Use of an all-D-pentapeptide chemokine antagonist to reduce opioid dose in a person with pain

Abstract

A method of treatment of pain in a person with a D peptide chemokine receptor antagonist (CRA), and a pharmaceutically acceptable carrier is disclosed. Because chemokines desensitize opiate receptors and enhance the perception of pain said D-peptide CRA, given with a suboptimal dose of an opioid, such as morphine, will restore opioid analgesic efficacy by blocking the cognate chemokine ligand from binding to its receptor and desensitizing the opioid receptor. This strategy of combining a suboptimal dose of morphine with a CRA enhances the potency of morphine, permitting use of lower doses of morphine to obtain equivalent and near maximal analgesia. Lower morphine (opioid) doses have less risk of adverse effects, and potentially also of development of tolerance and dependence.

What is claimed is: 
     
       1. A method of reducing the effective amount or duration of opioid in a patient using said opioids to manage pain comprising the steps of:
 preparing a chemokine receptor antagonist pharmaceutical composition comprising an all-D peptide and a pharmaceutically acceptable carrier, said peptide comprises five contiguous amino acids and is at most 8 amino acid residues in length, having the general structure: A-B-C-D-E in which:
 A is Ser, Thr, Asn, Glu, Ile, 
 B is Ser, Thr, Asp, Asn, 
 C is Thr, Ser, Asn, Arg, Trp, 
 D is Tyr, and 
 E is Thr, Ser, Arg, Gly, 
   all amino acids being the D stereoisomeric configuration and, administering said composition to the patient in a therapeutically effective dose,   wherein said composition acts to manage pain and reduce the effective amount or duration of opioid use in the patient.   
     
     
       2. The method as defined in  claim 1  wherein said D peptide is TTNYT (SEQ ID NO: 1). 
     
     
       3. The method as defined in  claim 1  wherein the D peptide has a sequence selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                     
                   Thr Thr Asn Tyr Thr, 
                 
                     
                 
                     
                   (SEQ ID NO: 2) 
                 
                     
                   Ser Ser Thr Tyr Arg, 
                 
                     
                 
                     
                   (SEQ ID NO: 3) 
                 
                     
                   Ser Thr Asn Tyr Thr, 
                 
                     
                 
                     
                   (SEQ ID NO: 4) 
                 
                     
                   Thr Thr Ser Tyr Thr, 
                 
                     
                 
                     
                   (SEQ ID NO: 5) 
                 
                     
                   Asn Thr Ser Tyr Gly, 
                 
                     
                 
                     
                   (SEQ ID NO: 6) 
                 
                     
                   Glu Thr Trp Tyr Ser 
                 
                     
                 
                     
                   (SEQ ID NO: 7) 
                 
                     
                   Asn Thr Ser Tyr Arg 
                 
                     
                 
                     
                   (SEQ ID NO: 8) 
                 
                     
                   Ile Asn Asn Tyr Thr, 
                 
                     
                 
                     
                   (SEQ ID NO: 9) 
                 
                     
                   Ile Asp Asn Tyr Thr 
                 
                     
                 
                     
                   (SEQ ID NO: 10) 
                 
                     
                   Thr Asp Asn Tyr Thr 
                 
                     
                 
                     
                   (SEQ ID NO: 11) 
                 
                     
                   Thr Asp Ser Tyr Ser 
                 
                     
                 
                     
                   (SEQ ID NO: 12) 
                 
                     
                   Thr Asn Ser Tyr Arg 
                 
                     
                 
                     
                   (SEQ ID NO: 13) 
                 
                     
                   Asn Thr Arg Tyr Arg. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       
        
       
     
     
       4. The method as defined in  claim 1  wherein E is esterified, glycosylated, or amidated to enhance tissue distribution. 
     
     
       5. The method as defined in  claim 1  wherein said composition is used as an oral pill having between 0.5 to 100 mgs of the peptide. 
     
     
       6. The method as defined in  claim 1  wherein said composition is used as an oral pill having between 0.1 to 500 mgs of the peptide. 
     
     
       7. The method as defined in  claim 1  wherein said chemokine receptor antagonist reduces the effective amount of opioid use by the patient. 
     
     
       8. The method as defined in  claim 1  wherein said chemokine receptor antagonist is Dala1-peptide T-amide (DAPTA). 
     
     
       9. The method as defined in  claim 1  wherein said chemokine receptor antagonist is Dala1-peptide T-amide (DAPTA) and is used to reduce the effective amount of opioid used by need for opioid used by the patient. 
     
