Duloxetine and pregabalin: High-dose monotherapy or their combination? The “COMBO-DN study” – a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain

Abstract

This multicentre, double-blind, parallel-group study in diabetic peripheral neuropathic pain addressed whether, in patients not responding to standard doses of duloxetine or pregabalin, combining both medications is superior to increasing each drug to its maximum recommended dose. For initial 8-week therapy, either 60 mg/day duloxetine (groups 1, 2) or 300 mg/day pregabalin (groups 3, 4) was given. Thereafter, in the 8-week combination/high-dose therapy period, only nonresponders received 120 mg/day duloxetine (group 1), a combination of 60 mg/day duloxetine and 300 mg/day pregabalin (groups 2, 3), or 600 mg/day pregabalin (group 4). Primary outcome (Brief Pain Inventory Modified Short Form [BPI-MSF] 24-hour average pain change after combination/high-dose therapy) was analyzed comparing combination (groups 2, 3 pooled) with high-dose monotherapy (groups 1, 4 pooled). Secondary end points included response rates, BPI-MSF severity items, and comparison of duloxetine and pregabalin in BPI-MSF average pain. Eight hundred four patients were evaluated for initial therapy and 339 for combination/high-dose therapy. There were no significant differences between combination and high-dose monotherapy regarding BPI-MSF average pain (mean change: combination: -2.35; high-dose monotherapy: -2.16; P = 0.370) and most secondary end points, which, however, consistently favoured combination therapy. Fifty-percent response rates were 52.1% for combination and 39.3% for high-dose monotherapy (P = 0.068). In exploratory analyses of the initial 8-week therapy uncorrected for multiple comparisons, 60 mg/day duloxetine was found superior to 300 mg/day pregabalin (P < 0.001). Both drugs and their combination were well tolerated. Although not significantly superior to high-dose monotherapy, combination therapy was considered to be effective, safe, and well tolerated.

Diabetic Neuropathy: A Position Statement by the American Diabetes Association

“…Doses of 60 and 120 mg/day showed efficacy in the treatment of pain associated with DSPN in multicenter randomized trials, although some of these had a rather high drop-out rate (15, 86,94,96,[98][99][100][101]. Duloxetine was also suggested to induce improvement in neuropathy-related quality of life (100).…”

“…Combination therapy, including combinations with opioids, may provide effective treatment for diabetic neuropathic pain at lower doses (94,139). A detailed approach for pain management is amply covered in other literature (15,109), and a simple algorithm for clinical practice use is shown in Fig.…”

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“…For severe pain, antiarrhythmics, anticonvulsants, antidepressants, etc., have been prescribed, but in many cases, the effect is not adequate. In recent years, pregabalin [25][26][27][28][29][30][31][32][33] and duloxetine, [25][26][27][28][29][30][31][32][33][34][35][36][37] which have high analgesic effects on neuropathic pain, have also, became usable for diabetic pain. These were a boon for patients with diabetic neuropathy.…”

Searching the optimal composition: combination pharmacotherapy of painful diabetic neuropathy

“…різні, але потенційно комплементарні механізми дії прегабаліна і дулоксетина можуть забезпечувати вищу клінічну ефективність у комбінації порівняно зі збільшенням дози монотерапії. Ця гіпотеза була покладена в основу міжнародного рандомізованого подвійного сліпого дослідження COMBO-DN [19]. пацієнти з больовою дпн (n=804), які не дали терапевтичної відповіді на прегабалін в дозі 300 мг на добу або дулоксетин в дозі 60 мг на добу, були рандомізовані для отримання комбінованої терапії прегабаліном та дулоксетином (300 та 60 мг на добу відповідно) або монотерапії цими препаратами в більш високих дозах (600 і 120 мг на добу відповідно).…”

“…Обидва препарати та їхня комбінація добре переносилися пацієнтами. автори зробили висновок, що комбінована терапія прегабаліном та дулоксетином є безпечною та ефективною [19].…”