title: 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.
authors.affiliation: University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK Regional Medical Affairs, Lilly Deutschland GmbH, Bad Homburg, Germany Unidad de Neurología, Clínica Creu Blanca, Barcelona, Spain Global Statistical Sciences, Lilly Deutschland GmbH, Bad Homburg, Germany Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität, München, Germany INSERM U987 Centre d'Evaluation et de Traitement de la Douleur, Hôpital Ambroise Paré, Boulogne Billancourt, France Sapienza University, Department of Neurology & Psychiatry, Roma, Italy Lilly Research Laboratories, Indianapolis, IN, USA Zentrum für Anästhesiologie, Intensivmedizin, Schmerztherapie & Palliativmedizin, Benedictus Krankenhaus, Tutzing & Klinik für Anästhesiologie, Technische Universität München, Germany.
authors.forename: Solomon
authors.initials: S
authors.lastname: Tesfaye
authors.forename: Stefan
authors.initials: S
authors.lastname: Wilhelm
authors.forename: Alberto
authors.initials: A
authors.lastname: Lledo
authors.forename: Alexander
authors.initials: A
authors.lastname: Schacht
authors.forename: Thomas
authors.initials: T
authors.lastname: Tölle
authors.forename: Didier
authors.initials: D
authors.lastname: Bouhassira
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cruccu
authors.forename: Vladimir
authors.initials: V
authors.lastname: Skljarevski
authors.forename: Rainer
authors.initials: R
authors.lastname: Freynhagen
mesh_terms: D000368:Aged; D000700:Analgesics / Q000008:administration & dosage; D003929:Diabetic Neuropathies / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D038622:Internationality; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology*; D000069583:Pregabalin; D013876:Thiophenes / Q000008:administration & dosage*; D016896:Treatment Outcome; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000700:Analgesics; D013876:Thiophenes; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000068736:Duloxetine Hydrochloride
keywords: Combination therapy; Diabetic neuropathy; Duloxetine; Pain treatment; Pregabalin