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 maimer 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 5 , 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 . 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 1 to about 28 pg/ml at about 6 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 14 to about 74 pg/ml at about 12 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 30 to about 161 pg/ml at about 24 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 51 to about 188 pg/ml at about 36 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 62 to about 246 pg/ml at about 48 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 79 to about 246 pg/ml at about 60 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 85 to about 263 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 77 to about 263 pg/ml over at least the next 48 hours.  
   
     
     
         7 . The method of  claim 6 , further comprising administering the buprenorphine in a manner such that the mean plasma concentrations are maintained as follows: 
 a mean plasma concentration from about 92 to about 263 pg/ml at about 96 hours after initiation of the dosing interval;    a mean plasma concentration from about 94 to about 263 pg/ml at about 120 hours after initiation of the dosing interval;    a mean plasma concentration from about 86 to about 243 pg/ml at about 144 hours after initiation of the dosing interval; and    a mean plasma concentration from about 77 to about 210 pg/ml at about 168 hours after initiation of the dosing interval.    
     
     
         8 . The method of  claim 6  wherein said administration of buprenorphine is accomplished via a mode selected from the group consisting of transdermally, continuous infusion, and a mixture of transdermally and continuous infusion.  
     
     
         9 . The method of  claim 6 , 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.  
     
     
         10 . The method of  claim 9 , further comprising maintaining a mean relative release rate of from about 13 ug/hr to about 21 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 1 ug/hr to about 2 ug/hr from about 72 hours after the initiation of the dosing interval until the end of the seven-day dosing interval.    
     
     
         11 . 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 7 pg/ml at about 6 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 4 to about 19 pg/ml at about 12 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 7 to about 40 pg/ml at about 24 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 13 to about 47 pg/ml at about 36 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 16 to about 62 pg/ml at about 48 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 20 to about 62 pg/ml at about 60 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 21 to about 66 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 66 pg/ml over at least the next 48 hours.  
   
     
     
         12 . The method of  claim 11 , 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 66 pg/ml at about 96 hours after initiation of the dosing interval;    a mean plasma concentration from about 23 to about 66 pg/ml at about 120 hours after initiation of the dosing interval;    a mean plasma concentration from about 22 to about 61 pg/ml at about 144 hours after initiation of the dosing interval; and    a mean plasma concentration from about 19 to about 53 pg/ml at about 168 hours after initiation of the dosing interval.    
     
     
         13 . The method of  claim 11  wherein said administration of buprenorphine is accomplished via a mode selected from the group consisting of transdermally, continuous infusion, and a mixture of transdermally and continuous infusion.  
     
     
         14 . The method of  claim 11 , 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.  
     
     
         15 . The method of  claim 14 , further comprising maintaining a mean relative release rate of from about 3 ug/hr to about 5 ug/hr from the initiation of the seven-day dosing interval until about 72 hours after the initiation of the seven-day dosing interval; and 
 a mean relative release rate of about 0.3 ug/hr to about 0.6 ug/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.    
     
     
         16 . 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 0.7 to about 14 pg/ml at about 6 hours after initiation of the dosing interval;    a mean plasma concentration from about 7 to about 37 pg/ml at about 12 hours after initiation of the dosing interval;    a mean plasma concentration from about 15 to about 80 pg/ml at about 24 hours after initiation of the dosing interval;    a mean plasma concentration from about 25 to about 94 pg/ml at about 36 hours after initiation of the dosing interval;    a mean plasma concentration from about 31 to about 123 pg/ml at about 48 hours after initiation of the dosing interval;    a mean plasma concentration from about 40 to about 123 pg/ml at about 60 hours after initiation of the dosing interval;    a mean plasma concentration from about 42 to about 132 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 38 to about 132 pg/ml over at least the next 48 hours.    
     
