhoid surgery, and circumcision. It is recommended that clinicians should consider use of surgical site-specific or peripheral regional analgesic techniques in adults and children as part of multimodal analgesia, particularly in patients who undergo lower extremity and upper extremity surgical procedures (Chou et al., 2016).
  • Capsaicin (8-methyl- N-vanillyl-6-nonenamide) is a highly selective agonist for transient receptor potential vanilloid 1 receptor (TRPV1; formerly known as vanilloid receptor 1 (VR1)), a ligand-gated, non-selective cation channel.
  • TRPV1 is preferentially expressed on small-diameter sensory neurons, predominately on C-fibers and to a lesser extent A-delta fibers which specialize in the detection of painful or noxious sensations.
  • TRPV1 responds to stimuli including capsaicin, heat, and extracellular acidification, and will integrate simultaneous exposures to these stimuli. (Caterina M J, Julius D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci. 2001. 24:487-517).
  • TRPV1 agonists such as capsaicin
  • TRPV1 -expressing (capsaicin-sensitive) nociceptors include burning sensations, hyperalgesia, allodynia, and erythema.
  • the small-diameter sensory axons become less sensitive to a variety of stimuli, including capsaicin or thermal stimuli.
  • capsaicin and other TRPVl agonists induce a long-lasting, selective reduction in pain responses lasting days to weeks.
  • These later- stage effects of capsaicin are frequently referred to as “desensitization” and are the rationale for the development of capsaicin formulations for the treatment of various pain syndromes and other conditions.
  • the protonated form cannot readily cross the lipid membrane, will not gain access to the sodium-channel binding sites, and in-turn will not have analgesic effect.
  • local anesthetics Upon reversibly binding to and inactivating sodium channels, local anesthetics produce anesthesia by inhibiting excitation of nerve endings or by blocking conduction in peripheral nerves. Sodium influx through these channels is necessary for the depolarization of nerve cell membranes and subsequent propagation of impulses along the course of the nerve.
  • Vasoconstrictor agents with an emphasis on epinephrine, are frequently coadministered with local anesthetics to reduce the rate of systemic absorption of co-administered agents, which in turn increases the neural uptake and decreases the clearance of local anesthetic agents at the site of injection. Based on this effect, vasoconstrictors increase the efficacy of the local anesthetic agent due to a decreased rate of systemic absorption of the agent.
  • vasoconstrictors are principally pharmacokinetic in nature, vasoconstrictors themselves can have antinociceptive effects and, when absorbed from the site of injection, vasoconstrictors may elicit cardiovascular effects able to alter the pharmacokinetics and effects of co-administered drugs. It has been suggested that the action of vasoconstrictors is likely influenced by a variety of aspects such as hydrophobicity of the co-administered drug, the tissue and blood flow at the site of administration, the dosing vehicle, and the amount of the drugs given.
  • vasoconstrictors limit the system absorption of local anesthetic is dependent on the type, dose, and concentration of local anesthetic and of the nature of the site of injection.
  • the peak blood levels (Cmax) of local anesthetics were decreased via the co-administration of epinephrine in addition to a delay in Tmax of the local anesthetics.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), and a local anesthetic.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor.
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1- carboxylate hydrochloride (Compound 1), and a local anesthetic.
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon- 6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor.
  • Compound 1 a pharmaceutical compound for the treatment or prevention of pain
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor.
  • Compound 1 an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor.
  • the methods and pharmaceutical compositions described herein provide pain relief for multiple days, following a single injection.
  • subject or “patient” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non- human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats;
  • the mammal is a human.
  • treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition (e.g., arresting the development of the disease or condition), relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.
  • module means to interact with a target protein either directly or indirectly so as to alter the activity of the target protein, including, by way of example only, to inhibit the activity of the target, or to limit or reduce the activity of the target.
  • a modulator refers to a compound that alters an activity of a target.
  • a modulator can cause an increase or decrease in the magnitude of a certain activity of a target compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities of a target.
  • an inhibitor completely prevents one or more activities of a target.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that one active ingredient, e.g. compound described herein, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that one active ingredient, e.g. compound described herein, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • combination means that one active ingredient, e.g. a compound described herein and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • active ingredient e.g. a compound described herein and a co-agent
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • composition refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the pharmaceutical composition that includes a compound described herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • co-administration are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
  • dilute refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution.
  • a "metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolism refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Further information on metabolism may be obtained from The
  • Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
  • Bioavailability refers to the percentage of the weight of the compound disclosed herein that is delivered into the general circulation of the animal or human being studied. The total exposure (AUC(0- ⁇ )) of a drug when administered intravenously is usually defined as 100% bioavailable (F%).
  • Oral bioavailability refers to the extent to which a compound disclosed herein, is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.
  • Blood plasma concentration refers to the concentration of a compound disclosed herein, in the plasma component of blood of a subject. It is understood that the plasma concentration of compounds described herein may vary significantly between subjects, due to variability with respect to metabolism and/or possible interactions with other therapeutic agents. In accordance with one embodiment disclosed herein, the blood plasma concentration of the compounds disclosed herein may vary from subject to subject. Likewise, values such as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (Tmax), or total area under the plasma concentration time curve (AUC(0- ⁇ )) may vary from subject to subject. Due to this variability, the amount necessary to constitute "a therapeutically effective amount" of a compound may vary from subject to subject.
  • Blood concentration refers to the concentration of a compound disclosed herein, in the blood of a subject. It is understood that the blood concentration of compounds described herein may vary significantly between subjects, due to variability with respect to metabolism and/or possible interactions with other therapeutic agents. In accordance with one embodiment disclosed herein, the blood concentration of the compounds disclosed herein may vary from subject to subject. Likewise, values such as maximum blood concentration (Cmax) or time to reach maximum blood concentration (Tmax), or total area under the blood concentration time curve (AUC ( o - ⁇ ) ) may vary from subject to subject. Due to this variability, the amount necessary to constitute "a therapeutically effective amount" of a compound may vary from subject to subject.
  • Compound 1 releases capsaicin (and cyclic urea Compound 2) under well-defined rates via a pH driven, intra-molecular cyclization release reaction after Compound 1 has been delivered to the body and/or is exposed to specific physiological conditions:
  • the chemical-release kinetics of Compound 1 to capsaicin imparts two desirable properties: (a) reduced and/or delayed pungency due to the avoidance of the rapid delivery of a bolus dose of capsaicin and (b) tuning of specific pharmacological activity/results.
  • Compound 1 has significantly higher hydrophilicity/water solubility than capsaicin and, hence, is better able to be incorporated into commonly used aqueous formulations.
  • the improved water solubility of Compound 1 is significant when co-delivering other medications, especially when administering multiple sterile agents via injection.
  • Compound 1 eliminates the reliance on special requirements for formulations or delivery devices for capsaicin in order to 1) accommodate the very low water solubility of capsaicin and 2) reduce the acute pungency associated with the administration of capsaicin.
  • the rate at which Compound 1 releases capsaicin is modified by the addition of buffers.
