Daniel M. Keller, PhD

October 08, 2012

October 8, 2012 (Berlin, Germany) —  The largest trial ever conducted for the treatment of diabetic peripheral neuropathic pain (DPNP) shows that combination therapy with duloxetine (Cymbalta, Eli Lilly and Company) and pregabalin (Lyrica, Pfizer) at standard doses in treatment-resistant patients was not superior to high-dose monotherapy with these drugs after 16 weeks, although it was safe, effective, and well tolerated.

During the initial phase of treatment in this trial, where patients were randomly assigned to 1 of the 2 drugs given as monotherapy at standard doses, an "important" secondary endpoint, investigators note, duloxetine was associated with significantly better pain relief at both weeks 4 and 8.

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 here at the European Association for the Study of Diabetes 48th Annual Meeting. The study was funded by Eli Lilly and Company.


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 study was to evaluate the drugs in combination in patients who had not responded to standard doses of these drugs alone vs high-dose monotherapy with pregabalin or duloxetine. The secondary objective of a double-blind, randomized, parallel-group comparison was to evaluate each drug at a standard dose as monotherapy for the initial treatment of pain up to 8 weeks.

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 whichever monotherapy the patients were receiving was doubled, or the other drug was added at its full standard dose for an additional 7 weeks, followed by a 2-week tapering phase. This phase was designed to investigate whether combination or high-dose monotherapy 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.

Duloxetine More Effective as Initial Treatment

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 this 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 there was no difference in BPI scores at 4 weeks (P = .098) or 8 (P = .370).

"The study design we used in the COMBO-DN study does not allow for a randomized comparison between duloxetine and pregabalin during the intensive treatment period; such a comparison is only valid for the initial treatment period," Dr. Wilhelm told Medscape Medical News.

However, the investigators are interested in whether a dose increase to 120 mg of duloxetine per day or a combination of 60 mg duloxetine plus 300 mg of pregabalin per day, provides better pain relief in patients who initially were nonresponders to duloxetine, or, conversely, a dose increase to 600 mg of pregabalin per day or a combination of pregabalin, 300 mg, plus duloxetine, 60 mg, provides better pain relief in those who did not respond initially to pregabalin.

"As you can imagine, we have already started to work on this question, but we will officially disclose this at a later time," he said. 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.

Treatment Options

In an interview with Medscape Medical News, 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.

The study was supported by Eli Lilly & Company. Dr. Wilhelm is an employee of Eli Lilly and reports owning stock in the company. Dr. Malik has disclosed no relevant financial relationships.

European Association for the Study of Diabetes (EASD) 48th Annual Meeting: Abstract 48. Presented October 2, 2012.