Treatment of pain by subarachnoid administration of sustained-release liposomal anesthetic compositions

Abstract

In some embodiments provided herein is a method of treating pain, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising: a) a multivesicular liposome comprising: at least one amphipathic lipid, and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the multivesicular liposome.

1 . A method of treating pain in a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising: a) a multivesicular liposome comprising: at least one amphipathic lipid, and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the multivesicular liposome. 
     
     
         2 . A method of treating pain in a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes comprising:
 bupivacaine or a salt thereof;   phosphoric acid;   a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and,   optionally, a cholesterol and/or a plant sterol wherein said multivesicular liposomes are made by a process comprising:   a) preparing a first aqueous component comprising phosphoric acid;   b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group;   c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof;   d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and   e) removing the organic solvent from the solvent spherules to form multivesicular liposomes encapsulating bupivacaine phosphate.   
     
     
         3 . The method of  claim 1  or  2 , wherein the aqueous phase further comprises hydrochloric acid. 
     
     
         4 . The method of any one of  claims 1  to  3 , wherein the amphipathic lipid is selected from the group consisting of phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, lysophosphatidylcholines, lysophosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, phosphatidic acids, cardiolipins, diacyl dimethylammonium propanes, and stearylamines. 
     
     
         5 . The method of any one of  claims 1  to  4 , wherein the neutral lipid is at least one triglyceride. 
     
     
         6 . The method of any one of  claims 1  to  5 , wherein the pharmaceutical composition comprises a therapeutically effective amount of bupivacaine phosphate. 
     
     
         7 . The method of claim any one of the preceding claims, wherein the pharmaceutical composition comprises from about 10 mg to about 60 mg of bupivacaine phosphate. 
     
     
         8 . The method of  claim 7 , wherein the pharmaceutical composition comprises from about 20 mg to about 60 mg of bupivacaine phosphate. 
     
     
         9 . The method of  claim 7 , wherein the pharmaceutical composition comprises from about 30 mg to about 60 mg of bupivacaine phosphate. 
     
     
         10 . The method of any one of the preceding claims, wherein the method comprises administering the pharmaceutical composition by epidural injection. 
     
     
         11 . The method of any one of the preceding claims, wherein the method does not comprise administering the pharmaceutical composition by epidural injection. 
     
     
         12 . The method of  claim 1 , wherein the pain is in a region below the diaphragm. 
     
     
         13 . The method of  claim 12 , wherein the pain is selected from abdomen pain, lower back pain, hip pain, pelvic pain, femur pain, knee pain, foot pain, and ankle pain. 
     
     
         14 . The method of any one of the preceding claims, wherein the method does not comprise administering an opioid to the subject following the injection of the pharmaceutical composition into the subarachnoid space of the subject. 
     
     
         15 . The method of any one of the preceding claims, wherein the method comprises administering an opioid to the subject following the injection of the pharmaceutical composition into the subarachnoid space of the subject. 
     
     
         16 . The method of  claim 15 , wherein the opioid is oxycodone and the method comprises administering oxycodone in a total amount less than 15 mg in the first about 72 hours following the injection of the pharmaceutical composition into the subarachnoid space of the subject. 
     
     
         17 . The method of any one of  claims 11  to  16 , wherein the method comprises administering a non-opioid analgesic to the subject following the injection of the pharmaceutical composition into the subarachnoid space of the subject. 
     
     
         18 . The method of claim any one of  claims 15  to  17 , wherein the subject is a first subject, wherein in the first about 72 hours following the injection of the pharmaceutical composition into the subarachnoid space of the first subject the opioid is administered to the first subject in a total amount that is lower than the total amount of an opioid that is administered to a second subject in the first about 72 hours following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition, wherein a pharmaceutical composition comprising: a) a multivesicular liposome comprising: at least one amphipathic lipid, and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the multivesicular liposome, is not administered to the second subject. 
     
