- Explain that a guideline from the American Academy of Neurology recommends pregabalin for the treatment of diabetic nerve pain based on evidence of modest efficacy from four placebo controlled trials.
- Note that several other anticonvulsants, some antidepressants, and transcutaneous electric nerve stimulation received a “probably effective” rating in the guideline.
HONOLULU — Among a variety of drugs and nonpharmacologic treatments for painful diabetic neuropathy, pregabalin (Lyrica) has the strongest evidence for efficacy, according to a new guideline issued by the American Academy of Neurology.
With four randomized trials testing pregabalin — three of which received the highest possible quality rating — the guideline authors, led by Vera Bril, MD, of the University of Toronto, indicated the drug's effect against diabetic nerve pain was relatively modest but “should be offered for the [condition's] treatment.”
It was the only treatment recommendation to receive an “A” grade indicating that its effectiveness had been firmly established in clinical trials.
The guideline was published online in Neurology and highlighted in a press conference here at the AAN's annual meeting. It's the first such guideline offered by the group, which developed the recommendations in collaboration with the American Association of Neuromuscular and Electrodiagnostic Medicine and the American Academy of Physical Medicine and Rehabilitation.
In the three highest-quality studies, pregabalin reduced pain by 11% to 13% on an 11-point Likert scale relative to placebo, Bril and colleagues noted.
The fourth study found that a relatively large dose (600 mg/day) cut pain scores by as much as 50% relative to placebo.
“I was surprised there weren't more level A [recommendations],” Bril said at the press briefing, explaining that she thought the evidence would be stronger for some of the other treatments evaluated during the guideline research.
Drugs getting a “B” recommendation as probably effective, based on moderate-quality randomized trials or matched cohort studies, included the following:
- Gabapentin (Neurontin)
- Sodium valproate (Depacon)
- Venlafaxine (Effexor)
- Duloxetine (Cymbalta)
- Opioids including dextromethorphan, tramadol, morphine sulfate, and oxycodone
- Topical capsaicin
But Bril and colleagues also noted that many of these agents have drawbacks. Sodium valproate is a known teratogen, for example, and opioids can produce so-called rebound headaches as well as frequently requiring dose escalations to maintain their analgesic efficacy.
The guideline also gave a “probably effective” rating to transcutaneous electric nerve stimulation.
In addition, the authors identified a number of treatments that scientific studies have demonstrated to be mostly ineffective. These included:
- Anticonvulsants such as oxcarbazepine, lamotrigine, and lacosamide
- Pulsed electromagnetic field therapy
- Low-intensity lasers
- Reiki therapy
For a considerable number of other treatments — such as antidepressants including imipramine and fluoxetine, as well as topiramate, alpha-lipoic acid, and vitamins — the evidence was insufficient to warrant any conclusions, the guideline authors decided.
In developing the guideline, Bril and colleagues reviewed 79 scientific studies that described interventions, reported completion rates, and defined the outcome measures (although these were not necessarily prespecified in lower-quality studies).
Reviews and case reports were excluded from consideration.
At the press briefing, Bril noted that diabetic nerve pain is among the most common neurological problems, affecting an estimated 16% of the 25 million Americans living with diabetes.
She said 39% of patients with the condition do not receive treatment, she added.
In fact, Bril said, 12% of the patients who suffer from neuropathy “won't even tell their physicians,” because they do not understand that the symptoms are related to their diabetes.
But the research on current treatment is inadequate in several important respects, she and her colleagues noted in their recommendations.
Measures of pain and quality of life vary significantly between studies, they noted, and data on long-term efficacy and safety were generally lacking.
Also, although some studies gave number-needed-to-treat estimates, none provided numbers needed to harm.
Moreover, according to Bril, most studies fail to address cost-effectiveness. But she also acknowledged that cost was not taken into account in the new guideline or others developed by the AAN.
The guideline authors called for standardized rating scales for pain, quality of life, and physical function and that these should be reported for all future studies of treatments for diabetic nerve pain.
Another major gap has been in head-to-head comparisons of different treatments, they noted. These could be especially helpful given that, as with pregabalin, most treatments have shown relatively modest benefits when tested in rigorous placebo-controlled trials.
Finally, Bril and colleagues called for more research into the currently mysterious mechanism of action of transcutaneous nerve stimulation.
In a related development, the AAN announced that it is developing a set of care-quality measures for physicians treating neuropathic pain, which it plans to release in 2012.
The diabetic neuropathy guideline came with a disclaimer from the AAN emphasizing that final decisions on treatment are up to individual patients and their physicians “based on all of the circumstances involved,” and that the document should not be interpreted as a formal practice recommendation.
Bril noted that most patients with diabetes are treated by primary care physicians. “I can't tell you how many are referred to neurologists” with nerve pain,” she said.
“Perhaps not enough,” she added with a smile.