Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile

Abstract

Pharmaceutical compositions containing dihydroergotamine (DHE) and methods in which DHE is administered to patients for treatment of migraine without side effects or adverse effects are disclosed. Methods for rapid treatment of migraine with DHE are disclosed comprising: dampening the peak plasma concentration (C max ) and slightly delaying the peak such as to avoid activating the dopaminergic and adrenergic receptors, while achieving sufficient active binding to the serotonin receptors to provide relief from migraine symptoms within a timeframe that permits rapid resolution of migraine symptoms. Inhaler devices suitable for the methods are disclosed. Kits for practicing the methods of invention are disclosed.

What is claimed is: 
     
         1 . A method for rapid treatment of migraine in a human with dihydroergotamine (DHE), while minimizing side effects, the method comprising:
 administering to the individual an amount of a DHE formulation sufficient to provide relief from a migraine symptom, wherein said formulation is administered at a rate such that the peak plasma concentration (C max ) of DHE is less than 20,000 pg/ml, and the time to C max  (T max ) is less than 20 minutes, and further wherein a dose of less than 2.0 mg DHE is administered and rate of DHE administration causes a low incidence of a drug-induced side effect.   
     
     
         2 . The method of  claim 1 , wherein the side effect is selected from the group consisting of nausea, emesis, vasospasm, paraesthesia, hypertension, dizziness, anxiety, dyspnea, headache, flushing, diarrhea, rash, increased sweating, cardiac valvulopathy, pleural and retroperitoneal fibrosis, adverse cardiovascular effect, blood pressure instability and arterial constriction. 
     
     
         3 . The method of  claim 1 , wherein the side effect is selected from the group consisting of nausea and emesis. 
     
     
         4 . The method of  claim 1 , wherein the DHE is administered at a rate such that the C max  of DHE is less than 15,000 pg/ml. 
     
     
         5 . The method of  claim 4 , wherein the C max  of DHE is less than 10,000 pg/mL. 
     
     
         6 . The method of  claim 4 , wherein the C max  of DHE is less than 7500 pg/mL. 
     
     
         7 . The method of  claim 4 , wherein the DHE is administered at a rate such that T max  of is less than 15 minutes. 
     
     
         8 . The method of  claim 1 , wherein the DHE is administered at a rate such that the C max  of DHE is at least 10-fold reduced from the C max  of DHE administered by direct intravenous delivery. 
     
     
         9 . The method of  claim 1 , wherein the DHE is administered at a rate such that the T max  of DHE is at least 1 minute delayed from the T max  of DHE administered by direct intravenous delivery. 
     
     
         10 . The method of  claim 7 , wherein the administration of DHE to achieve the C max  and T max  levels results in at least partial relief from a migraine syndrome selected from the group consisting of pain, nausea, phonophobia and photophobia, wherein the relief is achieved in 30 minutes or less, and further wherein drug-induced nausea, cardiovascular side effects or other adverse effects are reduced. 
     
     
         11 . The method of  claim 1 , wherein a dose of less than 2.0 mg DHE is administered and an area under the curve of the concentration of the drug in the systemic circulation versus time (AUC) of the drug delivered is within 75% of the comparable intravenous (IV) delivered dose of DHE. 
     
     
         12 . The method of  claim 1 , wherein the administration results in a C max  of a primary active metabolite of DHE of less than 1,000 pg/mL. 
     
     
         13 . The method of  claim 12 , wherein the primary active metabolite of DHE is 8-hydroxy-dihydroergotamine. 
     
     
         14 . The method of  claim 12 , wherein the C max  of the primary metabolite is less than 500 pg/mL. 
     
     
         15 . The method of  claim 12 , wherein the C max  of the primary metabolite is less than 200 pg/mL. 
     
     
         16 . The method of  claim 12 , wherein the T max  of the primary metabolite is less than 90 minutes. 
     
     
         17 . The method of  claim 1 , wherein the DHE formulation is administered by a mode selected from the group consisting of: intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, sublingual, buccal, intranasal, oral inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, iontophoresis, and transdermal administration. 
     
     
         18 . The method of  claim 17 , wherein the DHE formulation is administered by pulmonary inhalation using an aerosol, a dry powder inhaler, nebulizer, vaporizer, or a pressurized metered dose inhaler (pMDI). 
     
     
         19 . The method of  claim 17 , wherein the DHE formulation is administered by a breath activated metered dose inhaler. 
     
     
         20 . The method of  claim 1 , wherein the DHE formulation is administered by a mode selected from the group consisting of intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, sublingual, buccal, intranasal, oral inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, iontophoresis, and transdermal administration, and
 further wherein the DHE is administered at a rate such that the C max  of DHE is less than 10,000 pg/mL and T max  is less than 20 minutes after administration.   
     
     
         21 . The method of  claim 20 , wherein the DHE formulation is administered by pulmonary inhalation using an aerosol, a dry powder inhaler, nebulizer, vaporizer, or a pressurized metered dose inhaler (pMDI). 
     
     
         22 . The method of  claim 21 , wherein the DHE formulation is administered by a breath activated metered dose inhaler. 
     
     
         23 . The method of  claim 22 , wherein the DHE formulation is administered without administering an anti-emetic to the individual. 
     
     
         24 . The method of  claim 1 , wherein the DHE formulation is administered to an individual by a breath activated metered dose inhaler,
 wherein the DHE is administered at a rate such that the C max  of DHE is less than 10,000 pg/mL and the T max  is less than 20 minutes after administration, and   further wherein the DHE formulation is administered without administering an anti-emetic to the individual.