No Clear Winner for Relief of Diabetic Neuropathy Pain

Pam Harrison

November 13, 2014

A new comparison of the effectiveness of different analgesic medications used for the treatment of diabetic neuropathy pain has not identified any clear winner.

Rather, several analgesics from different pharmacologic classes — serotonin-norepinephrine reuptake inhibitors (SNRIs), anticonvulsants, tricyclic antidepressants (TCAs) and topical capsaicin 0.75% — seem to be effective for the short-term management of this condition, say the researchers, led by Dr Marcio Griebeler (Sanford Health, Sioux Falls, South Dakota).

The comparative effectiveness of these agents also remains unclear, they say.

"We have four drug classes that are clearly better than placebo, but comparing them head-to-head is difficult to do, and we don't have a lot of good information as to which drug might be better," agreed Dr Brian Callaghan (University of Michigan, Ann Arbor, Michigan), who coauthored an accompanying editorial.

"I don't use capsaicin much because of the side effects, but the other three drug classes all have comparable evidence of their efficacy, so my thoughts about them come down to comorbidity, side effects, and maybe most important, cost," he told Medscape Medical News.

Dr Griebeler said the question she and her coauthors sought to answer was whether there is any medication that is better than any others for diabetic neuropathy. "Since very few studies were head-to-head comparisons, we had to do indirect comparisons using placebo as the comparator agent, and when we did this, some drugs were a bit better than others, but there wasn't a huge difference between them, so we cannot make a strong recommendation for any of them."

The research was published in the November 4, 2014 issue of the Annals of Internal Medicine.

Randomized Controlled Trials and Head-to-Head Studies Needed

Dr Griebeler and colleagues analyzed a total of 65 randomized controlled trials involving 12,632 patients in which 27 pharmacologic interventions for diabetic neuropathy pain were evaluated.

Out of these, nine head-to-head trials were identified in which medications from different pharmacologic classes were compared.

"In general, trials were brief (mean follow-up, 14 weeks) and enrolled mostly middle-aged men who had type 1 or 2 diabetes for more than 5 years," the authors observe.

Expressed as a standard mean difference (SMD) in pain relief, results from these nine head-to-head trials indicated that the SNRIs and the TCAs reduce pain more effectively than anticonvulsants (SMD, -0.34) and topical capsaicin 0.75%.

Because of the few head-to-head studies, Dr Griebeler and colleagues then used a network meta-analysis to indirectly compare drug classes. Although they found that SNRIs are more effective than anticonvulsants and TCAs are better than topical capsaicin, results of other comparisons among these four categories of medications did not significantly differ.

In conclusion, "evidence is scant, mostly indirect, and often derived from brief trials with an unclear or high risk of bias."

"Our network meta-analysis therefore has implications for future research efforts and highlights the need for properly designed randomized controlled trials and more head-to-head comparisons of the most commonly used medications for painful diabetic neuropathy (that is, amitriptyline, gabapentin, pregabalin, and duloxetine)."

Only Pregabalin, Duloxetine Approved for Painful Diabetic Neuropathy

Dr Griebeler and colleagues also note that varying recommendations for the management of painful diabetic neuropathy have been proposed.

The European Federation of Neurological Societies recommended in 2010 that tricyclics, gabapentin, pregabalin (Lyrica, Pfizer), and SNRIs (including duloxetine and venlafaxine) should be used as first-line agents. Tramadol or stronger opioids are considered as second- or third-line medications.

In 2011, the International Toronto Expert Panel on Diabetic Neuropathy proposed similar recommendations, while the American Academy of Neurology recommends offering pregabalin as a first-line option, whereas venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and controlled-release oxycodone), and capsaicin should be considered later.

The doctors note, however, that only pregabalin and duloxetine are approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of neuropathic pain in diabetes.

Cost May Be Deciding Factor

In their accompanying editorial, Dr Callaghan and colleague Dr Eva Feldman (University of Michigan, Ann Arbor), wonder, "Which medications should physicians prescribe while we wait for more definitive evidence? Unfortunately, current guidelines and the US FDA are less helpful to busy clinicians than one might hope."

They point out one of the marked differences among the medications used for the treatment of diabetic neuropathy is cost.

As Dr Callaghan observes, gabapentin and pregabalin both have the same mechanism of action and do the same thing to relieve painful diabetic neuropathy. "Yet one (gabapentin) is 10 times cheaper than the other," he points out.

Meanwhile the cost of venlafaxine, though now available generically, remains high and is not much less than the cost of duloxetine, until recently a patented drug.

"The tricyclic antidepressants have been around forever," Dr Callaghan added, "and while their market share has decreased over the years, they are probably some of our best medications and certainly the cheapest for neuropathic pain."

The approval of pregabalin and duloxetine for the treatment of painful diabetic neuropathy has given these two agents more prominence than the others, and perhaps an unfair market share, Dr. Callaghan suggested.

"I'm a neuromuscular physician with a special interest in neuropathy, so this is something that I deal with all the time," he remarked.

"I think cost is a big component in our choice of medication — both out-of-pocket costs for patients and then everybody's premiums having to go up if we are not careful [about] how we manage our resources. So if the medicines are the same, why not use the cheaper ones?

"Given the current price of these medications, we believe that the most cost-effective approach is to try one or more TCAs as first-line medications, followed by gabapentin. The high-cost options of venlafaxine, duloxetine, and pregabalin should be reserved for when these other medications have failed."

The study was funded by the Mayo Foundation for Medical Education and Research and Clinical and Translational Science Awards. Dr Griebeler and coauthors have reported no relevant financial relationships, nor have Dr Callaghan and Dr Feldman.

Ann Intern Med. 2014;161:639-649, 674-675. Abstract, Editorial

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