  • the addition of a buffer provides a time window where turnover to capsaicin is significantly delayed until the return of physiological pH.
  • the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.
  • the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4 th Ed., Vols.
  • local anesthetic means a drug which provides local pain relief. On average, these drugs average six to ten hours of pain relief when given in different sites and for different types of surgery. For many types of surgery, it would be preferable to have durations of pain relief that last two to five days or more.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), and a local anesthetic.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic.
  • Compound 1 a pharmaceutical composition for the treatment or prevention of pain
  • pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine,
  • propoxycaine hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien.
  • the local anesthetic is bupivacaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is bupivacaine.
  • the local anesthetic is levobupivacaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is tetracaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is ropivacaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is lidocaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is prilocaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is mepivacaine. In some embodiments of the methods and pharmaceutical
  • the local anesthetic is procaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is
  • the local anesthetic is propoxycaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is hexylcaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is cyclomethycaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is benoxinate. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is butacaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is proparacaine. In some embodiments of the methods and pharmaceutical
  • the local anesthetic is cocaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is phenacaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is dibucaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is falicaine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is dyclonine. In some embodiments of the methods and pharmaceutical compositions described herein, the local anesthetic is spramoxine. In some embodiments of the methods and pharmaceutical
  • compositions described herein the local anesthetic is dimethisoquien.
  • vasoconstrictor refers to compounds acting locally to restrict blood flow, and thereby retain the co-administered agents at the site in which they are injected.
  • the use of vasoconstrictors affords substantially decreasing systemic toxicity of the co-administered agent.
  • the vasoconstrictors are those acting on alpha adrenergic receptors.
  • the vasoconstrictor is epinephrine. In some embodiments, the
  • vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), and a vasoconstrictor.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor.
  • Compound 1 a pharmaceutical composition for the treatment or prevention of pain, wherein the
  • composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor.
  • Compound 1 a pharmaceutical composition for the treatment or prevention of pain
  • the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor.
  • the vasoconstrictor is epinephrine or phenylephrine. In some embodiments of the methods and pharmaceutical compositions described herein, the vasoconstrictor is epinephrine. In some embodiments of the methods and pharmaceutical compositions described herein, the vasoconstrictor is phenylephrine.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1) and a local anesthetic, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1) and a local anesthetic, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1) and a local anesthetic, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the local anesthetic is from about 1 mg to about 150 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 1 mg to about 150 mg.
  • described herein is a method of treating or preventing pain in a subj ect in need thereof, comprising administering to the subject in need thereof an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1) and a local anesthetic, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the local anesthetic is from about 1 mg to about 75 mg.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (E)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1) and a local anesthetic, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the local anesthetic is from about 1 mg to about 25 mg.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1) and a local anesthetic, wherein the effective dose of
  • Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the local anesthetic is from about 10 mg to about 75 mg.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine. In some embodiments, the local anesthetic is bupivacaine.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of
  • Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 125 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride
  • Compound 1 Compound 1 and a vasoconstrictor, wherein the effective dose of Compound 1 is from about
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of
  • Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 75 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • Compound 1 (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (E)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 25 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 5 ⁇ g to about 25 ⁇ g.
  • the vasoconstrictor is epinephrine.
  • the vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg, and the effective dose of the
  • vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about
  • the effective dose of the local anesthetic is from about 0.5 mg to about
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subj ect in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 150 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 1 mg to about 150 mg
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • Compound 1 (aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 75 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (E)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride
  • Compound 1 a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 10 mg to about 75 mg, and the effective dose of the vasoconstrictor is from about 10 ⁇ g to about 150 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 10 mg to about 75 mg
  • the effective dose of the vasoconstrictor is from about 10 ⁇ g to about 150 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • Compound 1 (aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 125 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (E)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride
  • Compound 1 a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound
  • 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about
  • the effective dose of the local anesthetic is from about 0.5 mg to about
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 25 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg, and the effective dose of the vasoconstrictor is from about 5 ⁇ g to about 25 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg
  • the effective dose of the vasoconstrictor is from
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • Compound 1 (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (E)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride
  • Compound 1 a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound
  • 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 1 mg to about 150 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg, and the effective dose of the
  • vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (7 ⁇ -2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about
  • the effective dose of the local anesthetic is from about 1 mg to about
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 75 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 1 mg to about 75 mg
  • the effective dose of the vasoconstrictor is from about 1
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • Compound 1 (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 25 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • described herein is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subject in need thereof an effective dose of (E)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride
  • Compound 1 a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 25 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 25 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 1 mg to about 25 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 25 ⁇ g.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien; and the vasoconstrictor is epinephrine.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine,
  • propoxycaine hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien;
  • vasoconstrictor is phenylephrine.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine; and the vasoconstrictor is epinephrine.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine; and the vasoconstrictor is phenylephrine.
  • the local anesthetic is bupivacaine and the vasoconstrictor is epinephrine.
  • the local anesthetic is bupivacaine and the vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1- carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride
  • Compound 1 Compound 1
  • a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • Compound 1 a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL)
  • a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • Compound 1 a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL)
  • a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subj ect in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subj ect in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • Compound 1 a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL)
  • a vasoconstrictor in a concentration range from about 2 ⁇ g/
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine,
  • dimethisoquien in some embodiments is a method of treating or preventing pain in a subject in need thereof, comprising administering to the subj ect in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.1% (10 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1- carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.1% (10 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phen
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.1% (10 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.1% (10 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05%
  • compositions comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1- carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.75% (7.5 mg/mL), wherein the effective dose of Compound
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05%
  • the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • the method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • Compound 1 (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.75% (7.5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05%
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperi dine- 1- carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1- carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL), wherein the effective dose of
  • Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, prop
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine,
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.75% (7.5 mg/mL), and a vasoconstrictor in a concentration range from about
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine,
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine, and the vasoconstrictor is epinephrine.
  • the method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is bupivacaine, and the vasoconstrictor is epinephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-2- methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine,
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine, and the vasoconstrictor is phenylephrine.
  • a method of treating or preventing pain in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is bupivacaine, and the vasoconstrictor is phenylephrine.
  • the effective dose of Compound 1 is from about 0.01 mg to about 300 mg. In some embodiments of the
  • the effective dose of Compound 1 is from about 0.01 mg to about 250 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 200 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 150 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 100 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 50 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 30 mg.
  • the effective dose of Compound 1 is from about 0.01 mg to about 25 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 20 mg. In some embodiments of the
  • the effective dose of Compound 1 is from about 0.01 mg to about 15 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 14 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 13 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 12 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 1 1 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 10 mg.
  • the effective dose of Compound 1 is from about 0.01 mg to about 9 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 8 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 7 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 6 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 5 mg. In some embodiments of the
  • the effective dose of Compound 1 is from about 0.01 mg to about 4 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 3 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 2 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 1 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.01 mg to about 0.5 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.1 mg to about 10 mg.
  • the effective dose of Compound 1 is from about 0.1 mg to about 25 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.1 mg to about 20 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.1 mg to about 15 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.1 mg to about 10 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.1 mg to about 5 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.5 mg to about 25 mg.