     
         19 . The method of claim any one of  claims 15  to  17 , wherein the subject is a first subject, wherein in the first about 72 hours following the injection of the pharmaceutical composition into the subarachnoid space of the first subject the opioid is administered to the first subject in a total amount that is lower than the total amount of an opioid that is administered to a second subject in the first about 72 hours following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition, wherein a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes comprising:
 bupivacaine or a salt thereof; 
 phosphoric acid; 
 a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and, 
 optionally, a cholesterol and/or a plant sterol wherein said multivesicular liposomes are made by a process comprising: 
 a) preparing a first aqueous component comprising phosphoric acid; 
 b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group; 
 c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof; 
 d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and 
 e) removing the organic solvent from the solvent spherules to form multivesicular liposomes encapsulating bupivacaine phosphate, 
 , is not administered to the second subject. 
 
     
     
         20 . The method of  claim 18  or  19 , wherein non-liposomal bupivacaine or a salt thereof is administered to the second subject following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition. 
     
     
         21 . The method of  claim 20 , wherein non-liposomal bupivacaine hydrochloride is administered to the second subject following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition. 
     
     
         22 . The method of  claim 18 ,  19 ,  20  or  21 , wherein the opioid is administered to the first subject in a total amount that is about 20% lower, such as at least about 30% lower, such as at least about 40% lower, such as at least about 50% lower than the total amount of the opioid that is administered to the second subject. 
     
     
         23 . The method of  claim 18 ,  19 ,  20 ,  21  or  22 , wherein in the first about 24 hours following the injection of the pharmaceutical composition into the subarachnoid space of the first subject the opioid is administered to the first subject in a total amount that is lower than the total amount of the opioid that is administered to the second subject in the first about 24 hours following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition. 
     
     
         24 . The method of any one of  claims 18  to  23 , wherein in the first about 48 hours following the injection of the pharmaceutical composition into the subarachnoid space of the first subject the opioid is administered to the first subject in a total amount that is lower than the total amount of the opioid that is administered to the second subject in the first about 48 hours following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition. 
     
     
         25 . The method of any one of  claims 18  to  24 , wherein in the first about 7 days following the injection of the pharmaceutical composition into the subarachnoid space of the first subject the opioid is administered to the first subject in a total amount that is lower than the total amount of the opioid that is administered to the second subject in the first about 7 days following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition. 
     
     
         26 . The method of any one of  claims 18  to  25 , wherein in the first about 14 days following the injection of the pharmaceutical composition into the subarachnoid space of the first subject the opioid is administered to the first subject in a total amount that is lower than the total amount of the opioid that is administered to the second subject in the first about 14 days hours following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition. 
     
     
         27 . The method of  claim 23 , wherein the opioid is administered to the first subject in a total amount in the first about 24 hours the injection of the pharmaceutical composition into the subarachnoid space of the first subject that is at least about 20% lower, such as at least about 30% lower, such as at least about 40% lower, such as at least about 50% lower than the total amount of the opioid that is administered to the second subject in the first about 24 hours following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition. 
     
     
         28 . The method of  claim 24 , wherein the opioid is administered to the first subject in a total amount in the first about 48 hours following the injection of the pharmaceutical composition into the subarachnoid space of the first subject that is at least about 20% lower, such as at least about 30% lower, such as at least about 40% lower, such as at least about 50% lower than the total amount of the opioid that is administered to the second subject in the first about 48 hours following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition 
     
     
         29 . The method of  claim 25 , wherein the opioid is administered to the first subject in a total amount in the first about 7 days hours following the injection of the pharmaceutical composition into the subarachnoid space of the first subject that is at least about 20% lower, such as at least about 30% lower, such as at least about 40% lower, such as about 50% lower than the total amount of the opioid that is administered to the second subject in the first about 7 days following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition. 
     
