RU2012149438A - COMPOSITIONS CONTAINING AN ENZYM-DIVISIBLE OPIOID MEDICINES AND THEIR INHIBITORS - Google Patents

Abstract

1. A composition comprising: an opioid prodrug containing an opioid covalently coupled to a profragment containing a fragment cleaved with a GI enzyme, wherein cleavage of a fragment cleaved with a GI enzyme by the GI enzyme mediates the release of the opioid; a GI enzyme inhibitor that interacts with a GI enzyme that mediates the enzymatically controlled release of an opioid from an opioid prodrug after ingestion of the composition. 2. A dosage unit containing the composition of claim 1, wherein the opioid prodrug and GI enzyme inhibitor are present in a dosage unit in an amount effective to provide a pre-selected pharmacokinetic (PK) profile after oral administration. The dose unit according to claim 2, wherein the pre-selected PK profile includes at least one PK parameter value that is less than the PK value of the opioid parameter released after ingestion of an equivalent dosage of an opioid prodrug in the absence of an inhibitor. The dosage unit according to claim 3, wherein the PK parameter value is selected from the Cmax value of the opioid, the exposure value of the opioid, and the value (1 / Tmax of the opioid). The dose unit according to claim 2, wherein the dose unit provides a pre-selected PK profile after ingestion of at least two dose units. The dosage unit according to claim 5, wherein the pre-selected PK profile is modified relative to the PK profile after ingestion of an equivalent dosage of an opioid prodrug in the absence of an inhibitor. The dose unit according to claim 5, wherein the dose unit provides a linear PK profile when ingested an increased number of dose units. The unit dose according to claim 5, where the unit dose provides an ingestion

Claims (39)

1. A composition comprising: an opioid prodrug containing an opioid covalently linked to a profragment containing a fragment cleaved by a GI enzyme, wherein cleavage of a fragment cleaved by a GI enzyme by the GI enzyme mediates the release of the opioid; and a GI enzyme inhibitor that interacts with a GI enzyme that mediates enzymatically controlled release of an opioid from an opioid prodrug after ingestion of the composition. 2. The unit dose containing the composition according to claim 1, where the opioid prodrug and the GI enzyme inhibitor are present in a unit dose in an amount effective to provide a pre-selected pharmacokinetic (PK) profile after oral administration. 3. The dosage unit according to claim 2, wherein the pre-selected PK profile includes at least one PK parameter value that is less than the PK value of the opioid parameter released after ingestion of an equivalent dosage of an opioid prodrug in the absence of an inhibitor. 4. The dose unit according to claim 3, where the value of the RK parameter is selected from the value of Cmax of the opioid, the value of exposure to the opioid and the value (1 / Tmax of the opioid). 5. The dose unit according to claim 2, where the dose unit provides a pre-selected PK profile after ingestion of at least two dose units. 6. The dosage unit according to claim 5, wherein the pre-selected PK profile is modified relative to the PK profile after ingestion of an equivalent dosage of an opioid prodrug in the absence of an inhibitor. 7. The dose unit according to claim 5, where the dose unit provides a linear PK profile when ingested with an increased number of dose units. 8. The dose unit according to claim 5, where the dose unit provides, when ingested an increased number of dose units, a non-linear PK profile. 9. The dose unit according to claim 5, wherein the PK parameter value is selected from the Cmax value of the opioid, the value (1 / Tmax of the opioid), and the value of the opioid exposure. 10. The composition concluded in: a container suitable for containing a composition for administration to a patient; containing unit dose containing the composition according to claim 1, placed inside the container. 11. The composition according to claim 1, which is a unit dose having a total weight of from 1 microgram to 2 grams. 12. The composition according to claim 1, which has a combined weight of an opioid prodrug and a GI enzyme inhibitor from 0.1% to 99% per gram of composition. 13. The composition according to any one of claims 1, 11, 12, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula PC- (1)

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, where the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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; each R ² and R ³ 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group or an amino acid residue, a dipeptide or N-acyl derivative of an amino acid or dipeptide; (b) compounds of the formula PC- (IIa):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, where the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (c) compounds of the formula PC- (IIb):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, where the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 is 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (d) a compound of the formula PC- (III):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, where the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (e) compounds of the formula PC- (IV):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a single bond; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group, or an amino acid residue, a dipeptide or N-acyl derivative of an amino acid or dipeptide; (f) compounds of the formula PC- (Va):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (g) compounds of the formula PC- (Vb):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a 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 is 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (h) compounds of formula PC- (VI):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a single bond; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (i) compounds of the formula PC- (VII):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, wherein the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —C (O) —NR ¹ - (C (R ² ) (R ³ )) n-NH-R ⁶ ; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3; and R ⁶ is a trypsin cleavable moiety; (j) a compound of formula PC- (VIII):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, wherein the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; and R ⁶ is a trypsin cleavable moiety; (k) compounds of the formula PC- (IX):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a single bond; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3; and R ⁶ is a trypsin cleavable moiety; (1) compounds of the formula PC- (X):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; and R ⁶ is a trypsin cleavable moiety; (m) compounds of the formula PC- (XI):

or its pharmaceutically acceptable salt, in which: X represents a phenolic opioid residue, wherein the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —C (O) —NR ¹ - (C (R ² ) (R ³ )) _n —NH — R ⁶ ; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3; and R ⁶ is a fragment cleaved by the GI enzyme; (n) compounds of the formula PC- (XII):

or its pharmaceutically acceptable salt, in which: X represents a phenolic opioid residue, wherein the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; and R ⁶ is a fragment cleaved by the GI enzyme; (o) compounds of the formula PC- (XIII):

or its pharmaceutically acceptable salt, in which: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a single bond; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3; and R ⁶ is a fragment cleaved by the GI enzyme; (p) a compound of formula PC- (XIV):

or its pharmaceutically acceptable salt, in which: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; and R ⁶ is a fragment cleaved by the GI enzyme; (q) compounds of the formula PC- (XV):

