Method of providing sustained analgesia with buprenorphine

Abstract

A method of effectively treating pain in humans is achieved by administering buprenorphine in accordance with first order kinetics over an initial three-day dosing interval, such that a maximum plasma concentration from about 20 pg/ml to about 1052 pg/ml is attained, and thereafter maintaining the administration of buprenorphine for at least an additional two-day dosing interval in accordance with substantially zero order kinetics, such that the patients experience analgesia throughout the at least two-day additional dosing interval.

1 . A method of effectively treating pain in humans, comprising
 administering buprenorphine to human patients in a manner such that the following mean plasma concentrations are achieved over a 72 hour dosing interval:   a mean plasma concentration from about 0.3 to about 113 pg/ml at about 6 hours after initiation of the dosing interval;   a mean plasma concentration from about 3 to about 296 pg/ml at about 12 hours after initiation of the dosing interval;   a mean plasma concentration from about 7 to about 644 pg/ml at about 24 hours after initiation of the dosing interval;   a mean plasma concentration from about 13 to about 753 pg/ml at about 36 hours after initiation of the dosing interval;   a mean plasma concentration from about 16 to about 984 pg/ml at about 48 hours after initiation of the dosing interval;   a mean plasma concentration from about 20 to about 984 pg/ml at about 60 hours after initiation of the dosing interval;   a mean plasma concentration from about 21 to about 1052 pg/ml at about 72 hours after initiation of the dosing interval; and   thereafter administering the buprenorphine in a manner such that the mean plasma concentrations are maintained from about 19 to about 1052 pg/ml over at least the next 48 hours.   
     
     
         2 . The method of  claim 1 , further comprising administering the buprenorphine in a manner such that the mean plasma concentrations are maintained as follows:
 a mean plasma concentration from about 23 to about 1052 pg/ml at about 96 hours after initiation of the dosing interval;   a mean plasma concentration from about 23 to about 1052 pg/ml at about 120 hours after initiation of the dosing interval;   a mean plasma concentration from about 22 to about 970 pg/ml at about 144 hours after initiation of the dosing interval; and   a mean plasma concentration from about 19 to about 841 pg/ml at about 168 hours after initiation of the dosing interval.   
     
     
         3 . The method of  claim 1  wherein said administration of buprenorphine is accomplished via a mode selected from the group consisting of transdermal, continuous infusion, and a mixture of transdermal and continuous infusion. 
     
     
         4 . The method of  claim 1 , wherein said administration is accomplished by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for at least 5 days. 
     
     
         5 . The method of  claim 4 , further comprising maintaining a mean relative release rate from about 3 ug/hr to about 86 ug/hr from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and a mean relative release rate from about 0.3 ug/hr to about 9 ug/hr from about 72 hours after the initiation of the dosing interval until the end of dosing interval. 
     
     
         6 .- 34 . (canceled) 
     
     
         35 . A method of effectively treating pain in humans, comprising administering buprenorphine transdermally to human patients such that mean relative release rates are achieved over a dosing interval as follows:
 a mean relative release rate of from about 3 ug/hr to about 86 ug/hr from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and   a mean relative release rate of about 0.3 ug/hr to about 9 ug/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.   
     
     
         36 .- 41 . (canceled) 
     
     
         42 . A method of effectively treating pain in humans, comprising
 applying transdermal delivery systems containing buprenorphine as the active ingredient onto the skin of patients which provide a substantially first order release rate of buprenorphine over a first three-day dosing interval, such that a mean plasma concentration from about 21 to about 1052 pg/ml is attained about 72 hours after application of said transdermal delivery system;   and maintaining said transdermal delivery systems on the skin of the patients for at least an additional two-day dosing interval during which said transdermal delivery system provides substantially zero order kinetics, such that a mean relative release rate from about 0.3 μg/hr to about 9 μg/hr is maintained over said at least two-day additional dosing interval and the patients experience analgesia throughout the at least two-day additional dosing interval.   
     
     
         43 . The method of  claim 42 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 
     
     
         44 . The method of  claim 43 , wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 
     
     
         45 .- 62 . (canceled) 
     
     
         63 . A method of effectively treating pain in humans, comprising
 applying a transdermal delivery system containing buprenorphine as the active ingredient onto the skin of patients which provide a first order release rate of buprenorphine over a three-day dosing interval, such that a maximum plasma concentration from about 20 pg/ml to about 1052 pg/ml is attained, and   maintaining said transdermal delivery systems on the skin of the patients for at least an additional two-day dosing interval during which said transdermal delivery system provides substantially zero order kinetics, such that the patients experience analgesia throughout the at least two-day additional dosing interval.   
     
     
         64 .- 67 . (canceled)