     
         30 . The method of  claim 26 , wherein the opioid is administered to the first subject in a total amount in the first about 14 days following the injection of the pharmaceutical composition into the subarachnoid space of the first subject that is at least about 20% lower, such as at least about 30% lower, such as about 40% lower than the total amount of the opioid that is administered to the second subject in the first about 14 days following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition. 
     
     
         31 . The method of any one of  claims 1  to  17 , wherein the subject has an AUC for VAS pain intensity scores over the first 72 hours following the injection of the pharmaceutical composition into the subarachnoid space of the subject of from about 100 to about 200, such as about 125 to 175, such as about 140 to 160, such as about 150, such as about 147.9. 
     
     
         32 . The method of any one of  claims 18  to  30 , wherein the first subject has an AUC for VAS pain intensity scores over the first 72 hours following the injection of the pharmaceutical composition into the subarachnoid space of the first subject of from about 100 to about 200, such as about 125 to 175, such as about 140 to 160, such as about 150, such as about 147.9; and the second subject has an AUC for VAS pain intensity scores over the first 72 hours following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition of from about 150 to about 250, such as about 165 to 200, such as about 170 to 190, such as about 175 to 180, such as about 178.5. 
     
     
         33 . The method of any one of  claims 18  to  30 , wherein the first subject has an AUC for VAS pain intensity scores over the first 72 hours following the injection of the pharmaceutical composition into the subarachnoid space of the first subject that is at least about 10% lower, such as at least about 17% lower, such as about 27% to about 25% lower, such as at least about 25% lower, than the AUC for VAS pain intensity scores for the second subject over the first 72 hours following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition. 
     
     
         34 . The method of any one of  claim 1  to  18  or  31 , wherein the subject has a pruritus score as determined by the 5-D itch scale of about 10 to about 20. 
     
     
         35 . The method of any one of  claims 18  to  30  or  32  to  33 , wherein the first subject has a pruritus score as determined by the 5-D itch scale that is lower than the pruritus score for the second subject. 
     
     
         36 . The method of any one of  claim 1  to  18 ,  31 , or  34 , wherein the plasma concentration of bupivacaine in the subject after about 120 hours following the injection of the pharmaceutical composition into the subarachnoid space of the subject is about is about 150 ng/mL to about 250 ng/mL, such as about 175 ng/mL to about 225 ng/mL, such as about 200 ng/mL, such as about 210 mg/mL, for an amount of the pharmaceutical composition described herein that is equivalent to about 133 mg of bupivacaine. 
     
     
         37 . The method of any one of  claim 18  to  30 ,  32  to  33 , or  35 , wherein the plasma concentration of bupivacaine in the first subject after about 120 hours following the injection of the pharmaceutical composition into the subarachnoid space of the first subject is at least about 10%, such as least about 20% higher, such as at least about 30% higher, such as at least about 40% higher, such as 50% higher than the plasma concentration of bupivacaine in the second subject after about 120 hours following injection into the subarachnoid space of the second subject of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition. 
     
     
         38 . The method of any one of the preceding claims, wherein the method does not comprise administering an opioid to the subject following the injection of the pharmaceutical composition into the subarachnoid space of the first subject. 
     
     
         39 . The method of claim any one of  claims 14  to  17 , wherein the subject is a first subject, wherein in the first about 72 hours following the injection of the pharmaceutical composition into the subarachnoid space of the first subject the opioid is administered to the first subject in a total amount that is lower than the total amount of an opioid that is administered to each of a plurality of second subjects in the first about 72 hours following respective injection into the subarachnoid space of each of the second subjects of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition, wherein a pharmaceutical composition comprising: a) a multivesicular liposome comprising: at least one amphipathic lipid, and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the multivesicular liposome, is not administered to the second subjects. 
     
