Opioid-ketamine and norketamine codrug combinations for pain management

A pharmaceutical composition comprising an analgesically effective amount of a compound selected from the group consisting of:

• the compound of formula Ia:
• wherein X is a bond, CH2, (CH2)2, or (CH2)3;
• R is H or OCH3;
• and * represents racemic norketamine, S-norketamine, or R-norketamine;
• the compound of the formula Ib:
• wherein Y is O, S, or NR1;
• R is H or OCH3;
• R1 is alkyl, and represents racemic norketamine, S-norketamine, or R-norketamine;
• the compound of the formula II:
• and the compound of the formula III:
• and at least one pharmaceutically acceptable excipient.

A method of synthesis of a codrug comprising a linker, an opioid and a ketamine or a norketamine, said method comprising:

• a) covalently bonding a first attachment point of the linker to the opioid;
• b) covalently bonding a second attachment point of the linker to the ketamine or norketamine;
• and
• c) recovering the codrug,
• wherein the norketamine is selected from the group consisting of S-norketamine, R-norketamine, and racemic norketamine;
• and
• wherein the ketamine is selected from the group consisting of S-ketamine, R-ketamine, and racemic ketamine.

A method of treatment comprising:

• joining an opioid together with a ketamine or a norketamine using a linker to form a cleavable codrug;
• and
• administering an analgesically effective amount of the codrug to a human patient in need thereof,
• wherein the norketamine is selected from the group consisting of S-norketamine, R-norketamine, and racemic norketamine;
• and wherein the ketamine is selected from the group consisting of S-ketamine, R-ketamine, and racemic ketamine.