Essential Insights On Managing Symptomatic Diabetic Neuropathy

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Given the common prevalence and debilitating effects of neuropathic pain, it is important to have a strong understanding of effective treatment options. Accordingly, this author reviews the literature on currently available modalities as well as emerging therapies.

   Chronic neuropathic pain is a significant public health issue, which is often associated with negative physical, psychological and social sequelae.^1-3 Pain is considered the third most common healthcare problem and it disables more individuals than heart disease and cancer combined.¹

   In particular, neuropathic pain includes nerve-injured neuropathy, diabetic neuropathy, chronic inflammatory pain, complex regional pain syndrome and postherpetic neuralgia. Pain is often characterized by a tactile allodynia and hyperalgesia.^2,4 Pain perception and interpretation is further complicated by cognitive, affective and behavioral factors. It is often associated with diminished physical and emotional functioning, as well as affective symptoms.⁵

   Painful or symptomatic neuropathy is a common and debilitating complication of diabetes mellitus. It is one of the most commonly encountered neuropathic pain syndromes in clinical practice.^2,6 Research has found that patients with symptomatic diabetic peripheral neuropathy have a significantly higher prevalence of comorbidities. This includes twice as many limb infections, a 2.5-fold higher likelihood of hospital admissions and nearly tenfold greater limb amputations.⁷

   Further, patients with painful diabetic peripheral neuropathy (DPN) have had consistently higher healthcare service utilization and costs across all categories of care.⁷ One study found that peripheral neuropathy, both symptomatic and non-symptomatic, was nearly twice as prevalent in patients with type 2 diabetes (50.8 percent) versus those with type 1 diabetes (25.6 percent).⁸

   There are three broad types of neuropathy (sensory, motor and autonomic) associated with diabetes. Sensory neuropathy is the most prevalent of the three and is often simply referred to as DPN. Patients typically experience diverse sensory symptoms including dysesthesias in the feet that may often be accompanied by sleep disturbances.^6,9 Small fiber neuropathy is increasingly being recognized as a major cause of painful burning sensations in the feet.¹⁰ Although patients generally retain their strength throughout the course of the disease, the pain and paresthesias are often disabling and impose subsequent negative impact on the patients’ health-related quality of life.¹⁰ [7]

   Diabetes is the most common identifiable cause of small fiber neuropathy. Impaired oral glucose tolerance and individual components of this metabolic syndrome are often associated with the rate of progression. Recent research has shown that in addition to poor glucose control, independent risk factors for incident DPN include traditional cardiovascular risk factors for macrovascular disease. Other factors include age, diabetes duration, nephropathy, obesity, low high-density lipoprotein (HDL) cholesterol, high triglyceride levels and the female gender.^8,11

   To date, there is still no comprehensive understanding of the underlying biologic processes responsible for diabetic neuropathic pain. However, studies have demonstrated differences in sural nerve epineurial blood flow, foot skin microcirculation, intraepidermal nerve fiber density and thalamic magnetic resonance spectroscopy between individuals with symptomatic versus painless neuropathy.^6,11

Key Principles To Consider In The Evaluation And Management Of Patients With Painful DPN

   Over the past five years, there have been significant advances in the pathogenesis and management of DPN pain. One of the most important fundamental principles of etiology-based treatment for painful DPN is the stabilization of glycemic control to help delay the onset and slow disease progression. However, patients with symptomatic DPN often have concomitant comorbidities and may be deficient in their diet and nutrition. These patients also may be taking a plethora of medications. This is often the case with elderly patients. [8]

   Accordingly, it is also important to recognize that diabetes may not be the only contributing cause of painful neuropathy in this patient population. 12

   In addition to emphasizing the importance of strict glycemic control, healthcare professionals should rule out other conditions with which DPN may be confused and which may coexist in patients with diabetes. Other causes of neuropathy include excessive alcohol intake, vitamin B12 deficiency, thiamine deficiency, hypothyroidism, nutritional deficiencies, malignancy and neurotoxic drugs.^13-18

