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 treating pain in a human patient, comprising
 administering buprenorphine transdermally to said human patient 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  a seven day dosing interval, said transdermal delivery system maintaining a mean relative release rate of from about 3 ug/hr to about 86 ug/hr and providing a substantially first order plasma level increase of buprenorphine 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 and providing a substantially zero order plasma level fluctuation of buprenorphine from about 72 hours after the initiation of the dosing interval until the end of at least  the five  seven-day dosing interval, such that the following mean plasma concentrations are achieved: 
 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  
 a mean plasma concentration from about 19 to about 1052 pg/ml over at least the next 48 hours  
 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.    
 
 
     
     
       2. The method of  claim 1 , further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin 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. A method of treating pain in a human patient, comprising
 administering buprenorphine transdermally to said human patient 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  a seven day dosing interval, said transdermal delivery system 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 at least  the five  seven-day dosing interval, such that the following mean plasma concentrations are achieved: 
 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  
 a mean plasma concentration from about 77 to about 263 pg/ml over at least the next 48 hours  
 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.    
 
 
     
     
       4. The method of  claim 3 , further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin 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.    
     
     
       5. A method of treating pain in a human patient, comprising
 administering buprenorphine transdermally to said human patient 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  a seven day dosing interval, said transdermal delivery system maintaining 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 at least  the five  seven-day dosing interval, such that the following mean plasma concentrations are achieved: 
 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  21 to about 62 pg/ml at about 60 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 21  20 to about 66 pg/ml at about 72 hours after initiation of the dosing interval; and  
 a mean plasma concentration from about 19 to about 66 pg/ml over at least the next 48 hours  
 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;    
   a mean plasma concentration from about  19  to about  53  pg/ml at about  168  hours after initiation of the dosing interval.    
 
 
     
     
       6. The method of  claim 5 , further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin 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.    
     
     
       7. A method of treating pain in a human patient, comprising
 administering buprenorphine transdermally to said human patient 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  a seven day dosing interval, said transdermal delivery system 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 at least  the five  seven-day dosing interval, such that the following mean plasma concentrations are achieved: 
 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  
 a mean plasma concentration from about 38 to about 132 pg/ml over at least the next 48 hours  
 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.    
 
 
     
     
       8. The method of  claim 7 , further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin 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.    
     
     
       9. A method of treating pain in a human patient, comprising
 administering buprenorphine transdermally to said human patient 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  a seven day dosing interval, said transdermal delivery system 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 at least  the five  seven-day dosing interval, such that the following mean plasma concentrations are achieved: 
 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  72 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 153 to about 526 pg/ml over at least the next 48 hours 
 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; and    
   a mean plasma concentration from about  153  to about  420  pg/ml at about  168  hours after initiation of the dosing interval.    
 
 
     
     
       10. The method of  claim 9 , further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin 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.    
     
     
       11. A method of treating pain in a human patient, comprising
 administering buprenorphine transdermally to said human patient 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  a seven day dosing interval, said transdermal delivery system 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 at least  the five  seven-day dosing interval, such that the following mean plasma concentrations are achieved: 
 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  60 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 254 to about 789 pg/ml at about 60  72 hours after initiation of the dosing interval;  
 a mean plasma concentration from about 230 to about 789 pg/ml over at least the next 48 hours 
 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; and    
   a mean plasma concentration from about  230  to about,  630  pg/ml at about  168  hours after initiation of the dosing interval.    
 
 
     
     
       12. The method of  claim 11 , further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin 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; and    a mean plasma concentration from about 230 to about, 630 pg/ml at about 168 hours after initiation of the dosing interval.    
     
     
       13. A method of treating pain in a human patient, comprising
 administering buprenorphine transdermally to said human patient 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  a seven day dosing interval, said transdermal delivery system 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 at least  the five  seven-day dosing interval, such that the following mean plasma concentrations are achieved: 
 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  
 a mean plasma concentration from about 306 to about 1052 pg/ml over at least the next 48 hours  
 a mean plasma concentration from about  369  to about  1052  pg/ml at about  95  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; and    
   a mean plasma concentration from about  306  to about  841  pg/ml at about  168  hours after initiation of the dosing interval.    
 
 
     
     
       14. The method of  claim 13 , further comprising maintaining the buprenorphine transdermal delivery system in contact with the patient's skin 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.    
     