     
       10. A method of pain treatment as defined in  claim 1  wherein said chemokine receptor antagonist is administered as a pill or liquid. 
     
     
       11. A method of treating an opioid use disorder in a patient comprising:
 administering to the patient a therapeutically effective dose of a pharmaceutical composition comprising an all-D peptide and a pharmaceutically acceptable carrier, wherein the all-D peptide comprises five contiguous amino acids and is at most 8 amino acid residues in length, having the general structure: A-B-C-D-E in which:
 A is Ser, Thr, Asn, Glu, or Ile, 
 B is Ser, Thr, Asp, or Asn, 
 C is Thr, Ser, Asn, Arg, or Trp, 
 D is Tyr, and 
 E is Thr, Ser, Arg, or Gly, 
   wherein in the all-D peptide, all stereoisomeric amino acids are in the D stereoisomeric configuration, and wherein the pharmaceutical composition acts to treat the opioid use disorder in the patient.   
     
     
       12. The method of  claim 11 , wherein the all-D peptide is TTNYT (SEQ ID NO: 1), and wherein in the all-D peptide, all stereoisomeric amino acids are in the D stereoisomeric configuration. 
     
     
       13. The method of  claim 11 , wherein the all-D peptide has a sequence selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                     
                   Thr Thr Asn Tyr Thr, 
                 
                     
                 
                     
                   (SEQ ID NO: 2) 
                 
                     
                   Ser Ser Thr Tyr Arg, 
                 
                     
                 
                     
                   (SEQ ID NO: 3) 
                 
                     
                   Ser Thr Asn Tyr Thr, 
                 
                     
                 
                     
                   (SEQ ID NO: 4) 
                 
                     
                   Thr Thr Ser Tyr Thr, 
                 
                     
                 
                     
                   (SEQ ID NO: 5) 
                 
                     
                   Asn Thr Ser Tyr Gly, 
                 
                     
                 
                     
                   (SEQ ID NO: 6) 
                 
                     
                   Glu Thr Trp Tyr Ser, 
                 
                     
                 
                     
                   (SEQ ID NO: 7) 
                 
                     
                   Asn Thr Ser Tyr Arg, 
                 
                     
                 
                     
                   (SEQ ID NO: 8) 
                 
                     
                   Ile Asn Asn Tyr Thr, 
                 
                     
                 
                     
                   (SEQ ID NO: 9) 
                 
                     
                   Ile Asp Asn Tyr Thr, 
                 
                     
                 
                     
                   (SEQ ID NO: 10) 
                 
                     
                   Thr Asp Asn Tyr Thr, 
                 
                     
                 
                     
                   (SEQ ID NO: 11) 
                 
                     
                   Thr Asp Ser Tyr Ser, 
                 
                     
                 
                     
                   (SEQ ID NO: 12) 
                 
                     
                   Thr Asn Ser Tyr Arg, and 
                 
                     
                 
                     
                   (SEQ ID NO: 13) 
                 
                     
                   Asn Thr Arg Tyr Arg, and 
                 
                     
                   wherein in the all-D peptide, all 
                 
                     
                   stereoisomeric amino acids are in   
                 
                     
                   the D stereoisomeric configuration. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       
        
       
     
     
       14. The method of  claim 11 , wherein E is esterified, glycosylated, or amidated. 
     
     
       15. The method of  claim 11 , wherein the pharmaceutical composition is in the form of an oral pill comprising from 0.5 mgs to 100 mgs of the all-D peptide and wherein the administering is oral administering. 
     
     
       16. The method of  claim 11 , wherein the pharmaceutical composition is in the form of an oral pill comprising from 0.1 mgs to 500 mgs of the all-D peptide and wherein the administering is oral administering. 
     
     
       17. The method of  claim 11 , wherein the pharmaceutical composition is in the form of a liquid. 
     
     
       18. A method of treating an opioid use disorder in a patient comprising:
 administering to the patient a therapeutically effective dose of a pharmaceutical composition comprising Dala1-peptide T-amide (DAPTA), which is at most 8 amino acids in length, and a pharmaceutically acceptable carrier, wherein the administering of the pharmaceutical composition acts to manage pain and wherein the administering of the pharmaceutical composition acts to treat the opioid use disorder in the patient.