  • the effective dose of Compound 1 is from about 0.5 mg to about 20 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.5 mg to about 15 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.5 mg to about 10 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 0.5 mg to about 5 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 1 mg to about 100 mg. In some embodiments of the aforementioned methods, the effective dose of Compound 1 is from about 1 mg to about 50 mg.
  • the effective dose of Compound 1 is about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg, including increments therein.
  • the effective dose of the local anesthetic is from about 0.01 mg to about 600 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 0.5 mg to about 400 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 0.5 mg to about 300 mg. In some
  • the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 0.5 mg to about 200 mg. In some
  • the effective dose of the local anesthetic is from about 0.5 mg to about 150 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 1 mg to about 150 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 1 mg to about 100 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 1 mg to about 75 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 1 mg to about 50 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 1 mg to about 40 mg.
  • the effective dose of the local anesthetic is from about 1 mg to about 30 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 1 mg to about 25 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 10 mg to about 500 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 10 mg to about 250 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 10 mg to about 200 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 10 mg to about 150 mg. In some
  • the effective dose of the local anesthetic is from about 10 mg to about 100 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 10 mg to about 75 mg. In some embodiments of the aforementioned methods, the effective dose of the local anesthetic is from about 10 mg to about 50 mg.
  • the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 1.8% (18 mg/mL). In some embodiments of the aforementioned methods, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 1.6% (16 mg/mL). In some embodiments of the aforementioned methods, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 1.4% (14 mg/mL). In some embodiments of the aforementioned methods, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 1.2% (12 mg/mL).
  • the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 1.0% (10 mg/mL). In some embodiments of the aforementioned methods, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.9% (9 mg/mL). In some embodiments of the aforementioned methods, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.8% (8 mg/mL). In some embodiments of the aforementioned methods, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.7% (7 mg/mL).
  • the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.6% (6 mg/mL). In some embodiments of the aforementioned methods, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL). In some embodiments of the aforementioned methods, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.4% (4 mg/mL). In some embodiments of the aforementioned methods, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.3% (3 mg/mL).
  • the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL). In some embodiments of the aforementioned methods, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.2% (2 mg/mL). In some embodiments of the aforementioned methods, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.15% (1.5 mg/mL). In some embodiments of the aforementioned methods, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.1% (1 mg/mL).
  • the local anesthetic is in a concentration range from about 0.1% (1 mg/mL) to about 1.0% (10 mg/mL). In some embodiments of the aforementioned methods, the local anesthetic is in a concentration range from about 0.1% (1 mg/mL) to about 0.5% (5 mg/mL). In some embodiments of the
  • the local anesthetic is in a concentration range from about 0.1% (1 mg/mL) to about 0.25% (2.5 mg/mL).
  • the effective dose of the vasoconstrictor is from about 0.1 ⁇ g to about 300 ⁇ g. In some embodiments of the
  • the effective dose of the vasoconstrictor is from about 0.1 ⁇ g to about 250 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 0.1 ⁇ g to about 200 ⁇ g. In some embodiments of the
  • the effective dose of the vasoconstrictor is from about 0.1 ⁇ g to about 150 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 0.5 ⁇ g to about 150 ⁇ g. In some embodiments of the
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 125 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 90 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 75 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 60 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the
  • vasoconstrictor is from about 1 ⁇ g to about 60 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 40 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 30 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from 1 ⁇ g to about 25 ⁇ g.
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 20 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 15 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 10 ⁇ g. In some 1 ⁇ g to about 5 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 10 ⁇ to about 150 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 10 ⁇ to about 125 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 10 ⁇ to about 100 ⁇ g. In some embodiments of the
  • the effective dose of the vasoconstrictor is from about 10 ⁇ to about 75 ⁇ g. In some embodiments of the aforementioned methods, the effective dose of the vasoconstrictor is from about 10 ⁇ to about 50 ⁇ g.
  • the vasoconstrictor is in a concentration range from about 2 ⁇ ⁇ ⁇ to about 10 ⁇ ⁇ ⁇ . In some embodiments of the aforementioned methods, the vasoconstrictor is in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ ⁇ ⁇ . In some embodiments of the aforementioned methods, the concentration of the vasoconstrictor is about 10 ⁇ ⁇ ⁇ . In some embodiments of the aforementioned methods, the concentration of the vasoconstrictor is about 9 ⁇ / ⁇ In some embodiments of the
  • the concentration of the vasoconstrictor is about 8 ⁇ g/mL. In some embodiments of the aforementioned methods, the concentration of the vasoconstrictor is about 7 ⁇ g/mL. In some embodiments of the aforementioned methods, the concentration of the vasoconstrictor is about 6 ⁇ ⁇ ⁇ . In some embodiments of the aforementioned methods, the concentration of the vasoconstrictor is about 5 ⁇ / ⁇ In some embodiments of the
  • the concentration of the vasoconstrictor is about 4 ⁇ g/mL. In some embodiments of the aforementioned methods, the concentration of the vasoconstrictor is about 3 ⁇ g/mL. In some embodiments of the aforementioned methods, the concentration of the vasoconstrictor is about 2 ⁇ ⁇ ⁇ . In some embodiments of the aforementioned methods, the concentration of the vasoconstrictor is about 1 ⁇ / ⁇ [00103] In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is post-surgical pain, post amputation pain, chronic post-surgical pain, and traumatic injury pain.
  • the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is post-surgical pain.
  • the postsurgical pain is pain from a laparotomy, thoracotomy, thoraco-abdominal incision, flank incision, total hip replacement, total knee replacement, ACL reconstruction, rotator cuff repair, bunionectomy, laparoscopy, dental extraction, or open reduction internal fixation of fractures.
  • the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the post-surgical pain is pain from a laparotomy. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the post-surgical pain is pain from a thoracotomy. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the post-surgical pain is pain from a thoraco-abdominal incision. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the post-surgical pain is pain from a flank incision.
  • the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the post-surgical pain is pain from a total hip replacement. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the post-surgical pain is pain from a total knee replacement. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the post-surgical pain is pain from an ACL reconstruction. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the post-surgical pain is pain from a rotator cuff repair.
  • the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the post-surgical pain is pain from a bunionectomy. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the post-surgical pain is pain from a laparoscopy. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the post-surgical pain is pain from a dental extraction. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the post-surgical pain is pain from an open reduction internal fixation of fractures.
  • the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is post amputation pain. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is chronic post-surgical pain. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is chronic post-surgical pain after mastectomy or lumpectomy referred to as "post mastectomy syndrome”. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is chronic post-surgical pain after thoracotomy.
  • the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is chronic post-surgical pain after amputation referred to as "stump pain".
  • the pain is a method of treating or preventing pain in a subject in need thereof, wherein the pain is traumatic injury pain.
  • the pain is traumatic injury pain from a long bone, short bone, flat bone, or irregular bone fracture.
  • the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is traumatic injury pain from a long bone fracture.
  • the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is traumatic injury pain from a short bone fracture. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is traumatic injury pain from a flat bone fracture. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is traumatic injury pain from an irregular bone fracture. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the traumatic injury pain is pain from a hip or rib fracture.
