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Combination treatment for diabetic peripheral neuropathic pain (DPNP) might offer additional relief in those with inadequate pain control, a randomized crossover trial showed.

In 130 patients randomized to one of six treatment pathways involving three commonly prescribed medications -- amitriptyline supplemented with pregabalin (Lyrica), pregabalin supplemented with amitriptyline, and duloxetine (Cymbalta) supplemented with pregabalin -- 7-day average pain numerical rating scale (NRS) scores decreased from a mean 6.6 at baseline to 3.3 at week 16 for all three pathways, reported Solomon Tesfaye, MD, of the Royal Hallamshire Hospital in Sheffield, England, and colleagues in .

Of the three treatment options, one didn't prove to be better than the others, with no significant differences in the mean reduction in pain scores:

• Duloxetine-pregabalin versus amitriptyline-pregabalin: mean difference -0.1 (98.3% CI -0.5 to 0.3)
• Pregabalin-amitriptyline versus amitriptyline-pregabalin: mean difference -0.1 (98.3% CI -0.5 to 0.3)
• Pregabalin-amitriptyline versus duloxetine-pregabalin: mean difference 0.0 (98.3% CI -0.4 to 0.4)

The main study result "implies that all three of these classes of medication had similar efficacy, which is what we would have predicted on the basis of similar effect sizes based on a meta-analysis of existing randomized clinical trials," noted Melissa A. Elafros, MD, PhD, and Brian C. Callaghan, MD, MS, both of the University of Michigan in Ann Arbor, in an .

"As a result, physicians should use factors other than efficacy (side effects, cost, and other comorbidities) when determining which medication to start and add on for treatment of DPNP," they advised.

All three drugs were titrated up to a maximum tolerated dose: 75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin.

Patients were initially prescribed monotherapy for 6 weeks, but if pain relief was suboptimal (defined as a mean daily pain NRS over 3), patients were then supplemented with a second drug.

Of the 130 patients who started a treatment pathway, 84 went on to complete at least two pathways.

The subset of patients who went on to follow a combination therapy pathway reaped additional pain benefits, seeing a greater average pain score reduction than patients who stuck with monotherapy (1 vs 0.2).

"Until now, we did not have good evidence to support the common practice of adding medications to patients' regimens who do not have adequate pain control with the first medication," wrote Elafros and Callaghan. "Although it is disappointing that only 35% of participants had substantial pain relief (NRS ≤3) with monotherapy, it is encouraging that an additional 18% achieved this level of pain control with combination therapy."

There were certain adverse events reported for each treatment that Tesfaye and team called "predictable for the monotherapies," which included dizziness with the pregabalin-amitriptyline pathway, nausea with the duloxetine-pregabalin pathway, and dry mouth with the amitriptyline-pregabalin pathway.

For this multicenter, double-blind trial, Tesfaye and colleagues included 130 patients with a mean daily pain NRS score of 4 or higher from 13 centers in the U.K. Mean age was 61, 74% were men, and 94% were white. Seventeen percent had type 1 diabetes, and average duration of diabetes was 15.1 years.

The most common medications previously used by the participants were amitriptyline, pregabalin, duloxetine, gabapentin, and opioids.

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