, Where: X represents a phenolic opioid, where the hydrogen atom of the hydroxyl group is substituted by a covalent bond on —C (O) —Y— (C (R ¹ ) (R ² )) _n —N— (R ³ ) (R ⁶ ); Y represents —NR5 ^- , —O— or —S—; n is an integer from 1 to 4; each R ¹ , R ² , R ³ and R ⁵ independently represents 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 represents

; each R ⁴ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ⁷ represents 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 independently represents —NR ⁸ -, —O— or —S—; and each R ⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. 14. The composition according to any one of claims 1, 11 and 12, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula PC- (XVI):

or its salts, solvates or hydrates, where: X is an opioid containing phenol, wherein the phenol hydrogen atom is covalently substituted with - (CR ¹² R ¹³ ) —YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; Y represents 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 independently represent 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 an atom the nitrogen to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents N (R ¹⁸ ) -, —O— or —S—; R ¹⁸ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or

; each W independently represents —NR ²⁰ -, —O— or —S—; each R ¹⁹ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²⁰ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²¹ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; n is an integer from 0 to 5; R ¹¹ represents

; each U independently represents —NR ²³ -, —O— or —S—; each R ²² independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²⁴ represents 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 in a vapor or ortho position with respect to X- (CR ¹² R ¹³ ) - and that both R ¹⁸ and R ¹¹ are not hydrogen; (b) compounds of formula PC- (XVII):

or its salts, solvates or hydrates, where: X is an opioid containing phenol, wherein X is connected using phenol; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; everyone $$R_k^{26}$$

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 represents 0, 1, 2, 3 or 4; R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ¹⁸ represents hydrogen or methyl; R ²² represents an amino acid side chain or an amino acid side chain derivative; each U independently represents —NR ²³ -, —O— or —S—; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; and R ²⁴ represents 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; (c) compounds of the formula PC- (XVIII):

or its salt, hydrate or MES, where: X is an opioid containing phenol, where the phenol hydrogen atom is replaced by a covalent bond with - (C (R ^31a ) (R ^32a ) -Ar-ZC (O) -Y- (C (R ³¹ ) (R ³² )) _n- N- (R ³³ ) (R ³⁴ ); R ^31a and R ^32a independently represent 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) (O”) ₂ , -P (O) (OR ^34a ) (O ”), -OP (O) (OR ^34a ) (OR ^35a ), -C (O) 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 attached to a polymer; R ^34a , R ^35a , R ^36a and R ^37a independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents O, S or NH; Y represents —NR ³⁵ -, —O— or —S—; n is an integer from 1 to 10; each R ³¹ , R ³² , R ³³ and R ³⁵ independently represents 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 represents

; each R ³⁶ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ³⁷ represents 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 independently represents —NR ³⁸ -, —O— or —S—; each R ³⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and A 'is an anion. 15. The composition according to any one of claims 1, 11 and 12, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula KC- (Ia):

, Where: R ^a represents 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 attached, form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (b) compounds of formula KC- (Ib):

, Where: R ^a represents 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 represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (c) compounds of formula KC- (II):

, Where: R ^a represents 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 H 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 a group; n represents 2 or 3; R ³ represents hydrogen; R ⁴ represents the remainder 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, tyros and valine, or the remainder of the N-acyl derivative of any of these amino acids; or a peptide residue consisting 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 the remainder of their N-acyl derivative, (d) compounds of formula KC- (IIIa):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 atoms, by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (e) compounds of formula KC- (IIIb):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 atoms, by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (f) compounds of formula KC- (IV):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 represents 2 or 3; R ³ represents hydrogen or (1-4C) alkyl; R ⁴ represents the remainder 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, tyros and valine, or the remainder of the N-acyl derivative of any of these amino acids; or a peptide residue consisting 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 the remainder of their N-acyl derivative; its salt, hydrate or solvate; (g) compounds of formula KC- (Va):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen; R ⁴ is a trypsin cleavable moiety; its salt, hydrate or solvate; (h) compounds of formula KC- (Vb):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen; R ⁴ is a fragment cleaved by a GI enzyme; its salt, hydrate or solvate; (i) compounds of formula KC- (VI):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond with —C (O) —Y— (C (R ¹ ) (R ² )) _n —NR ³ R ⁴ ; Y represents —NR ⁵ -, —O— or —S—; n is an integer from 1 to 4; each R ¹ , R ² , R ³ and R ⁵ independently represents 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 represents

; each R ⁶ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ⁷ represents 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 independently represents —NR ⁸ -, —O— or —S—; and each R ⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. 16. The composition according to any one of claims 1, 11 and 12, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula KC- (VII):

or its salts, solvates or hydrates, where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond - (CR ¹² R ¹³ ) —YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; Y represents 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 independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents N (R ¹⁸ ) -, —O— or —S—; R ¹⁸ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or

; each W independently represents —NR ²⁰ -, —O— or —S—; each R ¹⁹ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²⁰ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²¹ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; n is an integer from 0 to 5; R ¹¹ represents

; each U independently represents —NR ²³ -, —O— or —S—; each R ²² independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²³ independently represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or optionally R ²³ and R ²⁴ together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²⁴ represents 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 in the para- or ortho position with respect to X- (CR ¹² R ¹³ ) - and that both R ¹⁸ and R ¹¹ are not hydrogen; (b) compounds of formula KC- (VIII):

or its salts, solvates or hydrates, where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on - (CR ¹² R ¹³ ) -YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; everyone $$R_k^{26}$$