     
         40 . The method of claim any one of  claims 14  to  17 , wherein the subject is a first subject, wherein in the first about 72 hours following the injection of the pharmaceutical composition into the subarachnoid space of the first subject the opioid is administered to the first subject in a total amount that is lower than the total amount of an opioid that is administered to each of a plurality of second subjects in the first about 72 hours following respective injection into the subarachnoid space of each of the second subjects of non-liposomal bupivacaine containing the same amount of bupivacaine as the pharmaceutical composition, wherein a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes comprising:
 bupivacaine or a salt thereof; 
 phosphoric acid; 
 a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and, 
 optionally, a cholesterol and/or a plant sterol wherein said multivesicular liposomes are made by a process comprising: 
 a) preparing a first aqueous component comprising phosphoric acid; 
 b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group; 
 c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof; 
 d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and 
 e) removing the organic solvent from the solvent spherules to form multivesicular liposomes encapsulating bupivacaine phosphate, 
 is not administered to the second subjects. 
 
     
     
         41 . A method of inducing motor block in a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising: a) a multivesicular liposome comprising: at least one amphipathic lipid, and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the multivesicular liposome. 
     
     
         42 . A method of inducing motor block in a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes comprising:
 bupivacaine or a salt thereof;   phosphoric acid;   a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and,   optionally, a cholesterol and/or a plant sterol wherein said multivesicular liposomes are made by a process comprising:   a) preparing a first aqueous component comprising phosphoric acid;   b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group;   c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof;   d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and   
     
     
         43 . e) removing the organic solvent from the solvent spherules to form multivesicular liposomes encapsulating bupivacaine phosphate. A method of inducing sensory block in a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising: a) a multivesicular liposome comprising: at least one amphipathic lipid, and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the multivesicular liposome. 
     
     
         44 . A method of inducing sensory block in a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes comprising:
 bupivacaine or a salt thereof;   phosphoric acid;   a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and,   optionally, a cholesterol and/or a plant sterol wherein said multivesicular liposomes are made by a process comprising:   a) preparing a first aqueous component comprising phosphoric acid;   b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group;   c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof;   d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and   e) removing the organic solvent from the solvent spherules to form multivesicular liposomes encapsulating bupivacaine phosphate.   
     
     
         45 . A method of anesthetizing a subject in need thereof, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising: a) a multivesicular liposome comprising: at least one amphipathic lipid, and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the multivesicular liposome. 
     
     
         46 . A method of anesthetizing a subject in need thereof, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes comprising:
 bupivacaine or a salt thereof;   phosphoric acid;   a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and,   optionally, a cholesterol and/or a plant sterol wherein said multivesicular liposomes are made by a process comprising:   a) preparing a first aqueous component comprising phosphoric acid;   b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group;   c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof;   d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and   e) removing the organic solvent from the solvent spherules to form multivesicular liposomes encapsulating bupivacaine phosphate.   
     
     
         47 . A method of reducing pain in a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising: a) a multivesicular liposome comprising: at least one amphipathic lipid, and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the multivesicular liposome. 
     
     
         48 . A method of reducing pain in a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes comprising:
 bupivacaine or a salt thereof;   phosphoric acid;   a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and,   optionally, a cholesterol and/or a plant sterol wherein said multivesicular liposomes are made by a process comprising:   a) preparing a first aqueous component comprising phosphoric acid;   b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group;   c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof;   d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and   e) removing the organic solvent from the solvent spherules to form multivesicular liposomes encapsulating bupivacaine phosphate.   
     
     
         49 . A method of reducing an amount of opioid administered to a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising: a) a multivesicular liposome comprising: at least one amphipathic lipid, and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the multivesicular liposome. 
     
     
         50 . A method of reducing an amount of opioid administered to a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes comprising:
 bupivacaine or a salt thereof;   phosphoric acid;   a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and,   optionally, a cholesterol and/or a plant sterol wherein said multivesicular liposomes are made by a process comprising:   a) preparing a first aqueous component comprising phosphoric acid;   b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group;   c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof;   d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and   e) removing the organic solvent from the solvent spherules to form multivesicular liposomes encapsulating bupivacaine phosphate.   
     
