Compositions comprising enzyme-cleavable opioid prodrugs and inhibitors thereof

Abstract

Pharmaceutical compositions and their methods of use are provided, where the pharmaceutical compositions comprise an opioid prodrug that provides enzymatically-controlled release of an opioid, and an enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of the opioid from the opioid prodrug so as to attenuate enzymatic cleavage of the opioid prodrug.

1 . A composition comprising:
 an opioid prodrug comprising an opioid covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by a GI enzyme mediates release of the opioid; and   a GI enzyme inhibitor that interacts with the GI enzyme that mediates enzymatically-controlled release of the opioid from the opioid prodrug following ingestion of the composition.   
     
     
         2 . A dose unit comprising the composition of  claim 1 , wherein
 the opioid prodrug and GI enzyme inhibitor are present in the dose unit in an amount effective to provide for a pre-selected pharmacokinetic (PK) profile following ingestion.   
     
     
         3 . The dose unit of  claim 2 , wherein the pre-selected PK profile comprises at least one PK parameter value that is less than the PK parameter value of opioid released following ingestion of an equivalent dosage of opioid prodrug in the absence of inhibitor. 
     
     
         4 . The dose unit of  claim 3 , wherein the PK parameter value is selected from an opioid Cmax value, an opioid exposure value, and a (1/opioid Tmax) value. 
     
     
         5 . The dose unit of  claim 2 , wherein the dose unit provides for a pre-selected PK profile following ingestion of at least two dose units. 
     
     
         6 . The dose unit of  claim 5 , wherein the pre-selected PK profile is modified relative to the PK profile following ingestion of an equivalent dosage of opioid prodrug in the absence of inhibitor. 
     
     
         7 . The dose unit of  claim 5 , wherein the dose unit provides that ingestion of an increasing number of the dose units provides for a linear PK profile. 
     
     
         8 . The dose unit of  claim 5 , wherein the dose unit provides that ingestion of an increasing number of the dose units provides for a nonlinear PK profile. 
     
     
         9 . The dose unit of  claim 5 , wherein the PK parameter value is selected from an opioid Cmax value, a (1/opioid Tmax) value, and an opioid exposure value. 
     
     
         10 . A composition comprising:
 a container suitable for containing a composition for administration to a patient; and   a dose unit comprising the composition of  claim 1  disposed within the container.   
     
     
         11 . The composition of  claim 1 , wherein the composition is a dose unit having a total weight of from 1 microgram to 2 grams. 
     
     
         12 . The composition of  claim 1 , wherein the composition has a combined weight of opioid prodrug and GI enzyme inhibitor of from 0.1% to 99% per gram of the composition. 
     
     
         13 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(I)
   X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 )   (PC-(I))
   or a pharmaceutically acceptable salt thereof, wherein:   X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 );   R 1  represents a (1-4C)alkyl group;   R 2  and R 3  each independently represents a hydrogen atom or a (1-4C)alkyl group; n represents 2 or 3;   R 4  represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2  or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4  is attached corresponding with that in an L-amino acid; and   R 5  represents a hydrogen atom, an N-acyl group, or a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.   
     
     
         14 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(IIa):
   X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 )   (PC-(IIa))
   or a pharmaceutically acceptable salt thereof, wherein:   X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 );   R 1  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;   each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;   each R 3  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;   or R 2  and R 3  together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2  or R 3  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;   n represents an integer from 2 to 4;   R 4  represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2  or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4  is attached corresponding with that in an L-amino acid; and   R 5  represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.   
     
     
         15 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(IIb):
   X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 )   (PC-(IIb))
   or a pharmaceutically acceptable salt thereof, wherein:   X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 );   R 1  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;   each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;   each R 3  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;   or R 2  and R 3  together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 2  or R 3  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;   n represents an integer from 2 to 4;   R 4  represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2  or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4  is attached corresponding with that in an L-amino acid; and   R 5  represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.   
     
     
         16 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(III):
   X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 )   (PC-(III))
   or pharmaceutically acceptable salt thereof, wherein:   X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 );   R 1  represents a (1-4C)alkyl group;   R 2  and R 3  each independently represents a hydrogen atom or a (1-4C)alkyl group;   n represents 2 or 3;   R 4  represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2  or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4  is attached corresponding with that in an L-amino acid; and   R 5  represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.   
     
     
         17 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(IV): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         R a  is hydrogen or hydroxyl; 
         R b  is oxo (═O) or hydroxyl; 
         the dashed line is a double bond or single bond; 
         R 1  represents a (1-4C)alkyl group; 
         R 2  and R 3  each independently represents a hydrogen atom or a (1-4C)alkyl group; 
         n represents 2 or 3; 
         R 4  represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2  or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4  is attached corresponding with that in an L-amino acid; and 
         R 5  represents a hydrogen atom, an N-acyl group, or a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide. 
       