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 represents 0, 1, 2, 3 or 4; R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ¹⁸ represents hydrogen or methyl; R ²² represents an amino acid side chain or an amino acid side chain derivative; each U independently represents —NR ²³ -, —O— or —S—; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; and R ²⁴ represents 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; (c) compounds of formula KC- (IX):

or its salt, hydrate or MES, where: X represents the remainder of the ketone-containing opioid, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on - (C (R ^31a ) (R ^32a ) -Ar-ZC (O) -Y- (C (R ³¹ ) (R ³² )) _n -N- (R ³³ ) (R ³⁴ ); R ^31a and R ^32a independently represent 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) (O”) ₂ , -P (O) (OR ^34a ) (O ”), -OP (O ) (OR ^34a ) (OR ^35a ), -C (O) 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 attached to a polymer; R ^34a , R ^35a , R ^36a and R ^37a independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents O, S or NH; Y represents —NR ³⁵ -, —O— or —S—; n is an integer from 1 to 10; each R ³¹ , R ³² , R ³³ and R ³⁵ independently represents 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 represents

; each R ³⁶ independently represents 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 atoms, to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ³⁷ represents 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 independently represents —NR ³⁸ -, —O— or —S—; each R ³⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and A 'is an anion. 17. The composition according to any one of claims 1, 11 and 12, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula QS- (I):

or its salts, solvates or hydrates, where: X is an opioid containing an amine, where the hydrogen atom of the primary or secondary amine is substituted by the covalent bond at - (CR ¹² R ¹³ ) -YZR ¹¹ , or the unshared electron pair of the tertiary amine is substituted by the covalent bond at - (CR ¹² R ¹³ ) -YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; Y represents 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 independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents N (R ¹⁸ ) -, —O— or —S—; R ¹⁸ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or

; each W independently represents —NR ²⁰ -, —O— or —S—; each R ¹⁹ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²⁰ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²¹ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; n is an integer from 0 to 5; R ¹¹ represents

; each U independently represents —NR ²³ -, —O— or —S—; each R ²² independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²⁴ represents 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 in the para- or ortho position with respect to X- (CR ¹² R ¹³ ) - and that both R ¹⁸ and R ¹¹ are not hydrogen; (b) compounds of formula QS- (II):

or its salts, solvates or hydrates, where: X is an opioid containing an amine, where the hydrogen atom of the primary or secondary amine is substituted by the covalent bond at - (CR ¹² R ¹³ ) -YZR ¹¹ , or the unshared electron pair of the tertiary amine is substituted by the covalent bond at - (CR ¹² R ¹³ ) -YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; everyone $$R_k^{26}$$

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 represents 0, 1, 2, 3 or 4; R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ¹⁸ represents hydrogen or methyl; R ²² represents an amino acid side chain or an amino acid side chain derivative; each U independently represents —NR ²³ -, —O— or —S—; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; and R ²⁴ represents 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. (c) compounds of formula QS- (III):

or its salt, hydrate or MES, where: X represents an opioid residue, where an unshared pair of nitrogen electrons of the amino group is substituted by a bond on - (C (R ^31a ) (R ^32a ) -Ar-ZC (O) -Y- (C (R ³¹ ) (R ³² )) _n -N- (R ³³ ) (R ³⁴ ); R ^31a and R ^32a independently represent 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 ₂ -NO ₂ , -N3, -S (O) ₂ O ', -S (O) ₂ OH, -S (O) ₂ R ^34a , -OS (O ₂ ) O ”, -OS (O) ₂ R ^34a , -P (O) (O”) ₂ , -P (O) (OR ^34a ) (O ”), OP (O) (OR ^34a ) (OR ^35a ), -C (O) R ^34a , -C (S) R ^34a , -C (O) OR ^34a , -C (O) NR ^34a R ^35a , -C (O) O; -C (S) R ^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 attached to a polymer; R ^34a , R ^35a , R ^36a and R ^37a independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents O, S or NH; Y represents —NR ³⁵ -, —O— or —S—; n is an integer from 1 to 10; each R ³¹ , R ³² , R ³³ and R ³⁵ independently represents 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 represents

; each R ³⁶ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ³⁷ represents 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 independently represents —NR ³⁸ -, —O— or —S—; each R ³⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and A 'is an anion. 18. The composition according to any one of claims 1, 11 and 12, in which the opioid prodrug is selected from the group consisting of: (a) compounds of formula AE- (I):

, Where: X represents the remainder of the amide-containing opioid, where —C (O) —NR ⁵ - (C (R ¹ ) (R ² )) _n —NR ³ R ^{4 is} coupled to the amide-containing opioid via oxygen of the amide group, where the amide group is converted to the amide enol or 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen or (1-4C) alkyl;

; R ⁴ represents 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 atoms, by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (b) compounds of formula AE- (II):

, Where: X represents the remainder of the amide-containing opioid, where —C (O) —NR ⁵ - (C (R ¹ ) (R ² )) _n —NR ³ R ^{4 is} coupled to the amide-containing opioid via oxygen of the amide group, where the amide group is converted to the amide enol or imine tautomer; 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, 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n represents 2 or 3; R ³ represents hydrogen; R ⁴ is a fragment cleaved by a GI enzyme; its salt, hydrate or solvate; (c) compounds of formula AE- (III):

