The study showed that initial treatment with duloxetine provides better analgesia than pregabalin in treatment-resistant patients.
Combination therapy with the two drugs, although not superior to high-dose monotherapy, appeared to be safe, effective, and well tolerated.
Stefan Wilhelm, MD, senior medical advisor at Lilly Deutschland in Bad Homburg, Germany, presented the results of the Combination vs Monotherapy of Pregabalin and Duloxetine in Diabetic Neuropathy (COMBO-DN) study at the European Association for the Study of Diabetes 48th Annual Meeting. The 2 drugs are the only ones currently approved in the United States and Europe for the treatment of DPNP, and no previous large head-to-head or combination treatment trial has been conducted.
The primary objective of the double-blind randomized parallel-group study was to evaluate the drugs in combination in patients who had not responded to standard doses of each drug alone, and to evaluate each drug as monotherapy for the initial treatment of pain.
Study participants were men and women 18 years and older who had daily bilateral peripheral neuropathic pain for more than 3 months. Initial pain scores had to be at least 3 on the 10-point Michigan Neuropathy Screening Instrument and at least 4 on the Brief Pain Inventory Modified Short Form (BPI-MSF) 24-hour average pain severity scale.
Participants underwent a 1- to 2-week screening and washout period; they could not have been on either study drug for more than 15 days before the washout period and had to have stable glycated hemoglobin not greater than 12% at the beginning of the washout period.
In the initial period, patients were divided into 2 groups: 401 patients received a half dose of duloxetine for 1 week followed by a full dose of duloxetine (60 mg) for 8 weeks, and 403 patients received a half dose of pregabalin for 1 week followed by a full dose of pregabalin (300 mg) for 7 weeks.
The 339 patients who did not respond to therapy in the initial period entered the intensive period. In this phase, the dose of monotherapy was doubled or the other drug was added at its full dose for an additional 7 weeks, followed by a 2-week tapering phase. This phase was designed to investigate whether combination or high-dose therapy was a better option for patients with incomplete pain relief.
The mean age in each group was 61 years, and the groups were well matched for sex, weight, race, time since diabetes diagnosis (median, 11 years), time since neuropathy diagnosis, and time since neuropathic pain onset (median, 2 years). Two thirds of the patients in each group had not previously received DPNP therapy.
During the initial period, duloxetine was associated with significantly better pain relief at week 4 (P = .007) and at week 8 (P < .001). At week 8, the BPI-MSF score had decreased by about 2.3 points in the duloxetine group and by about 1.6 points in the pregabalin group.
During the initial period, more patients in the duloxetine group than in the pregabalin group experienced a pain reduction of at least 30% (52.0% vs 36.9%; P ≤ .001), at least 50% (40.3% vs 27.8%; P < .001), and at least 2 points (57.1% vs 45.7%; P = .002).
"For nonresponders, after 8 weeks of treatment in the intensive period, it makes no difference whether you combine these 2 drugs at the standard doses or whether you give high doses in both groups," Dr. Wilhelm reported. "There was no significant difference at the end of the intensive treatment phase," he noted.
In the initial period, a subgroup analysis showed that all outcomes favored duloxetine. In the intensive period, all outcomes trended toward favoring combination therapy, but no outcome was statistically significant.
The drugs were similar in safety and tolerability. In the initial period, about 56% of patients experienced a treatment-emergent adverse event, but only about 12% discontinued either drug. The main treatment-emergent adverse events were dizziness, somnolence, and nausea. Serious adverse events affected about 3% of patients on either drug.
Session moderator Rayaz Malik, MD, PhD, professor of medicine at the University of Manchester in the United Kingdom, succinctly summarized the trial results.
"This is the largest trial in painful diabetic neuropathy that’s ever been done…. Duloxetine was better, with no difference in side effects. When the combination was tried, although overall there was no difference, you could see that there were clearly trends," he explained. "From a clinical perspective, having 2 therapies gives me an option in terms of pushing up the dose to the maximum or giving the combination," he noted.
This study design, in which only treatment-resistant patients were included, leaves an unanswered question. Dr. Malik speculated that if other patients had been included, there might have been a difference.
For initial therapy in treatment-resistant patients, the choice is clear, he said. "For me, it would make me think twice if I have a choice between pregabalin and duloxetine, given that duloxetine has performed better," Dr. Malik said. Therefore, clinicians should feel comfortable acting on these results. "They have to. There are not going to be any more studies of combinations or single agents," he said.
European Association for the Study of Diabetes (EASD) 48th Annual Meeting: Abstract 48. Presented October 2, 2012.