     
         17 . The method of  claim 16 , further comprising administering the buprenorphine in a manner such that the mean plasma concentrations are maintained as follows: 
 a mean plasma concentration from about 46 to about 132 pg/ml at about 96 hours after initiation of the dosing interval;    a mean plasma concentration from about 47 to about 132 pg/ml at about 120 hours after initiation of the dosing interval;    a mean plasma concentration from about 43 to about 121 pg/ml at about 144 hours after initiation of the dosing interval; and    a mean plasma concentration from about 38 to about 105 pg/ml at about 168 hours after initiation of the dosing interval.    
     
     
         17 . The method of  claim 16 , wherein said administration of buprenorphine is accomplished via a mode selected from the group consisting of transdermally, continuous infusion, and a mixture of transdermally and continuous infusion.  
     
     
         18 . The method of  claim 16 , 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.  
     
     
         19 . The method of  claim 18 , further comprising maintaining a mean relative release rate of from about 6 ug/hr to about 11 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 0.7 ug/hr to about 1 ug/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.    
     
     
         20 . 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 3 to about 57 pg/ml at about 6 hours after initiation of the dosing interval;    a mean plasma concentration from about 28 to about 148 pg/ml at about 12 hours after initiation of the dosing interval;    a mean plasma concentration from about 59 to about 322 pg/ml at about 24 hours after initiation of the dosing interval;    a mean plasma concentration from about 102 to about 377 pg/ml at about 36 hours after initiation of the dosing interval;    a mean plasma concentration from about 124 to about 492 pg/ml at about 48 hours after initiation of the dosing interval;    a mean plasma concentration from about 159 to about 492 pg/ml at about 60 hours after initiation of the dosing interval;    a mean plasma concentration from about 169 to about 526 pg/ml at about 60 hours after initiation of the dosing interval;    thereafter administering the buprenorphine in a manner such that the mean plasma concentrations are maintained from about 153 to about 526 pg/ml over at least the next 48 hours.    
     
     
         21 . The method of  claim 20 , further comprising administering the buprenorphine in a manner such that the mean plasma concentrations are maintained as follows: 
 a mean plasma concentration from about 184 to about 526 pg/ml at about 96 hours after initiation of the dosing interval;    a mean plasma concentration from about 187 to about 526 pg/ml at about 120 hours after initiation of the dosing interval;    a mean plasma concentration from about 173 to about 485 pg/ml at about 144 hours after initiation of the dosing interval;    a mean plasma concentration from about 153 to about 420 pg/ml at about 168 hours after initiation of the dosing interval.    
     
     
         22 . The method of  claim 20 , wherein said administration of buprenorphine is accomplished via a mode selected from the group consisting of transdermally, continuous infusion, and a mixture of transdermally and continuous infusion.  
     
     
         23 . The method of  claim 20 , 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.  
     
     
         24 . The method of  claim 23 , further comprising maintaining a mean relative release rate of from about 26 ug/hr to about 43 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 2 ug/hr to about 4 ug/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.    
     
     
         25 . 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 4 to about 85 pg/ml at about 6 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 42 to about 222 pg/ml at about 12 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 89 to about 483 pg/ml at about 24 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 152 to about 565 pg/ml at about 36 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 186 to about 738 pg/ml at about 48 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 238 to about 738 pg/ml at about 48 hours after initiation of the dosing interval;  
   a mean plasma concentration from about 254 to about 789 pg/ml at about 60 hours after initiation of the dosing interval;    thereafter administering the buprenorphine in a manner such that the mean plasma concentrations are maintained from about 230 to about 789 pg/ml over at least the next 48 hours.    
     
     
         26 . The method of  claim 25 , further comprising administering the buprenorphine in a manner such that the mean plasma concentrations are maintained as follows: 
 a mean plasma concentration from about 276 to about 789 pg/ml at about 96 hours after initiation of the dosing interval;    a mean plasma concentration from about 281 to about 789 pg/ml at about 120 hours after initiation of the dosing interval;    a mean plasma concentration from about 259 to about 727 pg/ml at about 144 hours after initiation of the dosing interval;    a mean plasma concentration from about 230 to about 630 pg/ml at about 168 hours after initiation of the dosing interval.    
     