     
     
         18 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(Va): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         R a  is hydrogen or hydroxyl; 
         R b  is oxo (═O) or hydroxyl; 
         the dashed line is a double bond or single bond; 
         R 1  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 3  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 2  and R 3  together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2  or R 3  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; 
         n represents an integer from 2 to 4; 
         R 4  represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2  or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4  is attached corresponding with that in an L-amino acid; and 
         R 5  represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide. 
       
     
     
         19 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(Vb): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         R a  is hydrogen or hydroxyl; 
         R b  is oxo (═O) or hydroxyl; 
         the dashed line is a double bond or single bond; 
         R 1  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 3  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 2  and R 3  together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 2  or R 3  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group; 
         n represents an integer from 2 to 4; 
         R 4  represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2  or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4  is attached corresponding with that in an L-amino acid; and 
         R 5  represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide. 
       
     
     
         20 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(VI): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         R a  is hydrogen or hydroxyl; 
         R b  is oxo (═O) or hydroxyl; 
         the dashed line is a double bond or single bond; 
         R 1  represents a (1-4C)alkyl group; 
         R 2  and R 3  each independently represents a hydrogen atom or a (1-4C)alkyl group; 
         n represents 2 or 3; 
         R 4  represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2  or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4  is attached corresponding with that in an L-amino acid; and 
         R 5  represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide. 
       
     
     
         21 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(VII):
   X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—R 6    (PC-(VII))
   or a pharmaceutically acceptable salt thereof, wherein:   X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—R 6 ;   R 1  represents a (1-4C)alkyl group;   R 2  and R 3  each independently represents a hydrogen atom or a (1-4C)alkyl group;   n represents 2 or 3; and   R 6  is a trypsin-cleavable moiety.   
     
     
         22 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(VIII):
   X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—R 6    (PC-(VIII))
   or a pharmaceutically acceptable salt thereof, wherein:   X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—R 6 ;   R 1  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;   each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;   each R 3  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;   or R 2  and R 3  together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2  or R 3  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;   n represents an integer from 2 to 4; and   R 6  is a trypsin-cleavable moiety.   
     
     
         23 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(IX): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         R a  is hydrogen or hydroxyl; 
         R b  is oxo (═O) or hydroxyl; 
         the dashed line is a double bond or single bond; 
         R 1  represents a (1-4C)alkyl group; 
         R 2  and R 3  each independently represents a hydrogen atom or a (1-4C)alkyl group; 
         n represents 2 or 3; and 
         R 6  is a trypsin-cleavable moiety. 
       
     
     
         24 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(X): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         R a  is hydrogen or hydroxyl; 
         R b  is oxo (═O) or hydroxyl; 
         the dashed line is a double bond or single bond; 
         R 1  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 3  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 2  and R 3  together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2  or R 3  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; 
         n represents an integer from 2 to 4; and 
         R 6  is a trypsin-cleavable moiety. 
       
     
     
         25 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(XI):
   X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—R 6    (PC-(XI))
   or a pharmaceutically acceptable salt thereof, in which:   X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—R 6 ;   R 1  represents a (1-4C)alkyl group;   R 2  and R 3  each independently represents a hydrogen atom or a (1-4C)alkyl group;   n represents 2 or 3; and   R 6  is a GI enzyme-cleavable moiety.   
     
     
         26 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(XII):
   X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—R 6    (PC-(XII))
   or a pharmaceutically acceptable salt thereof, in which:   X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—R 6 ;   R 1  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;   each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;   each R 3  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;   or R 2  and R 3  together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2  or R 3  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;   n represents an integer from 2 to 4; and   R 6  is a GI enzyme-cleavable moiety.   
     
     
         27 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(XIII): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, in which: 
         R a  is hydrogen or hydroxyl; 
         R b  is oxo (═O) or hydroxyl; 
         the dashed line is a double bond or single bond; 
         R 1  represents a (1-4C)alkyl group; 
         R 2  and R 3  each independently represents a hydrogen atom or a (1-4C)alkyl group; 
         n represents 2 or 3; and 
         R 6  is a GI enzyme-cleavable moiety. 
       
     
     
         28 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(XIV): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, in which: 
         R a  is hydrogen or hydroxyl; 
         R b  is oxo (═O) or hydroxyl; 
         the dashed line is a double bond or single bond; 
         R 1  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 3  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 2  and R 3  together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2  or R 3  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; 
         n represents an integer from 2 to 4; and 
         R 6  is a GI enzyme-cleavable moiety. 
       