, Where: X represents: a residue of an amide-containing opioid, where —CO — C (R ⁶ ) —NR ⁸ R ^{7 is} coupled to the amide-containing opioid through oxygen of the amide group, where the amide group is converted to an amide enol or 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 atoms, by which they are attached to 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ^{7 is} selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, mixed alkoxycarbonyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl; its salt, hydrate or solvate. 19. A method of treating a patient, comprising administering a pharmaceutical composition or dosage unit according to any one of the preceding paragraphs to a patient in need thereof. 20. A method of producing a unit dose, the method comprising: combining in a unit dose: an opioid prodrug containing an opioid covalently linked to a profragment cleaved by the GI enzyme, where cleavage of the profragment by the enzyme mediates the release of the opioid from the opioid prodrug; and an inhibitor of a GI enzyme that interacts with an enzyme that mediates the enzymatically controlled release of an opioid from an opioid prodrug; where the opioid prodrug and GI enzyme inhibitor are present in a unit dose in an amount effective to reduce the release of the opioid from the opioid prodrug so that the patient does not provide a proportional release of the opioid by ingestion of multiple dose units. 21. The method according to claim 20, where the indicated release of the opioid is reduced compared with the release of the opioid by an equivalent dosage of the prodrug in the absence of an inhibitor. 22. A method for determining an opioid prodrug and a GI enzyme inhibitor suitable for unit dosage form comprising: a combination of an opioid prodrug, a GI enzyme inhibitor and a G1 enzyme in the reaction mixture, or the introduction of an opioid prodrug and G1 inhibitor of the enzyme to the animal or into the tissue of the animal, wherein the opioid prodrug contains an opioid covalently linked to a profragment containing a fragment cleaved by a GI enzyme, wherein cleavage of a fragment cleaved by a GI enzyme using a G1 enzyme mediates the release of the opioid; and prodrug conversion detection, where a decrease in the conversion of an opioid prodrug in the presence of a GI enzyme inhibitor compared to a conversion of a prodrug in the absence of a GI enzyme inhibitor indicates that the opioid prodrug and the GI enzyme inhibitor are suitable for unit dosage. 23. The method of claim 22, wherein said administration comprises administering to the animal increased doses of an inhibitor co-dosed with a selected fixed dose of an opioid prodrug. 24. The method according to item 22, where the specified detection facilitates the determination of the dose of the inhibitor and the dose of the opioid prodrug, which provides a pre-selected pharmacokinetic (PK) profile. 25. The method according to item 22, where the specified method includes in vivo analysis. 26. The method according to item 22, where the specified method includes ex vivo analysis. 27. The method according to any one of claims 20-26, wherein the portion cleaved by the GL enzyme is a portion cleaved by trypsin, and the G1 inhibitor of the enzyme is a trypsin inhibitor. 28. The unit dose according to any one of paragraphs. 2-9, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula PC- (I)

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, where the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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; each R ² and R ³ 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group or an amino acid residue, a dipeptide or N-acyl derivative of an amino acid or dipeptide; (b) compounds of the formula PC- (IIa):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, where the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (c) compounds of the formula PC- (IIb):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, where the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 is 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (d) a compound of formula PC- (III):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, where the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue: amino acids, a dipeptide or N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide; (e) compounds of the formula PC- (IV):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a single bond; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ 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 ; wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid; and R ⁵ represents a hydrogen atom, an N-acyl group, or an amino acid residue, a dipeptide or N-acyl derivative of an amino acid or dipeptide; (f) compounds of the formula PC- (Va):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (g) compounds of the formula PC- (Vb):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a 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 is 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (h) compounds of formula PC- (VI):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a single bond; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (i) compounds of the formula PC- (VII):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, wherein the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —C (O) —NR ¹ - (C (R ² ) (R ³ )) _n —NH — R ⁶ ; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3; and R ⁶ is a trypsin cleavable moiety; (j) a compound of formula PC- (VIII):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, wherein the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; and R ⁶ is a trypsin cleavable moiety; (k) compounds of the formula PC- (IX):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a single bond; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3; and R ⁶ is a trypsin cleavable moiety; (1) compounds of the formula PC- (X):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; and R ⁶ is a trypsin cleavable moiety; (m) compounds of the formula PC- (XI):

or its pharmaceutically acceptable salt, in which: X represents a phenolic opioid residue, wherein the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond with —C (O) —NR1— (C (R ² ) (R ³ )) _n —NH — R ⁶ ; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3; and R ⁶ is a fragment cleaved by the GI enzyme; (n) compounds of the formula PC- (XII):

or its pharmaceutically acceptable salt, in which: X represents a phenolic opioid residue, wherein the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; and R ⁶ is a fragment cleaved by the GI enzyme; (o) compounds of the formula PC- (XIII):

or its pharmaceutically acceptable salt, in which: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a single bond; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3; and R ⁶ is a fragment cleaved by the GI enzyme; (p) a compound of formula PC- (XIV):

or its pharmaceutically acceptable salt, in which: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; and R ⁶ is a fragment cleaved by the GI enzyme; (q) compounds of the formula PC- (XV):

, Where: X represents a phenolic opioid, where the hydrogen atom of the hydroxyl group is substituted by a covalent bond on —C (O) —Y— (C (R ¹ ) (R ² )) _n —N— (R ³ ) (R ⁶ ); Y represents —NR ⁵ -, —O— or —S—; n is an integer from 1 to 4; each R ¹ , R ² , R ³ and R ⁵ independently represents 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 represents

; each R ⁴ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ⁷ represents 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 independently represents —NR ⁸ -, —O— or —S—; and each R ⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. 29. The unit dose according to any one of claims 2 to 9, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula PC- (XVI):

or its salts, solvates or hydrates, where: X is an opioid containing phenol, wherein the phenol hydrogen atom is covalently substituted with - (CR ¹² R ¹³ ) —YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; Y represents 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 independently represent 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 an atom the nitrogen to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents N (R ¹⁸ ) -, —O— or —S—; R ¹⁸ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or

; each W independently represents —NR ²⁰ -, —O— or —S—; each R ¹⁹ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²⁰ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²¹ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; n is an integer from 0 to 5; R ¹¹ represents

; each U independently represents —NR ²³ -, —O— or —S—; each R ²² independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²⁴ represents 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 in a vapor or ortho position with respect to X- (CR ¹² R ¹³ ) - and that both R ¹⁸ and R ¹¹ are not hydrogen; (b) compounds of formula PC- (XVII):

or its salts, solvates or hydrates, where: X is an opioid containing phenol, wherein X is connected using phenol; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; everyone $$R_k^{26}$$