     
       15. A method of treating pain in a human patient, comprising
 administering buprenorphine transdermally to said human patient for a seven day dosing interval such that mean relative release rates are achieved over a  the 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 seven day dosing interval.  
 
 
     
     
       16. The method of  claim 15 , wherein the mean relative release rates achieved over the seven day 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 seven day dosing interval.  
 
     
     
       17. The method of  claim 15 , wherein the mean relative release rates achieved over the seven day 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 seven day dosing interval.  
 
     
     
       18. The method of  claim 15 , wherein the mean relative release rates achieved over the seven day 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 seven day dosing interval.  
 
     
     
       19. The method of  claim 15 , wherein the mean relative release rates achieved over the seven day 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 seven day dosing interval.  
 
     
     
       20. The method of  claim 15 , wherein the mean relative release rates achieved over the seven day 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 seven day dosing interval.  
 
     
     
       21. The method of  claim 15 , wherein the mean relative release rates achieved over the seven day 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 seven day dosing interval.  
 
     
     
       22. A method of treating pain in a human patient, comprising applying a transdermal delivery system containing buprenorphine as the active ingredient onto the skin of said human patient to provide a substantially first order plasma level increase 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 system on the skin of said human patient for at least  an additional two  four-day dosing interval, 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  four-day additional dosing interval and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two  four-day additional dosing interval. 
     
     
       23. The method of  claim 22 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 
     
     
       24. The method of  claim 23   claims  1 ,  3 ,  5 ,  7 ,  9 ,  11 ,  13 ,  15  or  22 , wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 
     
     
       25. The method of  claim 22 , 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 μg/hr to about 21 μg/hr and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two-day additional dosing interval. 
     
     
       26. The method of  claim 25 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 
     
     
       27. The method of  claim 25 , wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 
     
     
       28. The method of  claim 22 , wherein the mean plasma concentration attained about 72 hours after application of said transdermal delivery system is from about 21  20 to about 66 pg/ml; and the mean relative release rate maintained over said at least two  four-day additional dosing interval is from about 0.3 μg/hr to about 0.6 μg/hr and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two  four-day additional dosing interval. 
     
     
       29. The method of  claim 28 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 
     
     
       30. The method of  claim 28 , wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 
     
     
       31. The method of  claim 22 , 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  four-day additional dosing interval is from about 0.7 μg/hr to about 1 μg/hr and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two  four-day additional dosing interval. 
     
     
       32. The method of  claim 31 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 
     
     
       33. The method of  claim 31 , wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 
     
     
       34. The method of  claim 22 , 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  four-day additional dosing interval is from about 3  2 μg/hr to about 4 μg/hr and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two  four-day additional dosing interval. 
     
     
       35. The method of  claim 34 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 
     
     
       36. The method of  claim 34 , wherein the Tmax occurs from about 3 to about 5 days after applications of said transdermal delivery system. 
     
     
       37. The method of  claim 22 , 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  four-day additional dosing interval is from about 4 μg/hr to about 7 μg/hr and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two  four-day additional dosing interval. 
     
     
       38. The method of  claim 37 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 
     
     
       39. The method of  claim 37 , wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 
     
     
       40. The method of  claim 22 , 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  four-day additional dosing interval is from about 5 μg/hr to about 9 μg/hr and said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two  four-day additional dosing interval. 
     
     
       41. The method of  claim 40 , wherein from about 68% to about 95% of the buprenorphine is contained in the transdermal delivery system at the end of the dosing interval. 
     
     
       42. The method of  claim 40 , wherein the Tmax occurs from about 3 to about 5 days after application of said transdermal delivery system. 
     
     
       43. A method of treating pain in a human patient, comprising
 applying a transdermal delivery system containing buprenorphine as the active ingredient onto the skin of said human patient to 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  system on the skin of said human patient for at least  an additional two  four-day dosing interval during which said transdermal delivery system provides substantially zero order kinetics, such that said transdermal delivery system provides a therapeutic effect to said human patient throughout the at least two  four-day additional dosing interval.  
 
     
     
       44. A method of treating a human patient suffering from moderate to severe pain by applying a transdermal delivery system containing buprenorphine onto the skin of the human 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 therapeutic effect in the patient for approximately only 3 days, comprising maintaining the transdermal delivery system in contact with the human patient's skin for at least 2 to about 5  4 additional days beyond said 3 day dosing interval, such that the human patient continues to receive a therapeutic effect from said transdermal buprenorphine delivery system. 
     