   A major goal of pharmacological treatment in painful DPN is to control the pain and provide symptomatic relief. Although pharmacological pain management may offer significant relief for several pain-related diseases, the current symptomatic therapy for painful DPN remains unsatisfactory.^1,6

   Anticonvulsants, including carbamazepine, gabapentin (Neurontin, Pfizer) and lamotrigine (Lamictal, GlaxoSmithKline), have undergone studies in the management of symptomatic DPN since the 1960s.¹⁹ However, the only Food and Drug Administration (FDA) approved drugs for treating neuropathic pain are duloxetine (Cymbalta®, Eli Lilly), an antidepressant, and pregabalin (Lyrica®, Pfizer), an antiepileptic medication. [9]

Assessing The Efficacy Of Duloxetine

   Duloxetine hydrochloride is a selective serotonin/norepinephrine reuptake inhibitor (SSNRI).^5,20 Both serotonin and norepinephrine are involved in the modulation of endogenous analgesic mechanisms via the descending inhibitory pain pathways in the brain and spinal cord. Researchers have theorized that disinhibition and the imbalance of serotonin and norepinephrine in endogenous pain inhibitory pathways could contribute to persistent pain.

   Conversely, an increase in serotonin and norepinephrine may increase the inhibition of painful signals and help alleviate pain.⁵

   In a meta-analysis, Sultan and colleagues evaluated six qualifying randomized controlled trials using duloxetine and compared the results with published data for other antidepressants in the treatment of neuropathic pain.⁵ The authors concluded that duloxetine is effective for the treatment of painful DPN and fibromyalgia with at least 50 percent pain relief over 12 weeks. Patients tolerate the treatment fairly well. Further, the data showed inadequacies in the evidence for the efficacy of antidepressants in the treatment of painful DPN despite antidepressants being currently recommended in DPN care pathways and algorithms.⁵

   A post-hoc analysis of the safety and efficacy of duloxetine in the treatment of diabetic peripheral neuropathic pain found duloxetine to be well tolerated and efficacious regardless of the patient’s age.²⁰

What The Literature Reveals About Pregabalin

   Pregabalin is the next generation drug in the same class as gabapentin. Although pregabalin has a similar pharmacologic profile to its developmental predecessor, it has demonstrated greater analgesic activity in rodent models of neuropathic pain. Pregabalin also has anxiolytic and anticonvulsant activity, and received FDA approval in December of 2004 for the management of neuropathic pain associated with DPN and postherpetic neuralgia. As with gabapentin, the exact mechanism of action of pregabalin is unclear. However, it has been postulated that pregabalin reduces excitatory neurotransmitter release by binding to voltage-gated calcium channels.

   In a Cochrane Review, Moore and co-workers assessed the analgesic efficacy and associated adverse events of pregabalin in acute and chronic pain.¹⁹ Pregabalin at 150 mg daily was generally ineffective. Pregabalin at doses of 300 mg, 450 mg and 600 mg daily was effective in patients with postherpetic neuralgia, painful DPN, central neuropathic pain and fibromyalgia (19 studies, 7,003 participants).

   In regard to the use of 600 mg pregabalin, the researchers noted that daily somnolence occurred in 15 to 25 percent of patients and dizziness occurred in 27 to 46 percent. Treatment was discontinued due to adverse events in 18 to 28 percent of patients. However, the adverse events did not appear to be dose related. The researchers noted higher rates of substantial pain mitigation in patients with postherpetic neuralgia and painful DPN than in patients with central neuropathic pain and fibromyalgia.