     
     
         29 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(XV): 
       
         
           
           
               
               
           
         
         wherein: 
         X is a phenolic opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to —C(O)—Y—(C(R 1 )(R 2 )) n —N—(R 3 )(R 6 ); 
         Y is —NR 5 —, —O— or —S—; 
         n is an integer from 1 to 4; 
         each R 1 , R 2 , R 3  and R 5  is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R 1  and R 2  together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group; 
         R 6  is 
       
       
         
           
           
               
               
           
         
         each R 4  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 4  and R 7  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 7  is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; 
         p is an integer from 1 to 10; 
         each W is independently —NR 8 —, —O— or —S—; and 
         each R 8  is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R 4  and R 8  independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring. 
       
     
     
         30 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(XVI): 
       
         
           
           
               
               
           
         
         or salts, solvates or hydrates thereof wherein: 
         X is an opioid comprising a phenol wherein a hydrogen atom of the phenol is replaced by a covalent bond to —(CR 12 R 13 )—Y—Z—R 11 ; 
         R 12  and R 13  are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; 
         Y is aryl, heteroaryl or arylaryl optionally substituted with one or more —F, —Cl, —Br, —I, —R 14 , —O − , —OR 14 , —SR 14 , —S − , —NR 14 R 15 , —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O) 2 O − , —S(O) 2 OH, —S(O) 2 R 14 , —OS(O 2 )O − , —OS(O) 2 R 14 , —P(O)(O − ) 2 , —P(O)(OR 14 )(O − ), —OP(O)(OR 14 )(OR 15 ), —C(O)R 14 , —C(S)R 14 , —C(O)OR 14 , —C(O)NR 14 R 15 , —C(O)O − , —C(S)OR 14 , —NR 16 C(O)NR 14 R 15 , —NR 16 C(S)NR 14 R 15 , —NR 17 C(NR 16 )NR 15 R 14  or —C(NR 16 )NR 15 R 14 ; 
         R 14 , R 15 , R 16  and R 17  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 14  and R 15  together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         Z is N(R 18 )—, —O— or —S—; 
         R 18  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or 
       
       
         
           
           
               
               
           
         
         each W is independently —NR 20 —, —O— or —S—; 
         each R 19  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 19  and R 20  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         each R 20  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 20  and R 21  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 21  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; 
         n is an integer from 0 to 5; 
         R 11  is 
       
       
         
           
           
               
               
           
         
         each U is independently —NR 23 —, —O— or —S—; 
         each R 22  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 22  and R 23  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         each R 23  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 23  and R 24  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 24  is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; and 
         o is an integer from 1 to 100; 
         provided that Z is oriented para or ortho to X—(CR 12 R 13 )— and that both R 18  and R 11  are not hydrogen. 
       
     
     
         31 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(XVII): 
       
         
           
           
               
               
           
         
         or salts, solvates or hydrates thereof wherein: 
         X is an opioid comprising a phenol, wherein X is connected by the phenol; 
         R 12  and R 13  are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; 
         R k   26  are each independently selected from the group consisting of one or more of —F, —Cl, —Br, —I, —R 14 , —O − , —OR 14 , —SR 14 , —S − , —NR 14 R 15 , —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O) 2 O − , —S(O) 2 OH, —S(O) 2 R 14 , —OS(O)O − , —OS(O) 2 R 14 , —P(O)(O − ) 2 , —P(O)(OR 14 )(O − ), —OP(O)(OR 14 )(OR 15 ), —C(O)R 14 , —C(S)R 14 , —C(O)OR 14 , —C(O)NR 14 R 15 , —C(O)O − , —C(S)OR 14 , —NR 16 C(O)NR 14 R 15 , —NR 16 C(S)NR 14 R 15 , —NR 17 C(NR 16 )NR 15 R 14  and —C(NR 16 )NR 15 R 14 , and k is 0, 1, 2, 3, or 4; 
         R 14 , R 15 , R 16  and R 17  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 4  and R 5  together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 18  is hydrogen or methyl; 
         R 22  is a side chain of an amino acid or a derivative of a side chain of an amino acid; 
         each U is independently —NR 23 —, —O— or —S—; 
         each R 23  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 23  and R 24  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and 
         R 24  is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; and 
         o is an integer from 1 to 100. 
       
