Method of providing sustained analgesia with buprenorphine

Abstract

A method of effectively treating pain in humans is achieved by administering buprenorphinein 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 by applying a transdermal delivery system to the skin of said patient, and maintaining said transdermal delivery system in contact with said patient's skin for at least  5    7  days such that the following mean plasma concentrations are achieved over a  72    168  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.
 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 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  2    1 , further comprising maintaining a mean relative release rate from about 3 ug/hr to about 86 ug/hr from the initiation of the  168  hour 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.  
 
     
     
       4. A method of effectively treating pain in humans, comprising administering buprenorphine to human patients by applying a transdermal delivery system to the skin of said patient, and maintaining said transdermal delivery system in contact with said patient's skin for at least  5    7  days such that the following mean plasma concentrations are achieved over a  72    168  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.
 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. The method of  claim 4 , 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.    
     
     
       6. The method of  claim 5 , 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.    
     
     
       7. A method of effectively treating pain in humans, comprising administering buprenorphine to human patients by applying a transdermal delivery system to the skin of said patient, and maintaining said transdermal delivery system in contact with said patient's skin for at least  5    7  days such that the following mean plasma concentrations are achieved over a  72    168  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.
 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. 
 
     
     
       8. 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  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.    
     
     
       9. The method of  claim 8 , 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.    
     
     
       10. A method of effectively treating pain in humans, comprising administering buprenorphine to human patients by applying a transdermal delivery system to the skin of said patient, and maintaining said transdermal delivery system in contact with said patient's skin for at least  5    7  days such that the following mean plasma concentrations are achieved over a  72    168  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.
 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. 
 
     
     
       11. The method of  claim 10 , 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.    
     
     
       12. The method of  claim 11 , 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.    
     
     
       13. A method of effectively treating pain in humans, comprising administering buprenorphine to human patients by applying a transdermal delivery system to the skin of said patient, and maintaining said transdermal delivery system in contact with said patient's skin for at least  5    7  days such that the following mean plasma concentrations are achieved over a  72    168  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    72  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. 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.   
     
     
       14. The method of  claim 13 , 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.    
     
     
       15. The method of  claim 14 , 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.    
     
     
       16. A method of effectively treating pain in humans, comprising administering buprenorphine to human patients by applying a transdermal delivery system to the skin of said patient, and maintaining said transdermal delivery system in contact with said patient's skin for at least  5    7  days such that the following mean plasma concentrations are achieved over a  72    168  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    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;  
 
       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. 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.   
     
     
       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  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.    
     
     
       18. The method of  claim 17 , 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.    
     
     
       19. 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    168  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.  
 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; and  
 a mean plasma concentration from about  306  to about  841  pg/ml at about  168  hours after initiation of the dosing interval. 
 
     
     
       20. The method of  claim 19 , 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.    
     
     
       21. The method of claim  20    19 , further comprising maintaining a mean relative release rate of from about 51 ug/hr to about 86 ug/hr from the initiation of the  168  hour 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.  
 
     
     
       22. A method of effectively treating pain in humans, comprising administering buprenorphine to human patients in a manner selected from the group consisting of parenteral, sublingual, oral, buccal and rectal administration such that the following mean plasma concentrations are achieved over a  72    168  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.
 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. 
 
     
     
       23. The method of  claim 22 , 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.    
     
     
       24. The method of claim  23    22 , 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.  
 
     
     
       25. A method of effectively treating pain in humans, comprising applying a transdermal delivery system to the skin of a human patient, the transdermal delivery system comprising an active ingredient, wherein the active ingredient consists essentially of buprenorphine, and maintaining said transdermal delivery system in contact with said patient's skin for  7  days such that the following mean plasma concentrations are achieved over a  168  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;    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.   
     
     
       26. The method of  claim 25 , further comprising maintaining a mean relative release rate from about  3  ug/hr to about  86  ug/hr from the initiation of the  168  hour 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.   
     
     
       27. A method of effectively treating pain in humans, comprising applying a transdermal delivery system to the skin of a human patient, the transdermal delivery system comprising an active ingredient, wherein the active ingredient consists of buprenorphine, and maintaining said transdermal delivery system in contact with said patient's skin for  7  days such that the following mean plasma concentrations are achieved over a  168  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;    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.   
     
     
       28. The method of  claim 27 , further comprising maintaining a mean relative release rate from about  3  ug/hr to about  86  ug/hr from the initiation of the  168  hour 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.