   The authors concluded that a minority of patients will have a substantial benefit with pregabalin and more will have moderate benefit. Many will have no benefit or trivial benefit, or will discontinue treatment because of adverse events, according to the study.¹⁹

Comparing Oral Therapies: What The Studies Show

   An indirect meta-analysis compared the efficacy and tolerability of duloxetine, pregabalin, gabapentin and amitriptyline (Elavil, AstraZeneca) using a placebo as a common comparator. Three studies of duloxetine, six of pregabalin, two of gabapentin and none of amitriptyline met the inclusion criteria. In random effects and fixed effects analyses of duloxetine, pregabalin and gabapentin, all three were superior to placebo for all efficacy parameters with some tolerability trade-offs. 21

   An indirect comparison of duloxetine with pregabalin found no differences in 24-hour pain severity but researchers did note significant differences in the patient global impression of improvement/ change that favored pregabalin. When it came to the side effect of dizziness, the study found a significant difference in favor of duloxetine. 21

   The authors concluded that duloxetine showed comparable efficacy and tolerability to gabapentin and pregabalin in the treatment of DPN, and may provide an important option for this disabling condition.²¹

   O’Conner and colleagues evaluated the relative efficacy, costs and cost effectiveness of first-line treatment options for painful DPN. The authors compared four medications: desipramine (Norpramin, Sanofi-Aventis) 100 mg/day; gabapentin 2,400 mg/day; pregabalin 300 mg/day; and duloxetine 60 mg/day. Desipramine (100 mg/day) and duloxetine (60 mg/day) appear to be more cost effective than gabapentin or pregabalin for treating painful DPN.³

Emerging Developments With The Use Of Capsaicin

   Some clinicians advocate the use of topical creams that contain capsaicin, a pungent compound in chili peppers. Capsaicin is a highly selective agonist for the transient receptor potential vanilloid 1 receptor expressed in nociceptive sensory nerves to help alleviate neuropathic pain.^22,23

   Researchers have postulated that capsaicin blocks pain signals via the depletion of substance P to evoke a lasting and reversible refractory state in primary sensory neurons involved in the generation and maintenance of neuropathic pain.²⁴
   However, capsaicin usually requires numerous daily applications so it is not a user friendly option. In addition, it is difficult to ensure patient adherence.

   A high-concentration (640 µg/cm2) rapid delivery synthetic capsaicin (trans-capsaicin) dermal patch, NGX-4010 (Qutenza, NeurogesX Inc.), is currently in clinical evaluation for the management of peripheral neuropathic pain.^22,24 With NGX-4010, applying a single 30- or 60-minute patch directly to the site of pain may reportedly provide up to three months of symptomatic relief with minimum side effects. Patients can apply NGX-4010 to the painful skin area (up to a total surface area of 1,120 cm2) and one can use the patch alone or in combination with other pharmacologic agents for pain mitigation.

   In phase I clinical trials, NGX-4010 increased the threshold for warmth detection, reduced epidermal sensory nerve fiber density and patients tolerated it well. In phase II trials, NGX-4010 was effective in reducing pain in patients with post-herpetic neuralgia, HIV-associated distal sensory neuropathy and painful DPN.^23-25

   NGX-4010 appears to have the potential to be an effective adjunctive or a stand-alone therapy for postherpetic neuralgia, and has potential for HIV neuropathy and DPN as well. Self-limited, mild-to-moderate local skin reactions reportedly occur commonly at the site of application.^23,25

   NGX-4010 has received approval from the European Commission. The FDA has accepted a new drug application (NDA) for NGX-4010 for the management of postherpetic neuralgia.²⁴ The low systemic exposure and very rapid elimination half-life of capsaicin following NGX-4010 administration are unlikely to result in systemic effects and support the overall safety profile of this investigational cutaneous patch.²²

   In addition, NGX-1998, a non-patch liquid formulation of the same active ingredient used in NGX-4010, is currently in development.

Can Botulinum Toxin Injections Have An Impact?

   In recent years, botulinum toxins have allowed for safe, versatile and minimally invasive interventions that have revolutionized the field of cosmetic and therapeutic treatments.²⁶

   Botulinum toxins are high-molecular weight proteins produced by gram-positive, spore-forming clostridial bacteria. They cause temporary local paralysis of the injected muscle through the inhibition of acetylcholine release at the neuromuscular junction.²⁷ The toxins of five distinct strains (A, B, E, F and G) affect humans.

