Elsevier

Journal of Diabetes and its Complications

Volume 29, Issue 1, January–February 2015, Pages 146-156
Journal of Diabetes and its Complications

From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy

https://doi.org/10.1016/j.jdiacomp.2014.08.008Get rights and content

Abstract

Painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus, affecting, by some estimates, up to one quarter of diabetic patients. Since 2010, no fewer than 5 major international treatment guidelines for painful DPN have been issued, and there are meaningful differences among them. Duloxetine, pregabalin, gabapentin, and tricyclic antidepressants are the mainstays of treatment, but the choice of which class or agent to use in any given patient should be informed by patient characteristics. This review seeks to describe the differences among the recently issued guidelines, to assess the evidence on which they are based, and to offer insight into the most appropriate treatment choices based on patient characteristics.

Introduction

An estimated 246 million people worldwide have diabetes mellitus (DM), and this number is likely to increase in tandem with the global epidemic of obesity (Pluijms et al., 2010). Diabetic polyneuropathy is among the most common long-term complications of DM, affecting up to 50% of diabetic patients (Tesfaye et al., 2010). The prevalence of painful diabetic peripheral neuropathy (DPN) is estimated to be 10 to 15% of patients with diabetes (Guastella & Mick, 2009) and up to 26% in some surveys (Davies et al., 2006). These painful symptoms can have a profound negative impact on quality of life, sleep, and mood (Jensen et al., 2007, O'Connor, 2009).

Approximately 80% of patients with diabetic neuropathy have distal symmetric polyneuropathy; symptoms initially occur in the feet and gradually work their way up (Pluijms et al., 2010). In a survey conducted at 468 pain centers in Germany that assessed pain-symptom profiles in 2100 patients with painful DPN or postherpetic neuralgia (PHN), Baron et al. (2009) identified 5 distinct symptom clusters. The most common symptom cluster in painful DPN, seen in 26% of patients, was burning pain, paresthesias, and numbness, with fewer than 20% of patients complaining of either dynamic mechanical allodynia, thermal hyperalgesia, or pain attacks.

Neuropathic pain (NeP) occurs more often in patients whose diabetes is chronically poorly controlled (Pluijms et al., 2010), and increased blood glucose flux—ie, increased range of variance in blood glucose levels—may contribute to the occurrence and severity of painful symptoms (Oyibo et al., 2002). Age, obesity, and peripheral arterial disease (PAD) are also associated with an increased risk of painful DPN (Ziegler, Rathmann, Dickhaus, et al., 2009, Ziegler, Rathmann, Meisinger, et al., 2009).

Maximizing glucose control is a primary goal in patients at risk of or who already have painful DPN (American Diabetes Association, 2012). A recent meta-analysis (Callaghan et al., 2012) suggests that enhanced glucose control significantly prevents the development of clinical neuropathy in patients with type 1 diabetes; among patients with type 2 diabetes, however, the reported reduction in incidence did not reach statistical significance. Early open-label studies reported that intensive glucose control with continuous IV insulin infusion may reduce painful symptoms in patients with established painful DPN (Bertelsmann et al., 1987, Boulton et al., 1982). To our knowledge, controlled clinical trials to demonstrate whether intensive diabetes therapy improves extant painful DPN have not yet been published.

Typically, individualized treatment for pain should begin when pain interferes with a patient's lifestyle. In cases of severe pain, pain that significantly limits daily activity, or pain accompanied by deterioration of an underlying health condition, referral to a pain specialist should be considered.

Section snippets

Objective and methods

Despite a wealth of literature on the subject and despite multiple treatment guidelines, achieving optimal treatment of painful DPN is elusive. The purpose of this article is to critically review recently issued guidelines for the treatment of painful DPN and the evidence on which they are built and to consider patient characteristics as potential determinants of recommended treatments most likely to be successful in individual cases.

In January 2013,1

Guideline recommendations for first-line treatment

Five recent guidelines (Attal et al., 2010, Bril et al., 2011, Handelsman et al., 2011, National Institute for Health and Clinical Excellence, Tesfaye et al., 2011)—created or endorsed by several professional societies—offer treatment recommendations specific to painful DPN (Table 1). Drugs with demonstrated efficacy in improving pain in DPN generally fall into 4 categories: anticonvulsants (particularly α2-δ ligands), antidepressants (predominantly tricyclic antidepressants [TCAs] and

Comparisons between first-line agents: little guidance from guidelines

Taken as a whole, these guidelines offer limited support for choosing one first-line over another in the overall DPN population. These guidelines found no significant differences in terms of efficacy between antidepressants (TCA or SNRIs) and anticonvulsants (including α2-δ ligands). Recent studies support a lack of clear differentiation based on overall efficacy between duloxetine and pregabalin. Pooled analyses in painful DPN trials showed that 45 to 55% of duloxetine-treated patients had > 

First-line treatment choice informed by patient characteristics

Results from recent, high-quality trials demonstrate a lack of clear differentiation between first-line agents in terms of reduction in painful symptoms. As a result, patient-specific variables such as comorbidities, contraindications, and interactions with concomitant treatments may be important in determining optimal therapy, a decision-making process that is formally endorsed by some guidelines (Attal et al., 2010, National Institute for Health and Clinical Excellence, Tesfaye et al., 2011).

Options after first-line treatment

In the majority of painful DPN patients, first-line monotherapy does not provide satisfactory relief at maximally tolerated doses (Dworkin et al., 2007, Pluijms et al., 2010). In such cases, options include switching to a different agent within the same class, switching to a new class, or adding a second agent (combination therapy) (Fig. 1).

Discussion

Painful DPN exacts a heavy toll on patients, including impaired QoL, sleep disturbances, and effects on depression and anxiety. In randomized controlled trials, a number of agents have been shown to improve pain and other outcomes in DPN patients. Yet less than half of patients will achieve meaningful improvements in pain and global outcomes.

Recent treatment guidelines provide up to six first-line treatment options for painful DPN. Direct and indirect comparisons suggest similar efficacies

Author contributions

DZ and VF contributed equally to the development of this paper by making substantial contributions to the conception of this review and to the interpretation of the material discussed; by revising it critically for important intellectual content; and by giving final approval of the version to be published.

Acknowledgments

Medical writing support for this paper was provided by Karl Torbey, MD and Gregory Bezkorovainy, MA, both of Adelphi Communications, New York. This support was funded by Daiichi Sankyo, Inc.

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    Competing interests: The authors did not receive funding for this article. DZ has received honoraria for speaking and consulting activities from Takeda, Daiichi Sankyo Europe, Eisai, Eli Lilly, Meda, Wörwag, and Pfizer. VF declares that his institution has received grants from Abbott, Eli Lilly, and Reata. He has received honoraria for consulting activities from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Inc., Eli Lilly, GlaxoSmithKline, Intarcia, Merck, Novo Nordisk, Pan American Laboratories, and Sanofi, and he owns stock/options in NuMe Health.

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