     
         27 . The method of  claim 25 , wherein said administration of buprenorphine is accomplished via a mode selected from the group consisting of transdermally, continuous infusion, and a mixture of transdermally and continuous infusion.  
     
     
         28 . The method of  claim 25 , 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.  
     
     
         29 . The method of  claim 28 , further comprising maintaining a mean relative release rate of from about 38 ug/hr to about 64 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 4 ug/hr to about 7 ug/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.    
     
     
         30 . 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 5 to about 113 pg/ml at about 6 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 55 to about 296 pg/ml at about 12 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 118 to about 644 pg/ml at about 24 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 203 to about 753 pg/ml at about 36 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 247 to about 984 pg/ml at about 48 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 317 to about 984 pg/ml at about 60 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 339 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 306 to about 1052 pg/ml over at least the next 48 hours.  
   
     
     
         31 . The method of  claim 30 , further comprising administering the buprenorphine in a manner such that the mean plasma concentrations are maintained as follows: 
 a mean plasma concentration from about 369 to about 1052 pg/ml at about 96 hours after initiation of the dosing interval;    a mean plasma concentration from about 374 to about 1052 pg/ml at about 120 hours after initiation of the dosing interval;    a mean plasma concentration from about 346 to about 970 pg/ml at about 144 hours after initiation of the dosing interval;    a mean plasma concentration from about 306 to about 841 pg/ml at about 168 hours after initiation of the dosing interval.    
     
     
         32 . The method of  claim 31 , wherein said administration of buprenorphine is accomplished via a mode selected from the group consisting of transdermally, continuous infusion, and a mixture of transdermally and continuous infusion.  
     
     
         33 . The method of  claim 31 , 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.  
     
     
         34 . The method of  claim 33 , further comprising maintaining a mean relative release rate of from about 51 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 5 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.    
     
     
         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 . The method of  claim 35 , wherein the mean relative release rates achieved over the dosing interval are as follows: 
 a mean relative release rate of from about 3 ug/hr to about 5 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 0.6 ug/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.    
     
     
         37 . The method of  claim 35 , wherein the mean relative release rates achieved over the dosing interval are as follows: 
 a mean relative release rate of from about 6 ug/hr to about 11 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 0.7 ug/hr to about 1 ug/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.    
     
     
         38 . The method of  claim 35 , wherein the mean relative release rates achieved over the dosing interval are as follows: 
 a mean relative release rate of from about 13 ug/hr to about 21 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 1 ug/hr to about 2 ug/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.    
     
     
         39 . The method of  claim 35 , wherein the mean relative release rates achieved over the dosing interval are as follows: 
 a mean relative release rate of from about 26 ug/hr to about 43 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 3 ug/hr to about 4 ug/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.    
     
     
         40 . The method of  claim 35 , wherein the mean relative release rates achieved over the dosing interval are as follows: 
 a mean relative release rate of from about 39 ug/hr to about 64 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 4 ug/hr to about 7 ug/hr from about 72 hours after the initiation of the dosing interval until the end of the dosing interval.    
     
     
         41 . The method of  claim 35 , wherein the mean relative release rates achieved over the dosing interval are as follows: 
 a mean relative release rate of from about 51 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 5 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.    
     
     
         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 g/hr to about 9 g/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 . The method of  claim 42 , wherein the mean plasma concentration attained about 72 hours after application of said transdermal delivery system is from about 85 to about 263 pg/ml;  
       and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 13 g/hr to about 21 g/hr and the patients experience analgesia throughout the at least two-day additional dosing interval.  
     
     
         46 . The method of  claim 45 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval.  
     
     
         47 . The method of  claim 45 , wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system.  
     
     
         48 . The method of  claim 42 , wherein the mean plasma concentration attained about 72 hours after application of said transdermal delivery system is from about 21 to about 66 pg/ml;  
       and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 0.3 g/hr to about 0.6 g/hr and the patients experience analgesia throughout the at least two-day additional dosing interval.  
     