   Currently, type A (Botox®, Allergan) and type B (Myobloc®, Neurobloc®, Solstice Neurosciences) toxins are available for the treatment of human diseases in the United States. Indications approved by the FDA include cervical dystonia, strabismus, blepharospasm, hemifacial spasm and glabellar wrinkles for Botox and cervical dystonia for Myobloc.²⁸

   Recent evidence suggests that botulinum toxin type A (BoNT/A) may also have an analgesic effect independent of its actions on muscle tone and may help alleviate neuropathic pain.^4,28,29 Researchers have theorized that BoNT/A not only inhibits the release of acetylcholine at the neuromuscular junctions but may also act on neurogenic inflammation and modulate afferent sensory fiber firing, thereby relieving neuropathic pain.^6,9,29

   Ranoux and colleagues evaluated the direct analgesic effect of BoNT/A in 29 patients with focal painful neuropathies and allodynia in a randomized, double-blind, placebo-controlled trial.²⁹ Patients received a one-time intradermal administration of BoNT/A (20-190 units) into the painful area.

   The researchers found that BoNT/A treatment, relative to placebo, was associated with persistent effects on spontaneous pain intensity from two weeks after the injection to 14 weeks. BoNT/A also improved allodynia to brush and decreased pain thresholds to cold without affecting perception thresholds. The authors also noted sustained improvements in neuropathic symptoms and general activity. As would be expected, most patients reported pain during the injections but there were no other associated local or systemic side effects.

   Piovesan and co-workers treated 13 patients with trigeminal neuralgia using BoNT/A in an open-label pilot study.³⁰ The authors noted a reduction in the visual analog scale (VAS) score and a reduction in the surface area of pain with no major side effects. They suggested BoNT/A may be an efficient treatment.

   Yuan and co-workers evaluated the effectiveness of intradermal BoNT/A versus saline injections for diabetic neuropathic pain in 18 patients in a double-blind crossover study.⁶ The authors compared the change in pain via VAS scores between the treatment and placebo groups at four time-points. After four, eight and 12 weeks, significant reductions in pain occurred in the BoNT/A group in comparison to the saline group. Overall, 44.4 percent of the BoNT/A group reported reduced pain in comparison with none in the control group.

   These preliminary findings support the theory that intradermal BoNT/A injections can help to relieve neuropathic pain in people with diabetes. However, larger studies are needed to better understand and define the role of botulinum toxins as analgesics for nociceptive and neuropathic pain.^4,6

In Conclusion

   Diabetic neuropathy is one of the most common peripheral neuropathies. The identification of effective treatment regimens remains challenging and prevention remains the foundation of clinical intervention and the prerequisite of adequate treatment.⁴ Individualization of treatment is needed to maximize pain relief and minimize adverse events.

   Glycemic control is most essential to prevent the development of DPN. However, it is also helpful to restrict drinking and smoking, and maintain proper blood pressure to reduce risk factors and retard the progression of DPN.

   As basic and clinical science progress over the next few years, along with the introduction of novel pharmacologic agents, we anticipate greater potential in the elucidation of a pathogentically oriented symptomatic treatment to mitigate pain and improve the quality of life in patients with this debilitating disease.

Dr. Wu is an Associate Professor of Surgery at the Dr. William M. Scholl College of Podiatric Medicine and Associate Professor of Stem Cell and Regenerative Medicine at the School of Graduate Medical Sciences at Rosalind Franklin University of Medicine and Science in Chicago. She is also the Director for Educational Affairs and Outreach at the Center for Lower Extremity Ambulatory Research (CLEAR) in Chicago.

For further reading, see “Case Studies In Painful Diabetic Neuropathy” in the August 2006 issue of Podiatry Today or “Current And Emerging Options For Treating Diabetic Neuropathy” in the March 2005 issue.

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