     
       45. In a method of treating a human patient suffering from moderate to severe pain by applying a transdermal delivery system containing buprenorphine onto the skin of the human 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 therapeutic effect in the patient for about 3 days, the  an improvement comprising maintaining the transdermal delivery system in contact with the human patient's skin for at least 2 to about 5  4 additional days beyond said 3 day dosing interval. 
     
     
       46. The method of  claim 2  wherein the plasma level of buprenorphine at 72 hours does not decrease by more than 30% over the next 48 hours. 
     
     
       47. The method of  claim 2  wherein the plasma level of buprenorphine at 120 hours does not decrease by more than 30% over the next 48 hours. 
     
     
       48. The method of  claim 1 , wherein the transdermal delivery system comprises from about  0 . 1 %  to about  30   %  weight buprenorphine.   
     
     
       49. The method of  claim 48 , wherein the transdermal delivery system comprises  10 %  buprenorphine base,  10 - 15   %  acid,  10   %  softener,  55 - 70   %  polyacrylate, and  0 - 10   %  polyvinylpyrrollidone.   
     
     
       50. The method of  claim 43 , wherein the active ingredient consists essentially of buprenorphine. 
     
     
       51. The method of  claim 43 , wherein the active ingredient consists of buprenorphine. 
     
     
       52. A method of treating pain in a human patient, comprising transdermally administering an active ingredient, wherein the active ingredient consists essentially of buprenorphine, to said human patient 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 a seven day dosing interval, said transdermal delivery system maintaining a mean relative release rate of from about  3  ug/hr to about  86  ug/hr and providing a substantially first order plasma level increase of buprenorphine 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 and providing a substantially zero order plasma level fluctuation of buprenorphine from about  72  hours after the initiation of the dosing interval until the end of the seven- day dosing interval, such that the following mean plasma concentrations are achieved:      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;        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.     
     
     
       53. The method of  claim 52 , wherein the transdermal delivery system comprises from about  0 . 1 %  to about  30   %  weight buprenorphine.   
     
     
       54. The method of  claim 53 , wherein the transdermal delivery system comprises  10 %  buprenorphine base,  10 - 15   %  acid,  10   %  softener,  55 - 70   %  polyacrylate, and  0 - 10   %  polyvinylpyrrollidone.   
     
     
       55. A method of treating pain in a human patient, comprising transdermally administering an active ingredient, wherein the active ingredient consists of buprenorphine, to said human patient 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 a seven day dosing interval, said transdermal delivery system maintaining a mean relative release rate of from about  3  ug/hr to about  86  ug/hr and providing a substantially first order plasma level increase of buprenorphine 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 and providing a substantially zero order plasma level fluctuation of buprenorphine from about  72  hours after the initiation of the dosing interval until the end of the seven- day dosing interval, such that the following mean plasma concentrations are achieved:      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;        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.     
     
     
       56. The method of  claim 55 , wherein the transdermal delivery system comprises from about  0 . 1 %  to about  30   %  weight buprenorphine.   
     
     
       57. The method of  claim 56 , wherein the transdermal delivery system comprises  10 %  buprenorphine base˜ 10 - 15   %  acid,  10   %  softener,  55 - 70   %  polyacrylate, and  0 - 10   %  polyvinylpyrrollidone.   
     
     
       58. A method of treating a human patient suffering from moderate to severe pain by applying a transdermal delivery system containing an active ingredient wherein the active ingredient consists essentially of buprenorphine, onto the skin of the human 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 therapeutic effect in the patient for approximately only  3  days, comprising maintaining the transdermal delivery system in contact with the human patient's skin for  4  additional days beyond said  3  day dosing interval, such that the human patient continues to receive a therapeutic effect from said transdermal buprenorphine delivery system. 
     
     
       59. The method of  claim 58 , wherein the active ingredient consists of buprenorphine. 
     
     
       60. In a method of treating a human patient suffering from moderate to severe pain by applying a transdermal delivery system containing an active ingredient, wherein the active ingredient consists of buprenorphine, onto the skin of the human 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 therapeutic effect in the patient for about  3  days, the improvement comprising maintaining the transdermal delivery system in contact with the human patient's skin for  4  additional days beyond said  3  day dosing interval.