     
     
         32 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula PC-(XVIII):
   X—C(R 31a )(R 32a ))—Ar—Z—C(O)—Y—(C(R 31 )(R 32 )) n —N—(R 33 )(R 34 )A-   (PC-(XVIII)
   or a salt, hydrate or solvate thereof wherein:   X is an opioid comprising a phenol wherein a hydrogen atom of the phenol is replaced by a covalent bond to —(C(R 31a )(R 32a )—Ar—Z—C(O)—Y—(C(R 31 )(R 32 )) n —N—(R 33 )(R 34 );   R 31a  and R 32a  are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;   Ar is aryl, heteroaryl or arylaryl optionally substituted with one or more —F, —Cl, —Br, —I, —R 34a , —O − , —OR 34a , —SR 34a , —S—, —NR 34a R 35a , —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O) 2 O′, —S(O) 2 OH, —S(O) 2 R 34a , —OS(O 2 )O″, —OS(O) 2 R 34a , —P(0)(0″) 2 , —P(O)(OR 34a )(O″), —OP(O)(OR 34a )(OR 35a ), —C(0)R 34a , —C(S)R 34a , —C(O)OR 34a , —C(O)NR 34a R 35a , —C(O)O; —C(S)OR 34a , —NR 36a C(O)NR 34a R 35a , —NR 36a C(S)NR 34a R 35a , —NR 37a C(NR 36a )NR 35a R 34a  or —C(NR 36a )NR 35a R 34a , or tethered to a polymer;   R 34a , R 35a , R 36a  and R 37a  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 34  and R 35  together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;   Z is O, S or NH;   Y is —NR 35 —, —O— or —S—;   n is an integer from 1 to 10;   each R 31 , R 32 , R 33  and R 35  is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R 31  and R 32  together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 31  or R 32  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;   R 34  is   
       
         
           
           
               
               
           
         
         each R 36  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 36  and R 37  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 37  is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; 
         p is an integer from 1 to 5; 
         each W is independently —NR 38 —, —O— or —S—; 
         each R 38  is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R 36  and R 38  independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and 
         A′ represents an anion. 
       
     
     
         33 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula KC-(Ia): 
       
         
           
           
               
               
           
         
         wherein: 
         R a  is hydrogen or hydroxyl; 
         R 5  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; 
         each R 1  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 1  and R 2  together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 1  or R 2  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; 
         n is an integer from 2 to 4; 
         R 3  is hydrogen or (1-4C)alkyl; 
         R 4  is 
       
       
         
           
           
               
               
           
         
         each R 6  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6  and R 7  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         each W is independently —NR 8 —, —O— or —S—; 
         each R 8  is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6  and R 8  independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         p is an integer from one to 100; and 
         R 7  is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         34 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula KC-(Ib): 
       
         
           
           
               
               
           
         
         wherein: 
         R a  is hydrogen or hydroxyl; 
         R 5  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; 
         each R 1  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 1  and R 2  together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 1  or R 2  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group; 
         n is an integer from 2 to 4; 
         R 3  is hydrogen or (1-4C)alkyl; 
         R 4  is 
       
       
         
           
           
               
               
           
         
         each R 6  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6  and R 7  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         each W is independently —NR 8 —, —O— or —S—; 
         each R 8  is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6  and R 8  independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         p is an integer from one to 100; and 
         R 7  is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         35 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula KC-(II): 
       
         
           
           
               
               
           
         
         wherein: 
         R a  is hydrogen or hydroxyl; 
         R 5  is selected from (1-6C)alkyl, (1-6C) substituted alkyl, —(CH 2 ) q (C 6 H 4 )—COOH, —(CH 2 ) q (C 6 H 4 )—COOCH 3 , and —(CH 2 ) q (C 6 H 4 )—COOCH 2 CH 3 , where q is an integer from one to 10; 
         each R 1  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 1  and R 2  together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 1  or R 2  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group; 
         n is 2 or 3; 
         R 3  is hydrogen; 
         R 4  is a residue of an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, or a residue of an N-acyl derivative of any of said amino acids; or a residue of a peptide composed of at least two L-amino acid residues selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or a residue of an N-acyl derivative thereof. 
       
     
     
         36 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula KC-(IIIa): 
       
         
           
           
               
               
           
         
         wherein: 
         X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ; 
         R 5  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; 
         each R 1  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 1  and R 2  together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2  or R 3  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; 
         n is an integer from 2 to 4; 
         R 3  is hydrogen or (1-4C) alkyl; 
         R 4  is 
       
       
         
           
           
               
               
           
         
         each R 6  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6  and R 7  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         each W is independently —NR 8 —, —O— or —S—; 
         each R 8  is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6  and R 8  independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         p is an integer from one to 100; and 
         R 7  is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         37 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula KC-(IIIb): 
       
         
           
           
               
               
           
         
         wherein: 
         X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ; 
         R 5  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; 
         each R 1  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 1  and R 2  together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 1  or R 2  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group; 
         n is an integer from 2 to 4; 
         R 3  is hydrogen or (1-4C)alkyl; 
         R 4  is 
       
       
         
           
           
               
               
           
         
         each R 6  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6  and R 7  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         each W is independently —NR 8 —, —O— or —S—; 
         each R 8  is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6  and R 8  independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         p is an integer from one to 100; and 
         R 7  is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         38 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula KC-(IV): 
       
         
           
           
               