  • a method of treating or preventing pain in a subject in need thereof wherein the traumatic injury pain is pain from a hip fracture.
  • the traumatic injury pain is pain from a rib fracture.
  • the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is chronic pain.
  • embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is chronic pain associated with osteoarthritis. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is chronic pain associated with osteoarthritis of the knee. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is chronic musculoskeletal pain. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is musculoskeletal pain of the lower back.
  • the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is cancer pain, phantom limb pain, pain associated with spinal cord injury, complex regional pain syndrome, visceral pain, or peripheral neuropathy.
  • the pain is cancer pain.
  • the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is phantom limb pain.
  • the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is pain associated with spinal cord injury.
  • the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is complex regional pain syndrome. In some embodiments of the
  • aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is visceral pain. In some embodiments of the aforementioned methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is peripheral neuropathy.
  • the effective dose administered to the subject is in a dosing volume from about 1 mL to about 120 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 5 mL to about 120 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 10 mL to about 120 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 10 mL to about 110 mL.
  • the effective dose administered to the subject is in a dosing volume from about 10 mL to about 100 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 10 mL to about 90 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 10 mL to about 80 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 10 mL to about 70 mL.
  • the effective dose administered to the subject is in a dosing volume from about 10 mL to about 60 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 10 mL to about 50 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 10 mL to about 40 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 10 mL to about 30 mL.
  • the effective dose administered to the subject is in a dosing volume from about 10 mL to about 25 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 10 mL to about 30 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 30 mL to about 120 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 30 mL to about 100 mL.
  • the effective dose administered to the subject is in a dosing volume from about 30 mL to about 90 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 30 mL to about 80 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 1 mL to about 100 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 1 mL to about 75 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 1 mL to about 50 mL.
  • the effective dose administered to the subject is in a dosing volume from about 1 mL to about 25 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 1 mL to about 15 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume from about 1 mL to about 10 mL.
  • the effective dose administered to the subject is in a dosing volume of about 10 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume of about 8 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume of about 6 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume of about 5 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume of about 4 mL.
  • the effective dose administered to the subject is in a dosing volume of about 3 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume of about 2 mL. In some embodiments of the aforementioned methods, the effective dose administered to the subject is in a dosing volume of about 1 mL. [00107] In some embodiments of the aforementioned methods, the subject is awake. In some embodiments of the aforementioned methods, the subject is sedated.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine-l- carboxylate hydrochloride (Compound 1), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1- carboxylate hydrochloride (Compound 1) and a local anesthetic, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg.
  • described herein is a pharmaceutical composition for the treatment or prevention of pain
  • the pharmaceutical composition comprises an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1- carboxylate hydrochloride (Compound 1) and a local
  • compositions for the treatment or prevention of pain comprising an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1) and a local anesthetic, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy- 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1) and a local anesthetic, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 75 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1) and a local anesthetic, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 1 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy- 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine. In some embodiments, the local anesthetic is bupivacaine.
  • a pharmaceutical composition for the treatment or prevention of pain comprising an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1- carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 125 ⁇ g.
  • Compound 1 an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 125 ⁇
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon- 6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 75 ⁇ g.
  • the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-
  • Compound 1 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1) and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the effective dose of the vasoconstrictor is from about 5 ⁇ g to about 25 ⁇ g.
  • the vasoconstrictor is epinephrine. In some embodiments, the vasoconstrictor is phenylephrine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1- carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg, and the effective dose of the
  • vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 150 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • Compound 1 (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 75 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-
  • Compound 1 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 10 mg to about 75 mg, and the effective dose of the vasoconstrictor is from about 10 ⁇ g to about 150 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • Compound 1 (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 125 ⁇ g.
  • described herein is a pharmaceutical composition for the treatment or prevention of pain, wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-
  • the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • described herein is a pharmaceutical composition for the treatment or prevention of pain, wherein the pharmaceutical composition comprises an effective dose of (£)-
  • Compound 1 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 25 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 25 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon- 6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg, and the effective dose of the vasoconstrictor is from about 5 ⁇ g to about 25 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg
  • the effective dose of the vasoconstrictor is from about 5 ⁇ g to about 25 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 150 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 1 mg to about 150 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon- 6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 150 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 1 mg to about 150 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 75 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 1 mg to about 75 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon- 6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 25 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 1 mg to about 25 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 25 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 1 mg to about 25 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic, and a vasoconstrictor, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the effective dose of the local anesthetic is from about 1 mg to about 25 mg, and the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 25 ⁇ g.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the effective dose of the local anesthetic is from about 1 mg to about 25 mg
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 25 ⁇ g.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine,
  • propoxycaine hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien; and the vasoconstrictor is epinephrine.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien; and the vasoconstrictor is phenylephrine.
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine; and the vasoconstrictor is epinephrine. In some embodiments, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine; and the vasoconstrictor is phenylephrine. In some embodiments, the local anesthetic is bupivacaine and the vasoconstrictor is epinephrine. In some embodiments, the local anesthetic is bupivacaine and the vasoconstrictor is phenylephrine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1- carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l- carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL
  • a pharmaceutical composition for the treatment or prevention of pain comprising an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l- carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy- 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate
  • Compound 1 hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • the vasoconstrictor is epinephrine.
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1)
  • a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1- carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the
  • composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • Compound 1 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-
  • Compound 1 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • the pharmaceutical composition comprises an effective dose of (£)-
  • Compound 1 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • the pharmaceutical composition comprises an effective dose of (£)-
  • Compound 1 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • Compound 1 (aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is epinephrine.
  • Compound 1 a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL)
  • a vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 2 ⁇ g/mL to about 5 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the vasoconstrictor is phenylephrine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy- 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about
  • the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine. In some embodiments is a
  • compositions for the treatment or prevention of pain comprising an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.1% (10 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride
  • a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.1% (10 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.1% (10 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine,
  • propoxycaine hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien.
  • compositions for the treatment or prevention of pain
  • the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon- 6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.1% (10 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1- carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.1% (10 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride
  • Compound 1 and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.75%) (7.5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine,
  • dimethisoquien is a pharmaceutical composition for the treatment or prevention of pain, wherein the pharmaceutical composition comprises an effective dose of (£)-
  • Compound 1 (0.5 mg/mL) to about 0.75% (7.5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05%> (0.5 mg/mL) to about 0.75%
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-
  • Compound 1 (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine,
  • Compound 1 an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxy
  • propoxycaine hexylcaine, cyclomethycaine, benoxinate, butacaine, proparacaine, cocaine, phenacaine, dibucaine, falicaine, dyclonine, pramoxine, and dimethisoquien.
  • embodiments is a pharmaceutical composition for the treatment or prevention of pain, wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-
  • Compound 1 (5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of ( J E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine-l- carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8- methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride
  • Compound 1 and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25%) (2.5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethycaine, benoxinate, butacaine,
  • dimethisoquien is a pharmaceutical composition for the treatment or prevention of pain, wherein the pharmaceutical composition comprises an effective dose of (£)-
  • Compound 1 (0.5 mg/mL) to about 0.25% (2.5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), and a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL), wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • Compound 1 an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1)
  • a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL), wherein the effective
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy- 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexyl
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine.
  • Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, te
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the local anesthetic is bupivacaine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.75% (7.5 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)- 2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg.
  • Compound 1 is from about 0.01 mg to about 25 mg.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy- 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexyl
  • vasoconstrictor is epinephrine. In some embodiments is a
  • compositions for the treatment or prevention of pain comprising an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine, and the vasoconstrictor is epinephrine.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the local anesthetic is selected from the group consisting of bupivac
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l-carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is bupivacaine, and the vasoconstrictor is epinephrine.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (£)-2-methoxy- 4-((8-methylnon-6-enamido)methyl)phenyl 2-(aminom ethyl )piperidine- 1 -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, ropivacaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexyl
  • vasoconstrictor is phenylephrine. In some embodiments is a
  • compositions for the treatment or prevention of pain comprising an effective dose of (£)-2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl 2-(aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a vasoconstrictor in a concentration range from about 1 ⁇ g/mL to about 10 ⁇ g/mL, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg, the local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, tetracaine, and ropivacaine, and the vasoconstrictor is phenylephrine.
  • Compound 1 is from about 0.01 mg to about 25 mg
  • the local anesthetic is selected from the group consisting of bupivac
  • compositions for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of (i!r)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2- (aminomethyl)piperidine-l -carboxylate hydrochloride (Compound 1), a local anesthetic in a concentration range from about 0.05% (0.5 mg/mL) to about 2% (20 mg/mL), and a
  • the effective dose of Compound 1 is from about 0.01 mg to about 300 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.01 mg to about 250 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.01 mg to about 200 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of
  • Compound 1 is from about 0.01 mg to about 150 mg. In some embodiments of the
  • the effective dose of Compound 1 is from about
  • the effective dose of Compound 1 is from about 0.01 mg to about 50 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of
  • Compound 1 is from about 0.01 mg to about 30 mg. In some embodiments of the
  • the effective dose of Compound 1 is from about
  • the effective dose of Compound 1 is from about 0.01 mg to about 20 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of
  • Compound 1 is from about 0.01 mg to about 15 mg. In some embodiments of the
  • the effective dose of Compound 1 is from about
  • the effective dose of Compound 1 is from about 0.01 mg to about 13 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of
  • Compound 1 is from about 0.01 mg to about 12 mg. In some embodiments of the
  • the effective dose of Compound 1 is from about
  • the effective dose of Compound 1 is from about 0.01 mg to about 10 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of
  • Compound 1 is from about 0.01 mg to about 9 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.01 mg to about
  • the effective dose of Compound 1 is from about 0.01 mg to about 7 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about
  • the effective dose of Compound 1 is from about 0.01 mg to about 5 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of
  • Compound 1 is from about 0.01 mg to about 4 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.01 mg to about 3 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.01 mg to about 2 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.01 mg to about 1 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.01 mg to about 0.5 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of
  • Compound 1 is from about 0.1 mg to about 10 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.1 mg to about 25 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.1 mg to about 20 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.1 mg to about 15 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.1 mg to about 10 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of
  • Compound 1 is from about 0.1 mg to about 5 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.5 mg to about 25 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.5 mg to about 20 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.5 mg to about 15 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 0.5 mg to about 10 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of
  • Compound 1 is from about 0.5 mg to about 5 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 1 mg to about 100 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of Compound 1 is from about 1 mg to about 50 mg.
  • the effective dose of Compound 1 is about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg, including increments therein.
  • the effective dose of the local anesthetic is from about 0.01 mg to about 600 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 0.5 mg to about 500 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 0.5 mg to about 400 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 0.5 mg to about 300 mg. In some
  • the effective dose of the local anesthetic is from about 0.5 mg to about 250 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 0.5 mg to about 200 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 0.5 mg to about 150 mg. In some
  • the effective dose of the local anesthetic is from about 1 mg to about 150 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 1 mg to about 100 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 1 mg to about 75 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 1 mg to about 50 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 1 mg to about 40 mg.
  • the effective dose of the local anesthetic is from about 1 mg to about 30 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 1 mg to about 25 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 10 mg to about 500 mg. In some
  • the effective dose of the local anesthetic is from about 10 mg to about 250 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 10 mg to about 200 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 10 mg to about 150 mg. In some
  • the effective dose of the local anesthetic is from about 10 mg to about 100 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 10 mg to about 75 mg. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the local anesthetic is from about 10 mg to about 50 mg.
  • the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 1.8% (18 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 1.6% (16 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 1.4% (14 mg/mL).
  • the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 1.2% (12 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 1.0% (10 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.9% (9 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.8% (8 mg/mL).
  • the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.7% (7 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.6% (6 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.5% (5 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.4% (4 mg/mL).
  • the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.3% (3 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.25% (2.5 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.2% (2 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.15% (1.5 mg/mL).
  • the local anesthetic is in a concentration range from about 0.05% (0.5 mg/mL) to about 0.1% (1 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.1% (1 mg/mL) to about 1.0% (10 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.1% (1 mg/mL) to about 0.5% (5 mg/mL). In some embodiments of the aforementioned pharmaceutical compositions, the local anesthetic is in a concentration range from about 0.1% (1 mg/mL) to about 0.25% (2.5 mg/mL).
  • the effective dose of the vasoconstrictor is from about 0.1 ⁇ g to about 300 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 0.1 ⁇ g to about 250 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 0.1 ⁇ g to about 200 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 0.1 ⁇ g to about 150 ⁇ g. In some embodiments of the
  • the effective dose of the vasoconstrictor is from about 0.5 ⁇ g to about 150 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 150 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 125 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 100 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 90 ⁇ g.
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 75 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 60 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 60 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 50 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 40 ⁇ g.
  • the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 30 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from 1 ⁇ g to about 25 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 20 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 15 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 1 ⁇ g to about 10 ⁇ g.
  • the effective dose of the vasoconstrictor is from about 10 ⁇ to about 150 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 10 ⁇ to about 125 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 10 ⁇ to about 100 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 10 ⁇ to about 75 ⁇ g. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose of the vasoconstrictor is from about 10 ⁇ to about 50 ⁇ g.