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 represents 0, 1, 2, 3 or 4; R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ¹⁸ represents hydrogen or methyl; R ²² represents an amino acid side chain or an amino acid side chain derivative; each U independently represents —NR ²³ -, —O— or —S—; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; and R ²⁴ represents 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; (c) compounds of the formula PC- (XVIII):

or its salt, hydrate or MES, where: X is an opioid containing phenol, where the phenol hydrogen atom is replaced by a covalent bond with - (C (R ^31a ) (R ^32a ) -Ar-ZC (O) -Y- (C (R ³¹ ) (R ³² )) _n- N- (R ³³ ) (R ³⁴ ); R ^31a and R ^32a independently represent 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) (O”) ₂ , -P (O) (OR ^34a ) (O ”), -OP (O) (OR ^34a ) (OR ^35a ), -C (O) 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 attached to a polymer; R ^34a , R ^35a , R ^36a and R ^37a independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents O, S or NH; Y represents —NR ³⁵ -, —O— or —S—; n is an integer from 1 to 10; each R ³¹ , R ³² , R ³³ and R ³⁵ independently represents 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 represents

; each R ³⁶ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ³⁷ represents 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 independently represents —NR ³⁸ -, —O— or —S—; each R ³⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and A 'is an anion. 30. The unit dose according to any one of claims 2 to 9, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula KC- (Ia):

, Where: R ^a represents 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 atoms, by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (b) compounds of formula KC- (Ib):

, Where: R ^a represents 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 represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (c) compounds of formula KC- (II):

, Where: R ^a represents 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 H 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 a group; n represents 2 or 3; R ³ represents hydrogen; R ⁴ represents the remainder 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, tyros and valine, or the remainder of the N-acyl derivative of any of these amino acids; or a peptide residue consisting 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 the remainder of their N-acyl derivative, (d) compounds of formula KC- (IIIa):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 ⁹ independently together with the atoms to which they are attached 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; its salt, hydrate or solvate; (e) compounds of formula KC- (IIIb):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 ⁶ together with atoms, by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (f) compounds of formula KC- (IV):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 represents 2 or 3; R ³ represents hydrogen or (1-4C) alkyl; R ⁴ represents the remainder 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, tyros and valine, or the remainder of the N-acyl derivative of any of these amino acids; or a peptide residue consisting 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 the remainder of their N-acyl derivative; its salt, hydrate or solvate; (g) compounds of formula KC- (Va):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen; R ⁴ is a trypsin cleavable moiety; its salt, hydrate or solvate; (h) compounds of formula KC- (Vb):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen; R ⁴ is a fragment cleaved by a GI enzyme; its salt, hydrate or solvate; (i) compounds of formula KC- (VI):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond with —C (O) —Y— (C (R ¹ ) (R ² )) _n —NR ³ R ⁴ ; Y represents —NR ⁵ -, —O— or —S—; n is an integer from 1 to 4; each R ¹ , R ² , R ³ and R ⁵ independently represents 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 represents

; each R ⁶ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ⁷ represents 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 independently represents —NR ⁸ -, —O— or —S—; and each R ⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. 31. The unit dose according to any one of claims 2 to 9, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula KC- (VII):

or its salts, solvates or hydrates, where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond - (CR ¹² R ¹³ ) —YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; Y represents 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 independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents N (R ¹⁸ ) -, —O— or —S—; R ¹⁸ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or

; each W independently represents —NR ²⁰ -, —O— or —S—; each R ¹⁹ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²⁰ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²¹ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; n is an integer from 0 to 5; R ¹¹ represents

; each U independently represents —NR ²³ -, —O— or —S—; each R ²² independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²³ independently represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or optionally R ²³ and R ²⁴ together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²⁴ represents hydrogen, alkyl, substituted alkyl, acyl, substituted anil, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; and o is an integer from 1 to 100; provided that Z is in the para- or ortho position with respect to X- (CR ¹² R ¹³ ) - and that both R ¹⁸ and R ¹¹ are not hydrogen; (b) compounds of formula KC- (VIII):

or its salts, solvates or hydrates, where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on - (CR ¹² R ¹³ ) -YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; everyone $$R_k^{26}$$

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 represents 0, 1, 2, 3 or 4; R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ¹⁸ represents hydrogen or methyl; R ²² represents an amino acid side chain or an amino acid side chain derivative; each U independently represents —NR ²³ -, —O— or —S—; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; and R ²⁴ represents 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; (c) compounds of formula KC- (IX):

or its salt, hydrate or MES, where: X represents the remainder of the ketone-containing opioid, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on - (C (R ^31a ) (R ^32a ) -Ar-ZC (O) -Y- (C (R ³¹ ) (R ³² )) _n -N- (R ³³ ) (R ³⁴ ); R ^31a and R ^32a independently represent 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) (O”) ₂ , -P (O) (OR ^34a ) (O ”), OP (O) (OR ^34a ) (OR ^35a ), -C (O) 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 attached to a polymer; R ^34a , R ^35a , R ^36a and R ^37a independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents O, S or NH; Y represents —NR ³⁵ -, —O— or —S—; n is an integer from 1 to 10; each R ³¹ , R ³² , R ³³ and R ³⁵ independently represents 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 gtoms of carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group; R ³⁴ represents

; each R ³⁶ independently represents 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 atoms, to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ³⁷ represents 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 independently represents —NR ³⁸ -, —O— or —S—; each R ³⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and A 'is an anion. 32. The unit dose according to any one of claims 2 to 9, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula QS- (I):

or its salts, solvates or hydrates, where: X is an opioid containing an amine, where the hydrogen atom of the primary or secondary amine is substituted by the covalent bond at - (CR ¹² R ¹³ ) -YZR ¹¹ , or the unshared electron pair of the tertiary amine is substituted by the covalent bond at - (CR ¹² R ¹³ ) -YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; Y represents 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 independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents N (R ¹⁸ ) -, —O— or —S—; R ¹⁸ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or

; each W independently represents —NR ²⁰ -, —O— or —S—; each R ¹⁹ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²⁰ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²¹ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; n is an integer from 0 to 5; R ¹¹ represents