               
           
         
         wherein: 
         X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ; 
         R 5  is selected from (1-6C)alkyl, (1-6C) substituted alkyl, —(CH 2 ) q (C 6 H 4 )—COOH, —(CH 2 ) q (C 6 H 4 )—COOCH 3 , and —(CH 2 ) q (C 6 H 4 )—COOCH 2 CH 3 , where q is an integer from one to 10; 
         each R 1  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 1  and R 2  together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 1  or R 2  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group; 
         n is 2 or 3; 
         R 3  is hydrogen; 
         R 4  is a residue of an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, or a residue of an N-acyl derivative of any of said amino acids; or a residue of a peptide composed of at least two L-amino acid residues selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or a residue of an N-acyl derivative thereof; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         39 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula KC-(Va): 
       
         
           
           
               
               
           
         
         wherein: 
         X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ; 
         R 5  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; 
         each R 1  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 1  and R 2  together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 1  or R 2  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; 
         n is an integer from 2 to 4; 
         R 3  is hydrogen; 
         R 4  is a trypsin-cleavable moiety; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         40 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula KC-(Vb): 
       
         
           
           
               
               
           
         
         wherein: 
         X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ; 
         R 5  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; 
         each R 1  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 1  and R 2  together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 1  or R 2  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; 
         n is an integer from 2 to 4; 
         R 3  is hydrogen; 
         R 4  is a GI enzyme-cleavable moiety; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         41 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula KC-(VI): 
       
         
           
           
               
               
           
         
         wherein: 
         X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to —C(O)—Y—(C(R 1 )(R 2 )) n —NR 3 R 4 ; 
         Y is —NR 5 —, —O— or —S—; 
         n is an integer from 1 to 4; 
         each R 1 , R 2 , R 3  and R 5  is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R 1  and R 2  together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group; 
         R 4  is 
       
       
         
           
           
               
               
           
         
         each R 6  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 6  and R 7  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 7  is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; 
         p is an integer from 1 to 10; 
         each W is independently —NR 8 —, —O— or —S—; and 
         each R 8  is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R 6  and R 8  independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring. 
       
     
     
         42 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula KC-(VII): 
       
         
           
           
               
               
           
         
         or salts, solvates or hydrates thereof wherein: 
         X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond —(CR 12 R 13 )—Y—Z—R 11 ; 
         R 12  and R 13  are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; 
         Y is aryl, heteroaryl or arylaryl optionally substituted with one or more —F, —Cl, —Br, —I, —R 14 , —O − , —OR 14 , —SR 14 , —S − , —NR 14 R 15 , —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O) 2 O − , —S(O) 2 OH, —S(O) 2 R 14 , —OS(O 2 )O − , —OS(O) 2 R 14 , —P(O)(O − ) 2 , —P(O)(OR 14 )(O − ), —OP(O)(OR 14 )(OR 15 ), —C(O)R 14 , —C(S)R 14 , —C(O)OR 14 , —C(O)NR 14 R 15 , —C(O)O − , —C(S)OR 14 , —NR 16 C(O)NR 14 R 15 , —NR 16 C(S)NR 14 R 15 , —NR 17 C(NR 16 )NR 15 R 14  or —C(NR 16 )NR 15 R 14 ; 
         R 14 , R 15 , R 16  and R 17  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 14  and R 15  together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         Z is N(R 18 )—, —O— or —S—; 
         R 18  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or 
       
       
         
           
           
               
               
           
         
         each W is independently —NR 20 —, —O— or —S—; 
         each R 19  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 19  and R 20  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         each R 20  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 20  and R 21  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 21  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; 
         n is an integer from 0 to 5; 
         R 11  is 
       
       
         
           
           
               
               
           
         
         each U is independently —NR 23 —, —O— or —S—; 
         each R 22  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 22  and R 23  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         each R 23  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or optionally, R 23  and R 24  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 24  is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; and 
         o is an integer from 1 to 100; 
         provided that Z is oriented para or ortho to X—(CR 12 R 13 )— and that both R 18  and R 11  are not hydrogen. 
       
     
     
         43 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula KC-(VIII): 
       
         
           
           
               