     
         51 . A method of reducing a duration of time during which an opioid is administered to a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising: a) a multivesicular liposome comprising: at least one amphipathic lipid, and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the multivesicular liposome. 
     
     
         52 . A method of reducing a duration of time during which an opioid is administered to a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes comprising:
 bupivacaine or a salt thereof;   phosphoric acid;   a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and,   optionally, a cholesterol and/or a plant sterol wherein said multivesicular liposomes are made by a process comprising:   a) preparing a first aqueous component comprising phosphoric acid;   b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group;   c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof;   d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and   e) removing the organic solvent from the solvent spherules to form multivesicular liposomes encapsulating bupivacaine phosphate.   
     
     
         53 . The method of  claim 49 ,  50 ,  51  or  52 , wherein the opioid is administered to the subject following a surgical procedure in the subject. 
     
     
         54 . The method of  claim 53 , wherein the opioid reduces pain in the subject following the surgical procedure. 
     
     
         55 . A method of reducing an amount of a non-opioid analgesic administered to a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising: a) a multivesicular liposome comprising: at least one amphipathic lipid, and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the multivesicular liposome. 
     
     
         56 . A method of reducing an amount of a non-opioid analgesic administered to a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes comprising:
 bupivacaine or a salt thereof;   phosphoric acid;   a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and,   optionally, a cholesterol and/or a plant sterol wherein said multivesicular liposomes are made by a process comprising:   a) preparing a first aqueous component comprising phosphoric acid;   b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group;   c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof;   d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and   e) removing the organic solvent from the solvent spherules to form multivesicular liposomes encapsulating bupivacaine phosphate.   
     
     
         57 . A method of reducing a duration of time during which a non-opioid analgesic is administered to a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising: a) a multivesicular liposome comprising: at least one amphipathic lipid, and at least one neutral lipid; and b) an aqueous phase comprising bupivacaine phosphate, wherein the aqueous phase is encapsulated within the multivesicular liposome. 
     
     
         58 . A method of reducing a duration of time during which a non-opioid analgesic is administered to a subject, the method comprising injecting into the subarachnoid space of the subject a pharmaceutical composition comprising multivesicular liposomes encapsulating bupivacaine phosphate, said multivesicular liposomes comprising:
 bupivacaine or a salt thereof;   phosphoric acid;   a lipid component comprising at least one amphipathic lipid and at least one neutral lipid lacking a hydrophilic head group; and,   optionally, a cholesterol and/or a plant sterol wherein said multivesicular liposomes are made by a process comprising:   a) preparing a first aqueous component comprising phosphoric acid;   b) preparing a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and at least one neutral lipid lacking a hydrophilic head group;   c) mixing said first aqueous component and said lipid component to form a water-in-oil emulsion, wherein at least one component comprises bupivacaine or a salt thereof;   d) mixing said water-in-oil emulsion with a second aqueous component to form solvent spherules; and   e) removing the organic solvent from the solvent spherules to form multivesicular liposomes encapsulating bupivacaine phosphate.   
     
     
         59 . The method of  claim 55 ,  56 ,  57  or  58 , wherein the non-opioid analgesic is administered to the subject following a surgical procedure in the subject. 
     
     
         60 . The method of  claim 59 , wherein the opioid reduces pain in the subject following the surgical procedure. 
     
     
         61 . The method of any one of  claims 41  to  60 , wherein the pain is in a region below the diaphragm. 
     
     
         62 . The method of  claim 61 , wherein the pain is selected from abdomen pain, lower back pain, hip pain, pelvic pain, femur pain, knee pain, knee pain, foot pain, and ankle pain. 
     
     
         63 . The method of any one of the preceding claims, wherein the subject does not experience neurological side effects. 
     
     
         64 . The method of any one of the preceding claims, wherein the subject does not experience cardiac side effects.