Pharmacologic options for painful diabetic neuropathy reviewed

Good glycemic control is not sufficient to relieve painful diabetic neuropathy, necessitating investigation of other modalities to achieve analgesic efficacy. Dan Ziegler, MD, German Diabetes Clinic, German Diabetes Center, and professor of internal medicine, Leibniz Institute at the Heinrich Heine University, Düsseldorf, provided an overview of pharmacologic treatments that have been explored for painful diabetic neuropathy and the success achieved with each.

He started with a summary of the data obtained with alpha-lipoic acid, 600 mg/day, which was assessed in a meta-analysis of short-term placebo-controlled trials. In the analysis, a 25% improvement in the total symptom score was achieved with alpha-lipoic acid compared with placebo, and improvements in each of the components of the score (pain, burning, paresthesias, numbness).

In an assessment of the long-term efficacy, 35.6% of alpha-lipoic recipients compared with only 29% of placebo recipients were deemed as responders using the Neuropathy Impairment Score of the Lower Limbs (NISLL) over 4 years. Fewer patients randomized to alpha-lipoic acid had progression of their scores compared with placebo.

The tricyclic antidepressants have been tried for the treatment of diabetic neuropathy "but the problem is that these are very dirty drugs" that act on numerous receptors, said Dr. Ziegler, causing side effects (especially anticholinergic side effects). The serotonin-norepinephrine reuptake inhibitors (SNRIs) are "cleaner drugs" that act on the descending inhibitor pathway to reduce the perception of pain, he said.

Duloxetine, an SNRI, 20 to 120 mg/day, has been investigated in three studies. The number needed to treat (NNT) to achieve a response on the Brief Pain Inventory (BPI) was 4.9 with the 120-mg dose and 5.2 with the 60-mg dose. Dr. Ziegler noted that a NNT less than 6 is indicative of a successful intervention. Duloxetine starts to work within 1 week, he said, and its full effects are realized by week 2. In an exploratory analysis, the only predictor of response was a baseline score of 6 or greater on the BPI. Nausea is dose-dependent with duloxetine. "Titrate the dose from 30 mg to 60 mg in a few days," he recommended. "Sixty mg is too high to start with." Other common side effects include somnolence and dizziness.

The calcium channel modulators gabapentin and pregabalin have also been studied for the treatment of painful diabetic neuropathy. The evidence with gabapentin is not as strong as with pregabalin, he said. In one randomized study of gabapentin, 59.5% of the gabapentin group versus 32.9% of the placebo group had at least a 50% reduction in pain scores, equating to an NNT of 3.8 with gabapentin.

Seven clinical trials (six published) have been conducted with pregabalin. Response rates (>50% reduction in pain scores from baseline) were 39% with 300 mg/day (NNT = 5.9) and 47% with 600 mg/day (NNT = 4.0), compared with 18% in placebo recipients; lower dosages did not prove effective. Dose-dependent dizziness, somnolence, and peripheral edema are among the side effects reported with pregabalin.

Four clinical trials in patients with diabetic neuropathy have been conducted with lacosamide, two of which did not meet the primary endpoint (reduction of pain). In reviewing its efficacy, Dr. Ziegler said that lacosamide appears "a little less effective than pregabalin." The 400-mg dose has been submitted to the FDA for review for an indication for the treatment of diabetic neuropathic pain. The rate of side effects, especially somnolence, is especially low with lacosamide, he said.

Capsaicin cream was first studied in a vehicle-controlled trial as a treatment for diabetic neuropathic pain in 1991. Eight weeks of treatment yielded an NNT of 5.7; 90% of patients reported improvement in their pain. The number of adverse event-related withdrawals, however, was much higher with capsaicin compared with placebo.

Fears of abuse and addiction prevent widespread use of opioids for the treatment of painful diabetic neuropathy. One study in which morphine and gabapentin were used in combination found better pain relief with the combination compared with each monotherapy; the combination permitted a lower dosage of each component compared with the monotherapies.