               
           
         
         or salts, solvates or hydrates thereof wherein: 
         X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to —(CR 12 R 13 )—Y—Z—R 11 ; 
         R 12  and R 13  are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; 
         R k   26  are each independently selected from the group consisting of one or more of —F, —Cl, —Br, —I, R 14 , O − , —OR 14 , —SR 14 , —S − , —NR 14 R 15 , —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O) 2 O − , —S(O) 2 OH, —S(O) 2 R 14 , —OS(O 2 )O − , —OS(O) 2 R 14 , —P(O)(O − ) 2 , —P(O)(OR 14 )(O − ), —OP(O)(OR 14 )(OR 15 ), —C(O)R 14 , —C(S)R 14 , —C(O)OR 14 , —C(O)NR 14 R 15 , —C(O)O − , —C(S)OR 14 , —NR 16 C(O)NR 14 R 15 , —NR 16 C(S)NR 14 R 15 , —NR 17 C(NR 16 )NR 15 R 14  and —C(NR 16 )NR 15 R 14 , and k is 0, 1, 2, 3, or 4; 
         R 14 , R 15 , R 16  and R 17  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 4  and R 5  together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 18  is hydrogen or methyl; 
         R 22  is a side chain of an amino acid or a derivative of a side chain of an amino acid; 
         each U is independently —NR 23 —, —O— or —S—; 
         each R 23  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 23  and R 24  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and 
         R 24  is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; and 
         o is an integer from 1 to 100. 
       
     
     
         44 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula KC-(IX):
   X—C(R 31a )(R 32a ))—Ar—Z—C(O)—Y—(C(R 31 )(R 32 )) n —N—(R 33 )(R 34 )A-   (KC-(IX))
   or a salt, hydrate or solvate thereof wherein:   X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to —(C(R 31a )(R 32a )—Ar—Z—C(O)—Y—(C(R 31 )(R 32 )) n —N—(R 33 )(R 34 );   R 31a  and R 32a  are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;   Ar is aryl, heteroaryl or arylaryl optionally substituted with one or more —F, —Cl, —Br, —I, —R 34a , —O − , —OR 34a , —SR 34a , —S—, —NR 34a R 35a , —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O) 2 O′, —S(O) 2 OH, —S(O) 2 R 34a , —OS(O 2 )O″, —OS(O) 2 R 34a , —P(O)(0″) 2 , —P(O)(OR 34a )(O″), —OP(O)(OR 34a )(OR 35a ), —C(0)R 34a , —C(S)R 34a , —C(O)OR 34a , —C(O)NR 34a R 35a , —C(O)O; —C(S)OR 34a , —NR 36a C(O)NR 34a R 35a , —NR 36a C(S)NR 34a R 35a , —NR 37a C(NR 36a )NR 35a R 34a  or —C(NR 36a )NR 35a R 34a , or tethered to a polymer;   R 34a , R 35a , R 36a  and R 37a  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 34  and R 35  together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;   Z is O, S or NH;   Y is —NR 35 —, —O— or —S—;   n is an integer from 1 to 10;   each R 31 , R 32 , R 33  and R 35  is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R 31  and R 32  together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 31  or R 32  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;   R 34  is   
       
         
           
           
               
               
           
         
         each R 36  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 36  and R 37  together with 
         the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 37  is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; 
         p is an integer from 1 to 5; 
         each W is independently —NR 38 —, —O— or —S—; 
         each R 38  is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R 36  and R 38  independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and 
         A′ represents an anion. 
       
     
     
         45 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula QS-(I): 
       
         
           
           
               
               
           
         
         or salts, solvates or hydrates thereof wherein: 
         X is an opioid comprising an amine, wherein a hydrogen atom of the primary or secondary amine is replaced by a covalent bond to —(CR 12 R 13 )—Y—Z—R 11  or a lone pair of electrons of a tertiary amine is replaced by a covalent bond to —(CR 12 R 13 )—Y—Z—R 11 ; 
         R 12  and R 13  are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; 
         Y is aryl, heteroaryl or arylaryl optionally substituted with one or more —F, —Cl, —Br, —I, —R 14 , —O − , —OR 14 , —SR 14 , —S − , —NR 14 R 15 , —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O) 2 O − , —S(O) 2 OH, —S(O) 2 R 14 , —OS(O 2 )O − , —OS(O) 2 R 14 , —P(O)(O − ) 2 , —P(O)(OR 14 )(O − ), —OP(O)(OR 14 )(OR 15 ), —C(O)R 14 , —C(S)R 14 , —C(O)OR 14 , —C(O)NR 14 R 15 , —C(O)O − , —C(S)OR 14 , —NR 16 C(O)NR 14 R 15 , —NR 16 C(S)NR 14 R 15 , —NR 17 C(NR 16 )NR 15 R 14  or —C(NR 16 )NR 15 R 14 ; 
         R 14 , R 15 , R 16  and R 17  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 14  and R 15  together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         Z is N(R 18 )—, —O— or —S—; 
         R 18  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or 
       
       
         
           
           
               
               
           
         
         each W is independently —NR 20 —, —O— or —S—; 
         each R 19  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 19  and R 20  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         each R 20  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 20  and R 21  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 21  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; 
         n is an integer from 0 to 5; 
         R 11  is 
       
       
         
           
           
               
               
           
         
         each U is independently —NR 23 —, —O— or —S—; 
         each R 22  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 22  and R 23  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         each R 23  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 23  and R 24  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 24  is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; and 
         o is an integer from 1 to 100; 
         provided that Z is oriented para or ortho to X—(CR 12 R 13 )— and that both R 18  and R 11  are not hydrogen. 
       
