Synergistic combinations including N-acylated 4-Hydroxyphenylamine derivatives and caffeine
View Patent ↗The present invention relates to pharmaceutical combinations of opioid and non-opioid analgesics in an intimate admixture with caffeine and an analgesic from a series of N-acylated 4-hydroxyphenylamine derivatives, linked via an alkylene bridge to the nitrogen atom of a 1,2-benzisothiazol-3(2H)-one 1,1-dioxide group and methods for their use to alleviate pain in mammals. The analgesic combinations exhibit enhanced analgesic potency and are free from antipyretic activity, do not suppress blood coagulation, and have little hepatotoxic effect.
1. An analgesic composition comprising synergistic, safe, and pharmaceutically effective amounts of:
(a) an opioid analgesic;
(b) a non-narcotic analgesic of the general formula,
wherein n is a number from 1 to 5;
(c) caffeine; and
(d) a pharmaceutically acceptable carrier.
2. A composition according to claim 1 , wherein the opioid analgesic is a phenanthrene alkaloid of opium.
3. A composition according to claim 1 , wherein the opioid analgesic is selected from the group consisting of morphine and codeine.
4. A composition according to claim 1 , wherein the opioid analgesic is selected from the group consisting of hydrocodone, oxycodone, hydromorphone, oxymorphone, metopon, apomorphine, normorphine, and N-(2-phenylethyl)-normorphine.
5. A composition according to claim 1 , wherein the opioid analgesic is selected from the group consisting of etorphine and buprenorphine.
6. A composition according to claim 1 , wherein the opioid analgesic is selected from the group consisting of dextromethorphan, butorphanol, levorphanol, levallorphan, cyclorphan, and racemorphan.
7. A composition according to claim 1 , wherein the opioid analgesic is selected from the group consisting of phenazocine, pentazocine, and cylcazocine.
8. A composition according to claim 1 , wherein the opioid analgesic is selected from the group consisting of meperidine, anileridine, piminodine, ethoheptazine, alphaprodine, betaprodine, diphenoxylate, loperamide, fentanil, sufentanil, alfentanil, and remifentanil.
9. A composition according to claim 1 , wherein the opioid analgesic is selected from the group consisting of methadone, isomethadone, and propoxyphene.
10. An analgesic composition comprising synergistic, safe, and pharmaceutically effective amounts of:
(a) a non-opioid analgesic;
(b) a non-narcotic analgesic of the general formula,
wherein n is a number from 1 to 5;
(c) caffeine; and
(d) a pharmaceutically acceptable carrier.
11. A composition according to claim 10 , wherein the non-opioid analgesic is an NMDA receptor antagonist.
12. A composition according to claim 10 , wherein the non-opioid analgesic is selected from the group consisting of dextromethorphan and ketamine.
13. A composition according to claim 10 , wherein the non-opioid analgesic is an alpha 2 adrenoreceptor agonist.
14. A composition according to claim 10 , wherein the non-opioid analgesic is selected from the group consisting of clonidine, metomidine, detomidine, dexmetomidine, dexmedetomidine and xylazine.
15. A composition according to claim 10 , wherein the non-opioid analgesic is a monoamine re-uptake inhibitor.
16. A composition according to claim 10 , wherein the non-opioid analgesic is tramadol.
17. A composition according to claim 10 , wherein the non-opioid analgesic is a mixed agonist-antagonist analgesic.
18. A composition according to claim 10 , wherein the non-opioid analgesic is selected from the group consisting of buprenorphine, dezocine and nalbuphine.
19. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 1 .
20. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 2 .
21. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 3 .
22. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 4 .
23. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 5 .
24. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 6 .
25. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 7 .
26. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 8 .
27. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 9 .
28. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 10 .
29. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 11 .
30. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 12 .
31. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 13 .
32. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 14 .
33. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 15 .
34. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 16 .
35. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 17 .
36. A method of alleviating pain in a mammal which comprises administering to said mammal affected with pain an effective amount of the composition of claim 18 .