From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy
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.
References (95)
- et al.
A cross-sectional cohort survey in 2100 patients with painful diabetic neuropathy and postherpetic neuralgia: Differences in demographic data and sensory symptoms
Pain
(2009) - et al.
Management of painful neuropathies
Handbook of Clinical Neurology
(2013) - et al.
Pharmacologic management of neuropathic pain: Evidence-based recommendations
Pain
(2007) - et al.
Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations
The Journal of Pain
(2008) - et al.
Nortriptyline and gabapentin, alone and in combination for neuropathic pain: A double-blind, randomised controlled crossover trial
Lancet
(2009) - et al.
Effects of duloxetine on painful physical symptoms associated with depression
Psychosomatics
(2004) - et al.
Duloxetine vs. placebo in patients with painful diabetic neuropathy
Pain
(2005) - et al.
Strategies for the diagnosis and treatment of neuropathic pain secondary to diabetic peripheral sensory polyneuropathy
Diabetes & Metabolism
(2009) - et al.
NeuPSIG guidelines on neuropathic pain assessment
Pain
(2011) - et al.
American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan
Endocrine Practice
(2011)
Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients
European Journal of Pain
American Association of Clinical Endocrinologists Protocol for Standardized Production of Clinical Practice Guidelines—2010 update
Endocrine Practice
Health-related quality of life and its predictive role for analgesic effect in patients with painful polyneuropathy
European Journal of Pain
A randomized, double-blind comparison of duloxetine and venlafaxine in the treatment of patients with major depressive disorder
Journal of Psychiatric Research
Relief of painful diabetic peripheral neuropathy with pregabalin: A randomized, placebo-controlled trial
The Journal of Pain
Pregabalin for the treatment of painful diabetic peripheral neuropathy: A double-blind, placebo-controlled trial
Pain
Venlafaxine extended release in the treatment of painful diabetic neuropathy: A double-blind, placebo-controlled study
Pain
Duloxetine, pregabalin, and duloxetine plus gabapentin for diabetic peripheral neuropathic pain management in patients with inadequate pain response to gabapentin: An open-label, randomized, noninferiority comparison
Mayo Clinic Proceedings
Duloxetine and pregabalin: High-dose monotherapy or their combination? The “COMBO-DN study”—A multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain
Pain
Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: A randomized, double-blind study
European Journal of Pain
Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics
Diabetes & Metabolism
2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System
American Journal of Emergency Medicine
Prevalence and risk factors of neuropathic pain in survivors of myocardial infarction with prediabetes and diabetes. The KORA Myocardial Infarction Registry
European Journal of Pain
A randomized, controlled trial of oxycodone versus placebo in patients with postherpetic neuralgia and painful diabetic neuropathy treated with pregabalin
The Journal of Pain
A non-inferiority comparison of duloxetine and venlafaxine in the treatment of adult patients with generalized anxiety disorder
Journal of Psychopharmacology
Standards of medical care in diabetes 2012
Diabetes Care
Duloxetine for the management of diabetic peripheral neuropathic pain: Evaluation of functional outcomes
Pain Medicine
European Federation of Neurological Societies. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision
European Journal of Neurology
Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial
JAMA
Peripheral nerve function in patients with painful diabetic neuropathy treated with continuous subcutaneous insulin infusion
Journal of Neurology, Neurosurgery, and Psychiatry
Is duloxetine more effective than amitriptyline for painful diabetic neuropathy?
Current Diabetes Reports
Continuous subcutaneous insulin infusion in the management of painful diabetic neuropathy
Diabetes Care
Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral neuropathic pain: Impact on pain, polysomnographic sleep, daytime functioning, and quality of life
Diabetes Care
Guidance for the preparation of neurological management guidelines by EFNS scientific task forces—Revised recommendations 2004
European Journal of Neurology
Evidence-based guideline: Treatment of painful diabetic neuropathy: Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation
Neurology
The clinical landscape of painful diabetic neuropathy therapy: Perspectives for clinicians from clinical practice guidelines
The Clinical investigator
Enhanced glucose control for preventing and treating diabetic neuropathy (Review)
Cochrane Database of Systematic Reviews
The vital link between chronic disease and depressive disorders
Pain affects the quality of life of neuropathic patients
Neurological Sciences
Selective serotonin reuptake inhibitor toxicity
The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes
Diabetes Care
Topical capsaicin (low concentration) for chronic neuropathic pain in adults
Cochrane Database of Systematic Reviews
Topical capsaicin (high concentration) for chronic neuropathic pain in adults
Cochrane Database of Systematic Reviews
Duloxetine, 60 mg once daily, for major depressive disorder: A randomized double-blind placebo-controlled trial
Journal of Clinical Psychiatry
Changes in body weight with chronic, high-dose gabapentin therapy
Therapeutic Drug Monitoring
Evaluation of efficacy and safety of gabapentin, duloxetine, and pregabalin in patients with painful diabetic peripheral neuropathy
The Indian journal of pharmacy
Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine
The American Journal of Psychiatry
Cited by (72)
Microvascular complications: Diabetic nerve disease
2023, BIDE's Diabetes Desk Book: For Healthcare ProfessionalsScreening, diagnosis and management of diabetic sensorimotor polyneuropathy in clinical practice: International expert consensus recommendations
2022, Diabetes Research and Clinical PracticeCitation Excerpt :Therefore, magnesium substitution may be relevant in diabetes patients with magnesium deficiency, but further studies are needed to draw general conclusions. Overall, only 50% of subjects with painful DSPN respond to analgesic monotherapy [31,109]. Therefore, combination pharmacotherapy is required in patients who have only partial response or in whom the drug cannot be further titrated due to intolerable side effects.
Metformin attenuates diabetic neuropathic pain via AMPK/NF-κB signaling pathway in dorsal root ganglion of diabetic rats
2021, Brain ResearchCitation Excerpt :Diabetic neuropathic pain develops in about one third of patients with diabetic peripheral neuropathy (Alsaloum et al., 2019; Lee-Kubli et al., 2018; Ziegler and Fonseca, 2015).
Use of pain relieving drugs in community-dwelling older people with and without type 2 diabetes
2020, Primary Care DiabetesNRD.E1, an innovative non-opioid therapy for painful diabetic peripheral neuropathy—A randomized proof of concept study
2022, European Journal of Pain (United Kingdom)
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.