  • the vasoconstrictor is in a concentration range from about 2 ⁇ / ⁇ . to about 10 ⁇ / ⁇ .. In some embodiments of the aforementioned pharmaceutical compositions, the vasoconstrictor is in a concentration range from about 2 ⁇ / ⁇ . to about 5 ⁇ / ⁇ .. In some embodiments of the aforementioned pharmaceutical compositions, the concentration of the vasoconstrictor is about 10 ⁇ / ⁇ In some embodiments of the aforementioned pharmaceutical compositions, the concentration of the vasoconstrictor is about 9 ⁇ / ⁇ In some embodiments of the
  • the concentration of the vasoconstrictor is about 8 ⁇ / ⁇ . In some embodiments of the aforementioned pharmaceutical compositions, the concentration of the vasoconstrictor is about 7 ⁇ / ⁇ In some embodiments of the
  • the concentration of the vasoconstrictor is about 6 ⁇ / ⁇ . In some embodiments of the aforementioned pharmaceutical compositions, the concentration of the vasoconstrictor is about 5 ⁇ / ⁇ In some embodiments of the
  • the concentration of the vasoconstrictor is about 4 ⁇ / ⁇ . In some embodiments of the aforementioned pharmaceutical compositions, the concentration of the vasoconstrictor is about 3 ⁇ / ⁇ In some embodiments of the
  • the concentration of the vasoconstrictor is about 2 ⁇ / ⁇ . In some embodiments of the aforementioned pharmaceutical compositions, the concentration of the vasoconstrictor is about 1 ⁇ / ⁇
  • compositions for the treatment or prevention of pain, wherein the pain is postsurgical pain, post amputation pain, chronic post-surgical pain, and traumatic injury pain.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is post-surgical pain.
  • compositions for the treatment or prevention of pain, wherein the post-surgical pain is pain from a laparotomy, thoracotomy, thoraco-abdominal incision, flank incision, total hip replacement, total knee replacement, ACL reconstruction, rotator cuff repair, bunionectomy, laparoscopy, dental extraction, or open reduction internal fixation of fractures.
  • the post-surgical pain is pain from a laparotomy, thoracotomy, thoraco-abdominal incision, flank incision, total hip replacement, total knee replacement, ACL reconstruction, rotator cuff repair, bunionectomy, laparoscopy, dental extraction, or open reduction internal fixation of fractures.
  • the post-surgical pain is pain from a laparotomy.
  • the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the post-surgical pain is pain from a thoracotomy. In some embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the post-surgical pain is pain from a thoraco-abdominal incision. In some embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the post-surgical pain is pain from a flank incision. In some embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the post-surgical pain is pain from a total hip replacement.
  • the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the post-surgical pain is pain from a total knee replacement. In some embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the post-surgical pain is pain from an ACL reconstruction. In some embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the post-surgical pain is pain from a rotator cuff repair. In some embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the post-surgical pain is pain from a bunionectomy.
  • compositions for the treatment or prevention of pain, wherein the post-surgical pain is pain from a laparoscopy. In some embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the post-surgical pain is pain from a dental extraction. In some embodiments of the
  • aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the post-surgical pain is pain from an open reduction internal fixation of fractures.
  • the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is post amputation pain.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is chronic post-surgical pain.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is chronic post-surgical pain after mastectomy or lumpectomy referred to as "post mastectomy syndrome".
  • compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is chronic post-surgical pain after thoracotomy.
  • the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is chronic post-surgical pain after thoracotomy.
  • compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is chronic post-surgical pain after amputation referred to as "stump pain".
  • pain pain is chronic post-surgical pain after amputation referred to as "stump pain".
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is traumatic injury pain.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is traumatic injury pain from a long bone, short bone, flat bone, or irregular bone fracture.
  • the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is traumatic injury pain from a long bone fracture.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is traumatic injury pain from a short bone fracture. In some embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is traumatic injury pain from a flat bone fracture. In some embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is traumatic injury pain from an irregular bone fracture.
  • compositions for the treatment or prevention of pain, wherein the traumatic injury pain is pain from a hip or rib fracture. In some embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the traumatic injury pain is pain from a hip fracture. In some embodiments of the
  • aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the traumatic injury pain is pain from a rib fracture.
  • compositions for the treatment or prevention of pain, wherein the pain is chronic pain.
  • methods is a method of treating or preventing pain in a subject in need thereof, wherein the pain is chronic pain associated with osteoarthritis.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is chronic pain associated with osteoarthritis of the knee.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is chronic musculoskeletal pain.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is musculoskeletal pain of the lower back.
  • compositions for the treatment or prevention of pain, wherein the pain is cancer pain, phantom limb pain, pain associated with spinal cord injury, complex regional pain syndrome, visceral pain, or peripheral neuropathy.
  • the pain is cancer pain.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pain is cancer pain.
  • compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is phantom limb pain. In some embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is pain associated with spinal cord injury. In some embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is complex regional pain syndrome. In some
  • embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is visceral pain. In some embodiments of the aforementioned pharmaceutical compositions is a pharmaceutical composition for the treatment or prevention of pain, wherein the pain is peripheral neuropathy.
  • the effective dose is in a dosing volume from about 10 mL to about 120 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume from about 10 mL to about 110 mL. In some embodiments of the aforementioned
  • the effective dose is in a dosing volume from about 10 mL to about 100 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume from about 10 mL to about 90 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume from about 10 mL to about 80 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume from about 10 mL to about 70 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume from about 10 mL to about 60 mL.
  • the effective dose is in a dosing volume from about 10 mL to about 50 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume from about 10 mL to about 40 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume from about 10 mL to about 30 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume from about 10 mL to about 25 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume from about 10 mL to about 30 mL.
  • the effective dose is in a dosing volume from about 30 mL to about 120 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume from about 30 mL to about 100 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume from about 30 mL to about 90 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume from about 30 mL to about 80 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume less than about 10 mL. In some embodiments of the aforementioned pharmaceutical compositions,
  • the effective dose is in a dosing volume of about 10 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume of about 8 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume of about 6 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume of about 5 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume of about 4 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume of about 3 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume of about 2 mL. In some embodiments of the aforementioned pharmaceutical compositions, the effective dose is in a dosing volume of about 1 mL.
  • the subject is awake. In some embodiments of the aforementioned methods, the subject is sedated.
  • compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • a pharmaceutical composition refers to a mixture of Compound 1 with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a subject having a disease, disorder, or condition to be treated.
  • the subject is a human.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • Compound 1 can be used singly or in combination with one or more therapeutic agents as components of mixtures (as in combination therapy).
  • compositions described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
  • parenteral e.g., intravenous, subcutaneous, intramuscular
  • intranasal e.g., buccal
  • topical e.g., topical, rectal, or transdermal administration routes.
  • compositions described herein can be formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
  • aqueous oral dispersions liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
  • Such formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug may be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • the pharmaceutical compositions will include at least one compound described herein, as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
  • the methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity.
  • compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • compositions provided herein may also include one or more preservatives to inhibit microbial activity.
  • Suitable preservatives include quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and
  • Formulations suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, saline, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Formulations suitable for subcutaneous injection may also contain additives such as preserving, wetting, emulsifying, and dispensing agents.
  • Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
  • compounds described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally recognized in the field.
  • appropriate formulations may include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally recognized in the field.
  • Compound 1 is formulated in an aqueous solution. In some embodiments described herein, Compound 1 is formulated in an acidic aqueous solution. In some embodiments described herein, Compound 1 is a powder that is reconstituted at the time of use as an aqueous solution. In some embodiments described herein is a pharmaceutical composition for the treatment or prevention of pain, wherein the
  • composition comprises an effective dose of Compound 1, and a pharmaceutically acceptable carrier, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the carrier is sterile water.