     
         49 . The method of  claim 48 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval.  
     
     
         50 . The method of  claim 48 , wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system.  
     
     
         51 . The method of  claim 42 , wherein the mean plasma concentration attained about 72 hours after application of said transdermal delivery system is from about 42 to about 132 pg/ml;  
       and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 0.7 g/hr to about 1 g/hr and the patients experience analgesia throughout the at least two-day additional dosing interval.  
     
     
         52 . The method of  claim 51 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval.  
     
     
         53 . The method of  claim 51 , wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system.  
     
     
         54 . The method of  claim 42 , wherein the mean plasma concentration attained about 72 hours after application of said transdermal delivery system is from about 169 to about 526 pg/ml;  
       and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 3 g/hr to about 4 g/hr and the patients experience analgesia throughout the at least two-day additional dosing interval.  
     
     
         55 . The method of  claim 54 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval.  
     
     
         56 . The method of  claim 54 , wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system.  
     
     
         57 . The method of  claim 42 , wherein the mean plasma concentration attained about 72 hours after application of said transdermal delivery system is from about 254 to about 789 pg/ml;  
       and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 4 g/hr to about 7 g/hr and the patients experience analgesia throughout the at least two-day additional dosing interval.  
     
     
         58 . The method of  claim 57 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval.  
     
     
         59 . The method of  claim 57 , wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system.  
     
     
         60 . The method of  claim 42 , wherein the mean plasma concentration attained about 72 hours after application of said transdermal delivery system is from about 339 to about 1052 pg/ml;  
       and the mean relative release rate maintained over said at least two-day additional dosing interval is from about 5 g/hr to about 9 g/hr and the patients experience analgesia throughout the at least two-day additional dosing interval.  
     
     
         61 . The method of  claim 60 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval.  
     
     
         62 . The method of  claim 60 , wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system.  
     
     
         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 . A method of treating human patients suffering from moderate to severe pain by applying a transdermal delivery system containing buprenorphine onto the skin of the patient and maintaining the transdermal delivery system in contact with the skin for a 3 day dosing interval, the transdermal delivery system containing an amount of buprenorphine sufficient to maintain an adequate relative release rate to provide effective analgesia in the patient for approximately only 3 days, comprising maintaining the transdermal delivery system in contact with the patient's skin for at least 2 to about 5 additional days beyond said 3 day dosing interval, such that the patient continues to receive effective analgesia from said transdermal buprenorphine delivery system.  
     
     
         65 . In a method of treating human patients suffering from moderate to severe pain by applying a transdermal delivery system containing buprenorphine onto the skin of the patient and maintaining the transdermal delivery system in contact with the skin for a 3 day dosing interval, the transdermal delivery system containing an amount of buprenorphine sufficient to maintain an adequate relative release rate to provide effective analgesia in the patient for about 3 days, the improvement comprising maintaining the transdermal delivery system in contact with the patient's skin for at least 2 to about 5 additional days beyond said 3 day dosing interval, wherein maximal analgesia is experienced by the patient prior to attainment of peak plasma buprenorphine concentrations.  
     
     
         66 . A method of treating human patients suffering from opioid addiction by applying a transdermal delivery system containing buprenorphine onto the skin of the patient and maintaining the transdermal delivery system in contact with the skin for a 3 day dosing interval, the transdermal delivery system containing an amount of buprenorphine sufficient to maintain an adequate relative release rate to provide a plasma concentration of from about 1000 pg/ml to about 10,000 pg/ml at the end of said 3 day dosing interval, and maintaining the transdermal delivery system in contact with the patient's skin for at least 2 to about 5 additional days beyond said 3 day dosing interval, such that the patient continues to receive effective treatment for opioid addiction from said transdermal buprenorphine delivery system over said dosing interval.  
     
     
         67 . The method of  claim 66 , wherein the plasma concentration attained at the end of said 3 day dosing interval is from about 5000 pg/ml to about 8000 pg/ml.