Compositions and methods for preventing and/or treating disorders associated with cephalic pain

Abstract

Compounds, e.g., of formula (I) and (Ia), pharmaceutical compositions comprising the compounds and methods of using the compounds and pharmaceutical compositions for treating pain disorders, e.g., disorders associated with cephalic pain, are provided.

1 . Lysergic acid amide (LSA) in a substantially pure form in an amount of between 50 μg and about 5000 μg. 
     
     
         2 - 4 . (canceled) 
     
     
         5 . A pharmaceutical composition comprising the LSA of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         6 . The pharmaceutical composition of  claim 5 , which is in form suitable for parenteral administration or enteral administration. 
     
     
         7 . (canceled) 
     
     
         8 . A therapeutic package for dispensing the LSA of  claim 1  to, or for use in dispensing the LSA of  claim 1  to, a subject with a disorder associated with cephalic pain, which comprises: (a) the LSA of  claim 1 , wherein the LSA is present in one or more unit dosage forms suitable for parenteral administration; and (b) a container containing the unit dosage form or unit dosage forms of LSA, wherein said package optionally further comprises a package insert which indicates to physicians and purchasers that the LSA enclosed therein, when administered as instructed on the package insert, is effective in treating a disorder associated with cephalic pain. 
     
     
         9 . (canceled) 
     
     
         10 . The package of  claim 8 , wherein the LSA is in a form suitable for transmucosal administration or subcutaneous administration. 
     
     
         11 . The package of  claim 10 , wherein the LSA is in a form suitable for sublingual administration, rectal or vaginal administration. 
     
     
         12 - 13 . (canceled) 
     
     
         14 . A therapeutic package for dispensing the LSA of  claim 1  to, or for use in dispensing the LSA of  claim 1 , to a subject with a disorder associated with cephalic pain, which comprises (a) the LSA of  claim 1  in one or more unit dosage forms suitable for enteral administration; and (b) a container containing the unit dosage form or unit dosage forms of LSA wherein said package optionally further comprises a package insert which indicates to physicians and purchasers that the LSA enclosed therein, when administered as instructed on the package insert, is effective in treating a disorder associated with cephalic pain. 
     
     
         15 - 16 . (canceled) 
     
     
         17 . A method for treating a disorder associated with cephalic pain, comprising administering to a subject in need of such treatment a therapeutically effective amount of an ergoline derivative. 
     
     
         18 . The method of  claim 17 , wherein the ergoline derivative is a substantially pure form of LSA. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 17  wherein said cephalic pain is a trigeminal autonomic cephalalgia is selected from the group consisting of episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). 
     
     
         21 . The method of  claim 20 , wherein the trigeminal autonomic cephalalgia is episodic or chronic CH. 
     
     
         22 . The method of  claim 20 , wherein the disorder associated with cephalic pain is selected from the group consisting of a vascular headache, a tension headache, a headache associated with a substance or its withdrawal. 
     
     
         23 . The method of  claim 22 , wherein the vascular headache is a migraine headache. 
     
     
         24 . The method of  claim 17 , wherein the therapeutically effective amount is between about 50 μg and about 5000 μg. 
     
     
         25 . The method of  claim 17 , further comprising administering to the subject a second compound which acutely relieves at least one symptom of the disorder associated with cephalic pain. 
     
     
         26 . The method of  claim 25 , wherein the second compound is selected from the group consisting of oxygen, a serotonin receptor agonist, an ergot derivative, a hormone, and a local anesthetic. 
     
     
         27 . The method of  claim 17 , further comprising administering a second compound selected from the group consisting of lithium, melatonin, a calcium channel blocker, a hormone, an anticonvulsant agent, an opioid receptor antagonist and a sedative. 
     
     
         28 . The method of  claim 27 , wherein the second compound is an opioid receptor antagonist. 
     
     
         29 . The method of  claim 17 , comprising administering the ergoline derivative to the subject at least once a day. 
     
     
         30 . The method of  claim 17 , comprising administering the ergoline derivative to the subject at least once every other day. 
     
     
         31 - 36 . (canceled) 
     
     
         37 . The method of  claim 17 , wherein the ergoline derivative is administered enterally, orally, parenterally, transmucosally, sublingually or subcutaneously. 
     
     
         38 - 42 . (canceled) 
     
     
         43 . A method for treating a disorder associated with cephalic pain, comprising administering to a subject in need of such treatment a therapeutically effective amount of an ergoline derivative and a therapeutically effective amount of an opioid receptor antagonist. 
     
     
         44 . The method of  claim 43 , wherein the ergoline derivative is a substantially pure form of LSA. 
     
     
         45 . The method of  claim 43 , wherein the ergoline derivative and opioid receptor antagonist are administered at least once a day. 
     
     
         46 . (canceled) 
     
     
         47 . The method of  claim 43 , further comprising administering oxygen to the subject. 
     
     
         48 . The method of  claim 43 , wherein the subject has not received a headache medication for at least five days prior to administration of the ergoline derivative and the opioid receptor antagonist. 
     
     
         49 . The method of  claim 17  or  claim 43 , wherein the subject is a human. 
     
     
         50 . A method for preventing a disorder associated with cephalic pain in a subject in need thereof, comprising administering to the subject, during a period in which the subject is not suffering from cephalic pain, an ergoline derivative. 
     
     
         51 . The method of  claim 50 , wherein the ergoline derivative is a substantially pure form of LSA. 
     
     
         52 . (canceled) 
     
     
         53 . The method of,  claim 50  wherein said cephalic pain is a trigeminal autonomic cephalalgia is selected from the group consisting of episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). 
     
     
         54 . The method of  claim 53 , wherein the trigeminal autonomic cephalalgia is episodic or chronic CH. 
     
     
         55 . The method of  claim 54 , wherein the administration of the ergoline derivative is during a period of remission from a CH. 
     
     
         56 . The method of  claim 53 , wherein the disorder associated with cephalic pain is selected from the group consisting of a vascular headache, a tension headache, a headache associated with a substance or its withdrawal. 
     
     
         57 . The method of  claim 56 , wherein the vascular headache is a migraine headache. 
     
     
         58 . The method of  claim 50 , wherein the therapeutically effective amount of the ergoline derivative is between about 50 μg and about 5000 μg. 
     
     
         59 . The method of  claim 50 , wherein the ergoline derivative is administered at least once a week. 
     
     
         60 - 64 . (canceled) 
     
     
         65 . The method of  claim 50 , further comprising administering a second compound selected from the group consisting of a mood stabilizer, a hormone, a calcium channel blocker, an anticonvulsant agent, an opioid receptor antagonist and a sedative. 
     
     
         66 . The method of  claim 65 , wherein the mood stabilizer is lithium. 
     
     
         67 . The method of  claim 65 , wherein the hormone is melatonin.