; each U independently represents —NR ²³ -, —O— or —S—; each R ²² independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²⁴ represents 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 in the para- or ortho position with respect to X- (CR ¹² R ¹³ ) - and that both R ¹⁸ and R ¹¹ are not hydrogen; (b) compounds of formula QS- (II):

or its salts, solvates or hydrates, where: X is an opioid containing an amine, where the hydrogen atom of the primary or secondary amine is substituted by the covalent bond at - (CR ¹² R ¹³ ) -YZR ¹¹ , or the unshared electron pair of the tertiary amine is substituted by the covalent bond at - (CR ¹² R ¹³ ) -YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; everyone $$R_k^{26}$$

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 represents 0, 1, 2, 3 or 4; R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ¹⁸ represents hydrogen or methyl; R ²² represents an amino acid side chain or an amino acid side chain derivative; each U independently represents —NR ²³ -, —O— or —S—; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; and R ²⁴ represents 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; (c) compounds of formula QS- (III):

or its salt, hydrate or MES, where: X represents an opioid residue, where an unshared pair of nitrogen electrons of the amino group is substituted by a bond on - (C (R ^31a ) (R ^32a ) -Ar-ZC (O) -Y- (C (R ³¹ ) (R ³² )) _n -N- (R ³³ ) (R ³⁴ ); R ^31a and R ^32a independently represent 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) (O”) ₂ , -P (O) (OR ^34a ) (O ”), OP (O) ( OR ^34a ) (OR ^35a ), -C (O) 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 attached to a polymer; R ^34a , R ^35a , R ^36a and R ^37a independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents O, S or NH; Y represents —NR ³⁵ -, —O— or —S—; n is an integer from 1 to 10; each R ³¹ , R ³² , R ³³ and R ³⁵ independently represents 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 represents

; each R ³⁶ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ³⁷ represents 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 independently represents —NR ³⁸ -, —O— or —S—; each R ³⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and A 'is an anion. 33. The unit dose according to any one of claims 2 to 9, in which the opioid prodrug is selected from the group consisting of: (a) compounds of formula AE- (I):

, Where: X represents the remainder of the amide-containing opioid, where —C (O) —NR ⁵ - (C (R ¹ ) (R ² )) _n —NR ³ R ^{4 is} coupled to the amide-containing opioid via oxygen of the amide group, where the amide group is converted to the amide enol or 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 atoms, by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (b) compounds of formula AE- (II):

, Where: X represents the remainder of the amide-containing opioid, where —C (O) —NR ⁵ - (C (R ¹ ) (R ² )) _n —NR ³ R ^{4 is} coupled to the amide-containing opioid via oxygen of the amide group, where the amide group is converted to the amide enol or imine tautomer; 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, 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n represents 2 or 3; R ³ represents hydrogen; R ⁴ is a fragment cleaved by a GI enzyme; its salt, hydrate or solvate; (c) compounds of formula AE- (III):

, Where: X represents a residue of an amide-containing opioid, where —CO — C (R ⁶ ) —NR ⁸ R ^{7 is} coupled to the amide-containing opioid via oxygen of the amide group, where the amide group is converted to an amide enol or 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 atoms, by which they are attached to 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ^{7 is} selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, mixed alkoxycarbonyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl; its salt, hydrate or solvate. 34. The composition of claim 10, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula PC- (1)

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, where the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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; each R ² and R ³ 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group or an amino acid residue, a dipeptide or N-acyl derivative of an amino acid or dipeptide; (b) compounds of the formula PC- (IIa):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, where the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (c) compounds of the formula PC- (IIb):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, where the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 is 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (d) compounds of the formula PC- (III):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, where the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (e) compounds of the formula PC- (IV):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a single bond; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group, or an amino acid residue, a dipeptide or N-acyl derivative of an amino acid or dipeptide; (f) compounds of the formula PC- (Va):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (g) compounds of the formula PC- (Vb):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a 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 is 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (h) compounds of formula PC- (VI):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a single bond; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ 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 , wherein the configuration of the carbon atom to which R ^{4 is} attached corresponds to that in the L-amino acid ; and R ⁵ represents a hydrogen atom, an N-acyl group (including an N-substituted acyl), an amino acid residue, a dipeptide or an N-acyl derivative (including an N-substituted acyl derivative) of an amino acid or dipeptide; (i) compounds of the formula PC- (VII):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, wherein the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —C (O) —NR ¹ - (C (R ² ) (R ³ )) n-NH-R ⁶ ; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3; and R ⁶ is a trypsin cleavable moiety; (j) a compound of formula PC- (VIII):

or its pharmaceutically acceptable salt, where: X represents a phenolic opioid residue, wherein the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; and R ⁶ is a trypsin cleavable moiety; (k) compounds of the formula PC- (IX):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a single bond; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3; and R ⁶ is a trypsin cleavable moiety; (1) compounds of the formula PC- (X):

or its pharmaceutically acceptable salt, where: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; and R ⁶ is a trypsin cleavable moiety; (m) compounds of the formula PC- (XI):

or its pharmaceutically acceptable salt, in which: X represents a phenolic opioid residue, wherein the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —C (O) —NR ¹ - (C (R ² ) (R ³ )) _n —NH — R ⁶ ; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3; and R ⁶ is a fragment cleaved by the GI enzyme; ((n) a compound of formula PC- (XII):

or its pharmaceutically acceptable salt, in which: X represents a phenolic opioid residue, wherein the hydrogen atom of the phenolic hydroxyl group is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; and R ⁶ is a fragment cleaved by the GI enzyme; (o) compounds of the formula PC- (XIII):

or its pharmaceutically acceptable salt, in which: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a single bond; R ¹ represents a (1-4C) alkyl group; each R ² and R ³ independently represents a hydrogen atom or a (1-4C) alkyl group; n represents 2 or 3; and R ⁶ is a fragment cleaved by the GI enzyme; (p) a compound of formula PC- (XIV):

or its pharmaceutically acceptable salt, in which: R ^a represents hydrogen or hydroxyl; R ^b represents oxo (= O) or hydroxyl; the dashed line is a double bond or a 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; and R ⁶ is a fragment cleaved by the GI enzyme; (q) compounds of the formula PC- (XV):