     
     
         46 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula OS-(II): 
       
         
           
           
               
               
           
         
         or salts, solvates or hydrates thereof wherein: 
         X is an opioid comprising an amine, wherein a hydrogen atom of the primary or secondary amine is replaced by a covalent bond to —(CR 12 R 13 )—Y—Z—R 11  or a lone pair of electrons of a tertiary amine is replaced by a covalent bond to —(CR 12 R 13 )—Y—Z—R 11 ; 
         R 12  and R 13  are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; 
         R k   26  are each independently selected from the group consisting of one or more of —F, —Cl, —Br, —I, —R 14 , —O − , —OR 14 , —SR 14 , —S − , —NR 14 R 15 , —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O) 2 O − , —S(O) 2 OH, —S(O) 2 R 14 , —OS(O 2 )O − , —OS(O) 2 R 14 , —P(O)(O − ) 2 , —P(O)(OR 14 )(O − ), —OP(O)(OR 14 )(OR 15 ), —C(O)R 14 , —C(S)R 14 , —C(O)OR 14 , —C(O)NR 14 R 15 , —C(O)O − , —C(S)OR 14 , —NR 16 C(O)NR 14 R 15 , —NR 16 C(S)NR 14 R 15 , —NR 17 C(NR 16 )NR 15 R 14  and —C(NR 16 )NR 15 R 14 , and k is 0, 1, 2, 3, or 4; 
         R 14 , R 15 , R 16  and R 17  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 4  and R 5  together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 18  is hydrogen or methyl; 
         R 22  is a side chain of an amino acid or a derivative of a side chain of an amino acid; 
         each U is independently —NR 23 —, —O— or —S—; 
         each R 23  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 23  and R 24  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and 
         R 24  is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; and 
         o is an integer from 1 to 100. 
       
     
     
         47 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula QS-(III):
   X—C(R 31a )(R 32a ))—Ar—Z—C(O)—Y—(C(R 31 )(R 32 )) n —N—(R 33 )(R 34 ) A-   (QS-(III))
   or a salt, hydrate or solvate thereof wherein:   X is a residue of an opioid wherein the lone pair of electrons of the amino nitrogen is replaced with a bond to —(C(R 31a )(R 32a )—Ar—Z—C(O)—Y—(C(R 31 )(R 32 )) n —N—(R 33 )(R 34 );   R 31a  and R 32a  are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;   Ar is aryl, heteroaryl or arylaryl optionally substituted with one or more —F, —Cl, —Br, —I, —R 34a , —O − , —OR 34a , —SR 34a , —S—, —NR 34a R 35a , —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O) 2 O′, —S(O) 2 OH, —S(O) 2 R 34a , —OS(O 2 )O″, —OS(O) 2 R 34a , —P(0)(0″) 2 , —P(O)(OR 34a )(O″),—OP(O)(OR 34a )(OR 35a ), —C(0)R 34a , —C(S)R 34a , —C(O)OR 34a , —C(O)NR 34a R 35a , —C(O)O; —C(S)OR 34a , —NR 36a C(O)NR 34a R 35a , —NR 36a C(S)NR 34a R 35a , —NR 37a C(NR 36a )NR 35a R 34a  or —C(NR 36a )NR 35a R 34a , or tethered to a polymer;   R 34a , R 35a , R 36a  and R 37a  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 34  and R 35  together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;   Z is O, S or NH;   Y is —NR 35 —, —O— or —S—;   n is an integer from 1 to 10;   each R 31 , R 32 , R 33  and R 35  is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R 31  and R 32  together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 31  or R 32  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;   R 34  is   
       
         
           
           
               
               
           
         
         each R 36  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 36  and R 37  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 37  is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; 
         p is an integer from 1 to 5; 
         each W is independently —NR 38 —, —O— or —S—; 
         each R 38  is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R 36  and R 38  independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and 
         A′ represents an anion. 
       
