ADA Releases New Guidelines on Managing Diabetic Peripheral Neuropathy

Update of guidelines recommends FDA-approved treatments and cautions against the use of opioids.

The American Diabetes Association (ADA) has updated its guidelines on the management of diabetic peripheral neuropathy (DPN) in patients with diabetes.

The guidelines,¹ which were last updated in 2005, recommend pregabalin (Lyrica) or duloxetine (Cymbalta, generic) as first-line medication therapies for managing symptoms of DPN. Both agents are approved by the US Food and Drug Administration (FDA) for this indication. Gabapentin (Neurotin, generic) also is considered a possible initial approach to therapy, and tricyclic antidepressants, while currently not approved approved for this indication, also have evidence of efficacy for the treatment of neuropathic pain. However, the ADA also stressed the importance of practicing caution “given the higher risk of serious side effects.”¹

The ADA also has updated its clinical position concerning the use of opioids to treat DPN—it now recommends opioids should be used only in the event all other medications fail to adequately treat symptoms. Even in patients who are unresponsive to other medications and may benefit from an add-on opioid, “those patients first should be referred to specialized pain clinics,” according to the ADA.

The primary strategy for combating DPN is still prevention, according to Gary Jay, MD. Writing in Practical Pain Management, Dr. Jay and co-author Grazia Allepo, MD, noted that maintaining glycemic control is essential. “But because diabetic neuropathy has multifactorial pathogenesis, additional therapies should be aimed at controlling hypertension, normalizing dyslipidemia, smoking cessation, and weight reduction.”

However, despite the evidence in the literature and the multiple pharmacologic regimens available for diabetes treatment today, “normoglycemia is not achieved in the majority of patients with diabetes patients,” they noted.

ADA Recommends FDA-Approved Therapies, Recognizes Others

The ADA guidelines come at a pertinent time as the medical field continues to understand optimal and novel approaches to managing DPN pain symptoms in patients. Not only is DPN one of the most common ailments a patient with diabetes may develop, it also can be difficult for a physician to detect, diagnose, and effectively treat.

While effective glycemic control may help prevent DPN, no evidence suggests it can help manage symptoms once a patient already has DPN.^2-3 It raises the question of what hierarchal order of drug interventions primary care physicians should refer to when treating patients presenting with DPN-related pain.

The ADA guidelines start its recommendations with FDA-approved medications. Pregabalin, an anticonvulsant, is considered the most extensively studied agent for distal symmetric polyneuropathy (DSPN), the most common form of peripheral neuropathy found in patients with diabetes. Numerous studies have shown the drug’s possible efficacy in treating pain symptoms in patients, with a possible dose-dependent response,⁴ although some trials have been negative, particularly for patients with advanced, refractory cases of the condition.⁵

Other ADA-recommended first-line medications, such as duloxetine, gabapentin, and tricyclic antidepressants, are described in the guidelines. Indeed, some primary care physicians may opt for these alternatives, given their availability in more cost-effective generic forms.

There is a wide array of medications that have evidence of being beneficial for the treatment of DPN. This includes a pool of alternative anti-convulsants,⁶ combining dextromethorphan with memantine⁷ or quinidine,⁸  and even using onobotulinum toxin type A injections to modulate afferent sensor fiber firing.⁹

According to Dr. Jay, “control of symptoms constitutes a considerable management problem because the efficacy of a single therapeutic agent is not the rule, and simple analgesics are usually inadequate to control the pain. A reduction in symptoms of 30% to 50% is achievable in most patients with combination therapy.”

Just recently, Practical Pain Management reported development of a new topical form of pirenzepine, an antimuscarinic agent still awaiting human trial, to not only treat symptoms of neuropathies, but effectively prevent and reverse their systemic effects by blocking an implicated receptor in the pathology of the disease.

The ADA made no mention of pirenzepine, nor any other selective or nonselective antimuscarinic agents, save for topical glycopyrrolate for treating gustatory sweating.¹⁰

The ADA recognizes “a large evidence base” encompassing many of these alternative and novel therapies possibly being effective for DPN, with the caveat that that same research has not looked at DSPN, alone. “However, the results of studies performed on peripheral nondiabetic neuropathic pain or mixed neuropathic pain may be applicable to patients with neuropathic pain due to DSPN,” the ADA stated.

The ADA guidelines serve as a timely update by the association, not only considering the range of prospective therapies in the pipeline and clinical research, but also in terms of its policy concerning the use of opioids to treat DPN in patients. There is existing evidence that opioid medications like tramadol^11-12 and controlled-release oxycodone^13-14 have efficacy in treating the longterm effects of DPN pain. However, the risks^15-17 related to opioid use are noted. Therefore, “opioids are not recommended in the treatment of painful DSPN before failure of other agents that do not have these associated concerns,” the ADA wrote.

The ADA’s position to include opioids in its recommended therapies somewhat mirror aspects of guidelines released by the Centers for Disease Control and Prevention (CDC), which similarly advise doctors to refer patients to pain specialist practices if opioids are to be considered a necessary part of the patient’s treatment. This position has begun to come under scrutiny by some professionals, who claim that the relatively scarce pain specialist practices in the country already are becoming overwhelmed by increased referrals from primary care doctors in reaction to CDC recomendations, which may be leading to slowed patient access to pain specialists.

The guidelines were composed by a team of researchers representing academic institutions inside and outside the US. No potential conflicts of interest have been reported in conjunction with the ADA’s publication.

View Sources

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