, Where: X represents a phenolic opioid, where the hydrogen atom of the hydroxyl group is substituted by a covalent bond on —C (O) —Y— (C (R ¹ ) (R ² )) _n —N— (R ³ ) (R ⁶ ); Y represents —NR ⁵ -, —O— or —S—; n is an integer from 1 to 4; each R ¹ , R ² , R ³ and R ⁵ independently represents 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 represents

; each R ⁴ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ⁷ represents 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 independently represents —NR ⁸ -, —O— or —S—; and each R ⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. 35. The composition of claim 10, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula PC- (XVI):

or its salts, solvates or hydrates, where: X is an opioid containing phenol, wherein the phenol hydrogen atom is covalently substituted with - (CR ¹² R ¹³ ) —YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; Y represents 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 independently represent 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 an atom the nitrogen to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents N (R ¹⁸ ) -, —O— or —S—; R ¹⁸ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or

; each W independently represents —NR ²⁰ -, —O— or —S—; each R ¹⁹ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²⁰ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²¹ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; n is an integer from 0 to 5; R ¹¹ represents

; each U independently represents —NR ²³ -, —O— or —S—; each R ²² independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²⁴ represents 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 in a vapor or ortho position with respect to X- (CR ¹² R ¹³ ) - and that both R ¹⁸ and R ¹¹ are not hydrogen; (b) compounds of formula PC- (XVII):

or its salts, solvates or hydrates, where: X is an opioid containing phenol, wherein X is connected using phenol; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; everyone $$R_k^{26}$$

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 represents 0, 1, 2, 3 or 4; R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ¹⁸ represents hydrogen or methyl; R ²² represents an amino acid side chain or an amino acid side chain derivative; each U independently represents —NR ²³ -, —O— or —S—; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; and R ²⁴ represents 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; (c) compounds of the formula PC- (XVIII):

or its salt, hydrate or MES, where: X is an opioid containing phenol, where the phenol hydrogen atom is replaced by a covalent bond with - (C (R ^31a ) (R ^32a ) -Ar-ZC (O) -Y- (C (R ³¹ ) (R ³² )) _n- N- (R ³³ ) (R ³⁴ ); R ^31a and R ^32a independently represent 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 ₂ -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) (O”) ₂ , -P (O) (OR ^34a ) (O ”), OP (O) ( OR ^34a ) (OR ^35a ), -C (O) R ^34a , -C (S) R ^34a , -C (O) OR ^34a , -C (O) NR ^34a R ^35a , -C (O) O; -C (S) R ^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 attached to a polymer; R ^34a , R ^35a , R ^36a and R ^37a independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents O, S or NH; Y represents —NR ³⁵ -, —O— or —S—; n is an integer from 1 to 10; each R ³¹ , R ³² , R ³³ and R ³⁵ independently represents 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 represents

; each R ³⁶ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ³⁷ represents 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 independently represents —NR ³⁸ -, —O— or —S—; each R ³⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and A 'is an anion. 36. The composition of claim 10, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula KC- (Ia):

, Where: R ^a represents 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 atoms, by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (b) compounds of formula KC- (Ib):

Where: R ^a represents 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 represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (c) compounds of formula KC- (II):

, Where: R ^a represents 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 a group; n represents 2 or 3; R ³ represents hydrogen; R ⁴ represents the remainder 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, tyros and valine, or the remainder of the N-acyl derivative of any of these amino acids; or a peptide residue consisting 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 the remainder of their N-acyl derivative, (d) compounds of formula KC- (IIIa):

, Where: X represents a residue of an opioid containing a ketone, wherein the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 atoms, by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (e) compounds of formula KC- (IIIb):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 atoms, by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (f) compounds of formula KC- (IV):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 represents 2 or 3; R ³ represents hydrogen or (1-4C) alkyl; R ⁴ represents the remainder 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, tyros and valine, or the remainder of the N-acyl derivative of any of these amino acids; or a peptide residue consisting 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 the remainder of their N-acyl derivative; its salt, hydrate or solvate; (g) compounds of formula KC- (Va):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen; R ⁴ is a trypsin cleavable moiety; its salt, hydrate or solvate; (h) compounds of formula KC- (Vb):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on —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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen; R ⁴ is a fragment cleaved by a GI enzyme; its salt, hydrate or solvate; (i) compounds of formula KC- (VI):

, Where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond with —C (O) —Y— (C (R ¹ ) (R ² )) _n —NR ³ R ⁴ ; Y represents —NR ⁵ -, —O— or —S—; n is an integer from 1 to 4; each R ¹ , R ² , R ³ and R ⁵ independently represents 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 represents

; each R ⁶ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ⁷ represents 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 independently represents —NR ⁸ -, —O— or —S—; and each R ⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. 37. The composition of claim 10, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula KC- (VII):

or its salts, solvates or hydrates, where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond - (CR ¹² R ¹³ ) —YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; Y represents 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 independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents N (R ¹⁸ ) -, —O— or —S—; R ¹⁸ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or

; each W independently represents —NR ²⁰ -, —O— or —S—; each R ¹⁹ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²⁰ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²¹ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; n is an integer from 0 to 5; R ¹¹ represents

; each U independently represents —NR ²³ -, —O— or —S—; each R ²² independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²³ independently represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or optionally R ²³ and R ²⁴ together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²⁴ represents 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 in the para- or ortho position with respect to X- (CR ¹² R ¹³ ) - and that both R ¹⁸ and R ¹¹ are not hydrogen; (b) compounds of formula KC- (VIII):

or its salts, solvates or hydrates, where: X represents a residue of an opioid ketone containing, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on - (CR ¹² R ¹³ ) -YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; everyone $$R_k^{26}$$

