Table 2.
Combination therapy
| Drug combination | Setting | Outcome of studies | Number of studies examined in the review article per combination | Reference studies in the review article [71] |
|---|---|---|---|---|
| Indomethacin + prochlorperazine + caffeine | Acute treatment of migraine and TTH |
1. No difference with sumatriptan 50 mg 2. Superior to nimesulide 100 mg |
2 studies Primary endpoint: 2-h pain relief response1,2 |
1. Galeotti N et al. Pharmacol Res 2002, 46:245–50 2. Cerbo R et al. Eur J Neurol 2005, 12:759–767 |
| Triptans + NSAIDs or other drugs | Migraine | Multitarget combination therapy with a triptan plus an NSAID is more effective in acute migraine treatment than monotherapy with either drug alone; equal to superior pain relief (2-h pain response) |
11 studies, multiple triptans evaluated in different combinations with NSAIDs: sumatriptan, rizatriptan, almotriptan; multiple NSAIDs evaluated: tolfenamic acid, naproxen sodium, rofecoxib, trimebutine, paracetamol, aceclofenac Primary endpoint: recurrence rate of migraine attacks1,2,6,7; 24-h pain relief response3; 2-h pain relief4,8,9,11; pain-free response at 2 h and 24-h sustained pain-free response (co-primary endpoints)5,10 |
1. Krymchantowski AV, et al. Cephalalgia 1999, 19 2. Krymchantowski AV. Arq Neuropsiquiatr 2000, 58:428–430 3. Smith TR et al. Headache 2005, 45:983–991 4. Brandes JL, et al. JAMA 2007 297:1443–1454 5. Lipton RB et al. Cephalalgia 2009, 29:826–836 6. Krymchantowski AV. Cephalalgia 2002, 22:309–312 7. Krymchantowski AV. BMC Neurol 2004, 4:10 8. Krymchantowski AV et al. Cephalalgia 2006, 26:871–874 9. Freitag F et al. Headache 2008, 48 10. Schoenen J et al., the Belgian Headache Society. Cephalalgia 2008, 28:1095–1105 11. Brandes et al. JAMA 2007,297:1443–1454 |
| Caffeine in multitarget pain therapeutics | Migraine/headache |
1. Superior to placebo in alleviating non-migrainous headaches 2. Superior efficacy of the combination of ibuprofen (400 mg) and caffeine (200 mg) shown in a study in patients with TTH 3. Small pilot study in 12 children with headaches with ibuprofen (100–400 mg, dosage was selected depending on body weight) and caffeine (50–100 mg) combination showed trend toward superior efficacy 4. Diclofenac sodium (100 mg) and caffeine (100 mg) is more effective than diclofenac sodium (100 mg) alone in the acute treatment of migraine 5. Combination of paracetamol (1000 mg) and caffeine (130 mg) was significantly more effective than paracetamol alone in the treatment of TTH 6. In the treatment of TTH, the combination of paracetamol (1000 mg) with caffeine (130 mg) was significantly superior to placebo |
6 studies in headache + other pain models Primary endpoint of studies: Average pain change over time1: time to first perceptible relief and time to meaningful relief over 6 h2; cumulative response scores from five-faces severity scale, measure of clinical disability, and scale of pain severity3; percentage of subjects with headache relief at 60 min4; pain and its relief hourly for 4 h5: sum of pain intensity differences (SPID) and the total pain relief (TOTPAR)6 |
1. Ward N et al. Pain 1991, 44:151–155 2. Diamond S et al. Clin Pharmacol Ther 2000, 68:312–319 3. Dooley JM et al. Pediatr Neurol 2007, 37:42–46 4. Peroutka S et al. Headache 2004, 44 5. Migliardi JR et al. Clin Pharmacol Ther 1994, 56:576–586 6. Pini LA et al. J Headache Pain 2008, 9:367–373 |
| ASA + paracetamol + caffeine for the treatment of headache. In six randomized, controlled, double-blind studies | Migraine/headache |
Combination was superior both to placebo1,2 and to the control therapies sumatriptan (50 mg),3 ibuprofen (400 mg), ASA4 + paracetamol, ASA, paracetamol, and caffeine in patients with migraine and/or TTH in terms of their analgesic effectiveness |
4 studies in migraine (primary endpoints of studies: 2-h pain relief,1 time to 50% pain relief,2 sum of pain intensity differences from baseline at 4 h postdose—SPID4,,3 2-h pain relief4 |
1. Lipton RB et al. Arch Neurol 1998, 55:210–217 2. Diener HC et al. Cephalalgia 2005, 25:776–787 3. Goldstein J et al. Headache 2005, 45:973–982 4. Goldstein J et al. Headache 2006, 46:444–453 |
Data are adapted from efficacy outcomes reported in studies with different combinations of analgesics in the review by Straube et al. [71]
Superscript numbers in the table refer to the references in the final column
TTH tension-type headache, NSAIDs non-steroidal anti-inflammatory drugs, ASA acetylsalicylic acid