     
     
         48 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula AE-(I): 
       
         
           
           
               
               
           
         
         wherein: 
         X represents a residue of an amide-containing opioid, wherein —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4  is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer; 
         R 5  is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; 
         each R 1  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 1  and R 2  together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 1  or R 2  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; 
         n is an integer from 2 to 4; 
         R 3  is hydrogen or (1-4C)alkyl; 
         R 4  is 
       
       
         
           
           
               
               
           
         
         each R 6  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6  and R 7  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         each W is independently —NR 8 —, —O— or —S—; 
         each R 8  is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6  and R 8  independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         p is an integer from one to 100; and 
         R 7  is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         49 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula AE-(II): 
       
         
           
           
               
               
           
         
         wherein: 
         X represents a residue of an amide-containing opioid, wherein —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4  is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer; 
         R 5  is selected from (1-6C)alkyl, (1-6C) substituted alkyl, —(CH 2 ) q (C 6 H 4 )—COOH, —(CH 2 ) 1 (C 6 H 4 )—COOCH 3 , and —(CH 2 ) q (C 6 H 4 )—COOCH 2 CH 3 , where q is an integer from one to 10; 
         each R 1  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         each R 2  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; 
         or R 1  and R 2  together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 1  or R 2  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; 
         n is 2 or 3; 
         R 3  is hydrogen; 
         R 4  is a GI enzyme-cleavable moiety; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         50 . The composition of  claim 1 , wherein the opioid prodrug is a compound of formula AE-(III): 
       
         
           
           
               
               
           
         
         wherein: 
         X represents a residue of an amide-containing opioid, wherein —CO—C(R 6 )—NR 8 R 7  is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer; 
         each R 6  is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R 6  and R 7  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         each R 8  is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6  and R 8  independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 7  is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         51 . A method to treat a patient comprising administering a pharmaceutical composition or dose unit comprising the composition of  claim 1  to a patient in need thereof. 
     
     
         52 . A method of making a dose unit, the method comprising:
 combining in a dose unit:   an opioid prodrug comprising an opioid covalently bound to a promoiety cleavable by a GI enzyme, wherein cleavage of the promoiety by the GI enzyme mediates release of the opioid from the opioid prodrug; and   a GI enzyme inhibitor that interacts with the enzyme that mediates enzymatically-controlled release of the opioid from the opioid prodrug;   wherein the opioid prodrug and GI enzyme inhibitor are present in the dose unit in an amount effective to attenuate release of the opioid from the opioid prodrug such that ingestion of multiples of dose units by a patient does not provide a proportional release of opioid.   
     
     
         53 . A method of  claim 52 , wherein said release of opioid is decreased compared to release of opioid by an equivalent dosage of opioid prodrug in the absence of inhibitor. 
     
     
         54 . A method for identifying an opioid prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit, the method comprising:
 combining an opioid prodrug, a GI enzyme inhibitor, and GI enzyme in a reaction mixture, wherein the opioid prodrug comprises an opioid covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by the enzyme mediates release of the opioid; and   detecting opioid prodrug conversion,   wherein a decrease in opioid prodrug conversion in the presence of the GI enzyme inhibitor as compared to opioid prodrug conversion in the absence of the GI enzyme inhibitor indicates the opioid prodrug and GI enzyme inhibitor are suitable for formulation in a dose unit.   
     
     
         55 . A method for identifying an opioid prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit, the method comprising:
 administering to an animal an opioid prodrug and a GI enzyme inhibitor, wherein the opioid prodrug comprises an opioid covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by the enzyme mediates release of the opioid; and   detecting opioid prodrug conversion, wherein a decrease in opioid conversion in the presence of the GI enzyme inhibitor as compared to opioid conversion in the absence of the GI enzyme inhibitor indicates the opioid prodrug and GI enzyme inhibitor are suitable for formulation in a dose unit.   
     
     
         56 . The method of  claim 55 , wherein said administering comprises administering to the animal increasing doses of inhibitor co-dosed with a selected fixed dose of opioid prodrug. 
     
     
         57 . The method of  claim 55 , wherein said detecting facilitates identification of a dose of inhibitor and a dose of opioid prodrug that provides for a pre-selected pharmacokinetic (PK) profile. 
     
     
         58 . The method of  claim 55 , wherein said method comprises an in vivo assay. 
     
     
         59 . The method of  claim 55 , wherein said method comprises an ex vivo assay. 
     
     
         60 . A method for identifying an opioid prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit, the method comprising:
 administering to an animal tissue an opioid prodrug and a GI enzyme inhibitor, wherein the opioid prodrug comprises a opioid covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by the enzyme mediates release of the opioid; and   detecting opioid prodrug conversion, wherein a decrease in opioid prodrug conversion in the presence of the GI enzyme inhibitor as compared to opioid prodrug conversion in the absence of the GI enzyme inhibitor indicates the opioid prodrug and GI enzyme inhibitor are suitable for formulation in a dose unit.   
     
     
         61 . The compound of  claim 33 , wherein R 3  is hydrogen. 
     
     
         62 . The compound of  claim 34 , wherein R 3  is hydrogen. 
     
     
         63 . The compound of  claim 36 , wherein R 3  is hydrogen. 
     
     
         64 . The compound of  claim 37 , wherein R 3  is hydrogen. 
     
     
         65 . The compound of  claim 48 , wherein R 3  is hydrogen.