  • a pharmaceutical composition for the treatment or prevention of pain wherein the pharmaceutical composition comprises an effective dose of Compound 1, and a pharmaceutically acceptable carrier, wherein the effective dose of Compound 1 is from about 0.01 mg to about 25 mg and the carrier is sterile saline.
  • Parenteral injections may involve bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the pharmaceutical composition described herein may be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • compositions for oral use can be obtained by mixing one or more solid excipient with Compound 1, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets, pills, or capsules.
  • Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • the solid dosage forms disclosed herein may be in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol.
  • a tablet including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet
  • a pill including a sterile packaged powder
  • the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast-melt tablet. Additionally, pharmaceutical formulations of the compounds described herein may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.
  • rapidly release or “delayed release” as used herein refers to the delivery so that the release can be accomplished at some generally predictable rate.
  • the method for delay of release is either the tuning of the intramolecular cyclization-release reaction or via the addition of buffers to modify the initiation of the intramolecular cyclization- release reaction.
  • pharmaceutical formulations that include particles of Compound 1, and at least one dispersing agent or suspending agent for oral administration to a subject.
  • the formulations may be a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained.
  • the aqueous suspensions and dispersions described herein can remain in a homogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905), for at least 4 hours. The homogeneity should be determined by a sampling method consistent with regard to determining homogeneity of the entire composition. In one
  • an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 1 minute. In another embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 30 seconds. In still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion.
  • the pharmaceutical formulations described herein can be self- emulsifying drug delivery systems (SEDDS).
  • SEDDS self- emulsifying drug delivery systems
  • Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets.
  • emulsions are created by vigorous mechanical dispersion.
  • SEDDS as opposed to emulsions or microemulsions, spontaneously form emulsions when added to an excess of water without any external mechanical dispersion or agitation.
  • An advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. Additionally, water or the aqueous phase can be added just prior to administration, which ensures stability of an unstable or hydrophobic active ingredient.
  • the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients.
  • SEDDS may provide improvements in the bioavailability of hydrophobic active ingredients.
  • Methods of producing self-emulsifying dosage forms include, but are not limited to, for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.
  • compositions and formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients.
  • suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels.
  • Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents may also be present.
  • the nasal dosage form should be isotonic with nasal secretions.
  • compositions provided herein also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate),
  • polyacrylamide polycarbophil
  • acrylic acid/butyl acrylate copolymer sodium alginate and dextran.
  • Compound 1 is administered in an amount effective for amelioration of, or prevention of the development of symptoms of, the disease or disorder (i.e., a therapeutically effective amount).
  • a therapeutically effective amount can be an amount that is capable of at least partially preventing or reversing a disease or disorder.
  • the dose required to obtain an effective amount may vary depending on the agent, formulation, disease or disorder, and individual to whom the agent is administered.
  • Determination of effective amounts may also involve in vitro assays in which varying doses of agent are administered to cells in culture and the concentration of agent effective for ameliorating some or all symptoms is determined in order to calculate the concentration required in vivo. Effective amounts may also be based in in vivo animal studies.
  • An agent can be administered prior to, concurrently with and subsequent to the appearance of symptoms of a disease or disorder.
  • an agent is administered to a subject with a family history of the disease or disorder, or who has a phenotype that may indicate a predisposition to a disease or disorder, or who has a genotype which predisposes the subject to the disease or disorder.
  • Targets for delivery can be specific cells which are causing or contributing to a disease or disorder.
  • a target cell can be resident or infiltrating cells in the nervous system contributing to a neurological, neurodegenerative or demyelinating disease or disorder.
  • Administration of an agent can be directed to one or more cell types or subsets of a cell type by methods recognized in the field.
  • an agent can be coupled to an antibody, ligand to a cell surface receptor or a toxin, or can be contained in a particle that is selectively internalized into cells, e.g., liposomes or a virus in which the viral receptor binds specifically to a certain cell type, or a viral particle lacking the viral nucleic acid, or can be administered locally.
  • Compound 1 described herein can be used in the preparation of medicaments for the modulation of TRPV1, or for the treatment of diseases or conditions that would benefit, at least in part, from modulation of TRPV1.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of a pharmaceutical composition containing Compound 1 described herein.
  • compositions containing Compound 1 described herein can be administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
  • compositions containing Compound 1 described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
  • prophylactically effective amount or dose the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • Compound 1 may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment will typically be in the range of about 0.001 mg per day to about 5000 mg per day, in some embodiments, about 1 mg per day to about 1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Non- limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
  • compositions described herein are combination treatments comprising Compound 1, and at least one of a local anesthetic and vasoconstrictor.
  • the compositions described herein and, in embodiments where combinational therapy is employed the agents do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes.
  • the determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition is well within the knowledge of the clinician.
  • the initial administration can be made according to established protocols recognized in the field, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the clinician.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • the overall benefit experienced by the patient may simply be additive of the therapeutic agents or the patient may experience a synergistic benefit.
  • the particular choice of compounds used will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.
  • the compounds may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the disease, disorder, or condition, the condition of the patient, and the actual choice of compounds used.
  • the determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the physician after evaluation of the disease being treated and the condition of the patient.
  • Therapeutically-effective dosages can vary when the drugs are used in treatment combinations. Methods for experimentally determining therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects, has been described extensively in the literature. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
  • the compound provided herein may be administered either simultaneously with the biologically active agent(s), or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein in combination with the biologically active agent(s).
  • the multiple therapeutic agents described herein may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single injection or as two separate injections). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may vary from more than zero weeks to less than four weeks.
  • the combination methods, compositions and formulations are not to be limited to the use of only two agents; the use of multiple therapeutic combinations are also envisioned.
  • the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought can be modified in accordance with a variety of factors. These factors include the disorder or condition from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the dosage regimens set forth herein.
  • the pharmaceutical agents which make up the combination therapy disclosed herein may be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration.
  • the pharmaceutical agents that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration.
  • the two-step administration regimen may call for sequential administration of the active agents or spaced-apart administration of the separate active agents.
  • the time period between the multiple administration steps may range from, a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent. Circadian variation of the target molecule concentration may also determine the optimal dose interval.
  • the compounds described herein also may be used in combination with procedures that may provide additional or synergistic benefit to the patient.
  • patients are expected to find therapeutic and/or prophylactic benefit in the methods described herein, wherein pharmaceutical composition of a compound disclosed herein and /or combinations with other therapeutics are combined with genetic testing to determine whether that individual is a carrier of a mutant gene that is known to be correlated with certain diseases or conditions.
  • the compounds described herein and combination therapies can be administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound can vary.
  • the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms.
  • the administration of the compounds can be initiated within the first 48 hours of the onset of the symptoms, preferably within the first 48 hours of the onset of the symptoms, more preferably within the first 6 hours of the onset of the symptoms, and most preferably within 3 hours of the onset of the symptoms.