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 represents 0, 1, 2, 3 or 4; R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ¹⁸ represents hydrogen or methyl; R ²² represents an amino acid side chain or an amino acid side chain derivative; each U independently represents —NR ²³ -, —O— or —S—; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; and R ²⁴ represents 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; (c) compounds of formula KC- (IX):

or its salt, hydrate or MES, where: X represents the remainder of the ketone-containing opioid, where the hydrogen atom of the corresponding enol group of the ketone is substituted by a covalent bond on - (C (R ^31a ) (R ^32a ) -Ar-ZC (O) -Y- (C (R ³¹ ) (R ³² )) _n -N- (R ³³ ) (R ³⁴ ); R ^31a and R ^32a independently represent 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) (O”) ₂ , -P (O) (OR ^34a ) (O ”), OP (O) (OR ^34a ) (OR ^35a ), -C (O) R ^34a , -C (S) R ^34a , -C (O) OR ^34a , -C (O) NR ^34a R ^35a , -C (O) O; -C (S) R ^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 attached to a polymer; R ^34a , R ^35a , R ^36a and R ^37a independently represent hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R ³⁴ and R ³³ together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents O, S or NH; Y represents —NR ³⁵ -, —O— or —S—; n is an integer from 1 to 10; each R ³¹ , R ³² , R ³³ and R ³⁵ independently represents 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 represents

; each R ³⁶ independently represents 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 atoms, to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ³⁷ represents 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 independently represents —NR ³⁸ -, —O— or —S—; each R ³⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and A 'is an anion. 38. The composition of claim 10, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula QS- (I):

or its salts, solvates or hydrates, where: X is an opioid containing an amine, where the hydrogen atom of the primary or secondary amine is substituted by the covalent bond at - (CR ¹² R ¹³ ) -YZR ¹¹ , or the unshared electron pair of the tertiary amine is substituted by the covalent bond at - (CR ¹² R ¹³ ) -YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; Y represents 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 independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents N (R ¹⁸ ) -, —O— or —S—; R ¹⁸ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or

; each W independently represents —NR ²⁰ -, —O— or —S—; each R ¹⁹ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²⁰ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²¹ represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; n is an integer from 0 to 5; R ¹¹ represents

; each U independently represents —NR ²³ -, —O— or —S—; each R ²² independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²⁴ represents 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 in the para- or ortho position with respect to X- (CR ¹² R ¹³ ) - and that both R ¹⁸ and R ¹¹ are not hydrogen. (b) compounds of formula QS- (II):

or its salts, solvates or hydrates, where: X is an opioid containing an amine, where the hydrogen atom of the primary or secondary amine is substituted by the covalent bond at - (CR ¹² R ¹³ ) -YZR ¹¹ , or the unshared electron pair of the tertiary amine is substituted by the covalent bond at - (CR ¹² R ¹³ ) -YZR ¹¹ ; R ¹² and R ¹³ independently represent hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; everyone $$R_k^{26}$$

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 represents 0, 1, 2, 3 or 4; R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ¹⁸ represents hydrogen or methyl; R ²² represents an amino acid side chain or an amino acid side chain derivative; each U independently represents —NR ²³ -, —O— or —S—; each R ²³ independently represents 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 cycloheteroalkyl or substituted cycloheteroalkyl ring; and R ²⁴ represents 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. (c) compounds of formula QS- (III):

or its salt, hydrate or MES, where: X represents an opioid residue, where an unshared pair of nitrogen electrons of the amino group is substituted by a bond on - (C (R ^31a ) (R ^32a ) -Ar-ZC (O) -Y- (C (R ³¹ ) (R ³² )) _n -N- (R ³³ ) (R ³⁴ ); R ^31a and R ^32a independently represent 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) (O”) ₂ , -P (O) (OR ^34a ) (O ”), -OP (O) (OR ^34a ) (OR ^35a ), -C (O) 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 attached to a polymer; R ^34a , R ^35a , R ^36a and R ^37a independently represent 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; Z represents O, S or NH; Y represents —NR -, —O— or —S—; n is an integer from 1 to 10; each R ³¹ , R ³² , R ³³ and R ³⁵ independently represents 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 represents

; each R ³⁶ independently represents 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 atoms, c by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ³⁷ represents 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 independently represents —NR ³⁸ -, —O— or —S—; each R ³⁸ independently represents 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and A 'is an anion. 39. The composition of claim 10, in which the opioid prodrug is selected from the group consisting of: (a) compounds of the formula AE- (I):

, Where: X represents the remainder of the amide-containing opioid, where —C (O) —NR ⁵ - (C (R ¹ ) (R ² )) _n —NR ³ R ^{4 is} coupled to the amide-containing opioid via oxygen of the amide group, where the amide group is converted to the amide enol or 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n is an integer from 2 to 4; R ³ represents hydrogen or (1-4C) alkyl; R ⁴ represents

; 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 atoms, by which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W independently represents —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 attached 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; its salt, hydrate or solvate; (b) compounds of formula AE- (II):

, Where: X represents the remainder of the amide-containing opioid, where —C (O) —NR ⁵ - (C (R ¹ ) (R ² )) _n —NR ³ R ^{4 is} coupled to the amide-containing opioid via oxygen of the amide group, where the amide group is converted to the amide enol or imine tautomer; 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, 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 cycloalkyl, substituted cycloalkyl, aryl or substituted aryl group; n represents 2 or 3; R ³ represents hydrogen; R ⁴ is a fragment cleaved by a GI enzyme; its salt, hydrate or solvate; (c) compounds of formula AE- (III):

, Where: X represents: a residue of an amide-containing opioid, where —CO — C (R ⁶ ) —NR ⁸ R ^{7 is} coupled to the amide-containing opioid through oxygen of the amide group, where the amide group is converted to an amide enol or 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 atoms, by which they are attached to 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ^{7 is} selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, mixed alkoxycarbonyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl; or a salt, hydrate or solvate thereof.