  • the initial administration can be via any route practical, such as, for example, an intravenous injection, a bolus injection, infusion over about 5 minutes to about 5 hours, a pill, a capsule, transdermal patch, buccal delivery, and the like, or combination thereof.
  • a compound is preferably administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from 1 day to about 3 months.
  • the length of treatment can vary for each subject, and the length can be determined using the known criteria.
  • the compound or a formulation containing the compound can be administered for at least 2 weeks, preferably about 1 month to about 5 years.
  • kits and articles of manufacture are also described herein.
  • Such kits can include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) including one of the separate elements to be used in a method described herein.
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers can be formed from a variety of materials such as glass or plastic.
  • the container(s) can include one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein.
  • the container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.
  • a kit will typically may include one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein.
  • materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use.
  • a set of instructions will also typically be included.
  • the kit is a two chamber container that holds the local anesthetic (liquid) and compound 1 (solid) to facilitate sterile reconstitution.
  • a label can be on or associated with the container.
  • a label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein.
  • This Example compares the pharmacokinetics of capsaicin from either capsaicin or from Compound 1 (with or without co-administered bupivacaine or lidocaine or bupivacaine with epinephrine or lidocaine with epinephrine) administered subcutaneously (SC) to rats.
  • this example compares the pharmacokinetics of cyclic urea metabolite (Compound 2) from Compound 1 (with or without co-administered bupivacaine or lidocaine or bupivacaine with epinephrine or lidocaine with epinephrine).
  • SC dosing Four groups of five male Sprague-Dawley rats (vendor was Charles River Laboratories) each were to receive a single subcutaneous dose (4 mL/kg) of one of the following test articles:
  • Group 2 1.57 mg/kg Compound 1 HO in 0.5% bupivacaine hydrochloride for injection ( ⁇ ); Group 3) 1.57 mg/kg Compound 1 HO in 0.5% bupivacaine hydrochloride plus epinephrine, (1 :200,000 for injection) (+)
  • bupivacaine/lidocaine for Groups 1-5 were within 10%> of the intended doses.
  • the concentrations of the two main analytes in rat plasma was determined simultaneously using a qualified LC-MS/MS assay. The results for both analytes were reported in ng/mL.
  • the calibration range was 1 to 1,000 ng/mL for Compound 1 (data not shown) and capsaicin in the mixed matrix.
  • the calibration range was 5 to 1,000 ng/mL for Compound 2.
  • Table 1, Fig. 1, and Fig. 2 provide dose-corrected capsaicin exposure results for rats administered as described above. Results in Table 1 are reported, for each group of rats, as (a) maximum plasma concentration (Cmax) of capsaicin (average), (b) time after administration of test article for capsaicin to reach maximum concentration (Tmax) (average), and (c) area under the curve (AUC) from 0 to 24 h for capsaicin (average).
  • Table 1 PK parameters for Capsaicin from Groups 1-5 for dosing of Compound 1
  • Table 2, Fig. 3, and Fig. 4 provide Compound 2 exposure results for rats administered as described above. Results in Table 2 are reported, for each group of rats, as (a) maximum plasma concentration (Cmax) of Compound 2 (average), (b) time after administration of test article for Compound 2 to reach maximum concentration (Tmax) (average), and (c) area under the curve (AUC) from 0 to 24h for Compound 2 (average).
  • Example 3 Efficacy of Compound 1 in Comparison to Standard of Care for the Treatment of Post-Operative Dental Implant Pain

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Abstract

La présente invention concerne des composés, des compositions pharmaceutiques et des médicaments contenant de tels composés, et des procédés d'utilisation de tels composés afin de moduler l'activité du récepteur vanilloïde 1 à potentiel de récepteur transitoire (TRPV1).
PCT/US2018/034206 2017-05-24 2018-05-23 Promédicaments à base d'agonistes de trpv1 phénoliques en combinaison avec des anesthésiques locaux et des vasoconstricteurs pour améliorer une anesthésie locale WO2018217937A1 (fr)

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US10493047B2 (en) 2016-11-02 2019-12-03 Centrexion Therapeutics Corporation Stable aqueous capsaicin injectable formulations and medical uses thereof
US11026903B2 (en) 2017-07-20 2021-06-08 Centrexion Therapeutics Corporation Methods and compositions for treatment of pain using capsaicin
US11254659B1 (en) 2019-01-18 2022-02-22 Centrexion Therapeutics Corporation Capsaicinoid prodrug compounds and their use in treating medical conditions
US11447444B1 (en) 2019-01-18 2022-09-20 Centrexion Therapeutics Corporation Capsaicinoid prodrug compounds and their use in treating medical conditions

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US20040156931A1 (en) * 2002-12-18 2004-08-12 Algorx Administration of capsaicinoids
US20160145225A1 (en) * 2014-11-25 2016-05-26 Concentric Analgesics, Inc. Prodrugs of phenolic trpv1 agonists
WO2017205534A1 (fr) * 2016-05-25 2017-11-30 Concentric Analgesics, Inc. Promédicaments à base d'agonistes de trpv1 phénoliques en association avec des anesthésiques locaux et des vasoconstricteurs pour améliorer une anesthésie locale

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WO2017205534A1 (fr) * 2016-05-25 2017-11-30 Concentric Analgesics, Inc. Promédicaments à base d'agonistes de trpv1 phénoliques en association avec des anesthésiques locaux et des vasoconstricteurs pour améliorer une anesthésie locale

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US10493047B2 (en) 2016-11-02 2019-12-03 Centrexion Therapeutics Corporation Stable aqueous capsaicin injectable formulations and medical uses thereof
US10765649B2 (en) 2016-11-02 2020-09-08 Centrexion Therapeutics Corporation Stable aqueous capsaicin injectable formulations and medical uses thereof
US10772853B2 (en) 2016-11-02 2020-09-15 Centrexion Therapeutics Corporation Stable aqueous capsaicin injectable formulations and medical uses thereof
US11000490B2 (en) 2016-11-02 2021-05-11 Centrexion Therapeutics Corporation Stable aqueous capsaicin injectable formulations and medical uses thereof
US11344516B2 (en) 2016-11-02 2022-05-31 Centrexion Therapeutics Corporation Stable aqueous capsaicin injectable formulations and medical uses thereof
US11992470B2 (en) 2016-11-02 2024-05-28 Centrexion Therapeutics Corporation Stable aqueous capsaicin injectable formulations and medical uses thereof
US11026903B2 (en) 2017-07-20 2021-06-08 Centrexion Therapeutics Corporation Methods and compositions for treatment of pain using capsaicin
US11254659B1 (en) 2019-01-18 2022-02-22 Centrexion Therapeutics Corporation Capsaicinoid prodrug compounds and their use in treating medical conditions
US11447444B1 (en) 2019-01-18 2022-09-20 Centrexion Therapeutics Corporation Capsaicinoid prodrug compounds and their use in treating medical conditions
US11820727B1 (en) 2019-01-18 2023-11-21 Centrexion Therapeutics Corporation Capsaicinoid prodrug compounds and their use in treating medical conditions

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