Expert Insights On Painful Diabetic Neuropathy
Painful diabetic neuropathy is perhaps one of the most discussed and hotly debated subjects in podiatry. Emerging research and emerging treatments have fueled the fire even further. With this in mind, David G. Armstrong, DPM, a member of the American Diabetes Association’s National Board of Directors, posed a number of questions to leading authorities on this controversial subject. Here’s what they had to say … Q: How prevalent is painful diabetic neuropathy in your practice? A: All of the panelists note they see a large number of patients with neuropathy secondary to diabetes. At his facility, Barry Rosenblum, DPM, estimates that between 20 to 30 percent of these patients have some degree of pain related to their neuropathy. A. Lee Dellon, MD, says “all” diabetic patients who are referred to him have some degree of discomfort in their feet. Dr. Dellon says half of these patients describe their discomfort as numbness, buzzing, tightness or pressure whereas the other half of these patients use the word “pain” and also describe feeling a burning sensation. When he asks the patients who complain of pain if they have numbness as well, 80 percent of those patients say they do. When Dr. Dellon proceeds to evaluate these patients with neurosensory testing, he notes that all “have some loss of large fiber-mediated sensibility.” Out of 45,000 (mostly older male) patients seen at the Carl T. Hayden VA Medical Center, approximately 6,000 have been diagnosed with peripheral neuropathy, according to Jeffrey Page, DPM. Dr. Page says a third of the diabetes patients at the center have been diagnosed with peripheral neuropathy and approximately 15 percent of those patients are symptomatic. Andrew Boulton, MD, concurs with Dr. Page. While there’s a common misperception that the majority of patients with sensorimotor neuropathy have painful symptoms warranting treatment, Dr. Boulton says it’s more in the 10 to 15 percent range. He says it is much more common to see an insensitive foot at risk of ulceration and Dr. Boulton adds that a foot ulcer may be the first presentation of neuropathy. Dr. Boulton cites a number of studies. He points out that a 1993 study of over 6,000 diabetes patients in the United Kingdom revealed that the overall prevalence of neuropathy was 28 percent yet only a minority of these patients had significant symptoms.1 A population-based community study of foot ulceration among older patients with Type 2 diabetes in 1994 revealed that nearly half of the patients had significant sensory loss.2 Of these patients, less than half had significant symptoms, according to Dr. Boulton. Citing a more recent community-based study of nearly 10,000 diabetes patients, Dr. Boulton notes that approximately a fifth of the patients had significant neuropathic symptoms.3Q: What are the latest theories on the causes of painful diabetic neuropathy? A: Dr. Boulton and his colleagues have looked at the cause of this condition for many years and he says instability of blood glucose control is one of the most important causal factors. He adds that a recent paper in Diabetic Medicine showed that blood glucose flux is associated with neuropathic pain.4 According to Dr. Rosenblum, one of the latest theories on the cause of painful diabetic neuropathy centers on the possibility of an entrapment mechanism. He says this would substantiate the “double-crush phenomenon,” as espoused by Dr. Dellon. Dr. Dellon says patients with painful neuropathy have a unique histopathology. To document this condition, Dr. Dellon says you need measured cutaneous thermal thresholds, a sural nerve biopsy demonstrating a shift in nerve fiber diameter histogram and normal large fiber function (normal cutaneous pressure and vibratory thresholds). The most common tests for diagnosing neuropathy (e.g. nerve conduction velocity) are only capable of recognizing large fiber disease, according to Dr. Page. However, he notes that when these tests are positive, the disease is already “well-advanced.” What has become better understood in recent years is the fact that diabetic neuropathy is “initially and foremost a small fiber neurological disease,” maintains Dr. Page.5 He says newer objective studies allow earlier detection of changes in the smaller myelinated and non-myelinated nerve fibers (e.g. changes in cutaneous perfusion and perceptual loss to the application of noxious heat and topical algogens). Dr. Page says these studies enable you to detect neurologic changes much earlier in the disease process, “even before the patient has been diagnosed with diabetes.” A Few Thoughts About Nerve Fiber Pathology The etiology of true small fiber neuropathy remains a mystery, according to Dr. Dellon, who adds that it is rare. In Dr. Dellon’s experience, he has found that the majority of patients with symptomatic, painful diabetic neuropathy have a mixed nerve fiber pathology related to compression of their peripheral nerves at known sites of anatomic narrowing. Dr. Dellon says these peripheral nerves have the following three characteristics: • increased water content related to conversion of glucose to sorbitol by aldose reductase; • a decreased anterograde component of axoplasmic transport that hampers easy rebuilding of cell membranes; and • increased glycosylation of collagen (AGE products) within the nerve that decrease its elasticity. However, Dr. Boulton disagrees, emphasizing that diabetic peripheral sensory motor neuropathy is not an entrapment neuropathy. What About Nitric Oxide Generation? Another emerging theory implicates impaired nitric oxide generation in the pathogenesis of diabetic neuropathic pain, according to Dr. Rosenblum, who notes that decreased nitric oxide production may play a role in decreasing endoneurial blood flow. Dr. Page says the role of oxidative stress in the onset and progression of neurologic changes in the diabetic population is of “great significance.” He points out there’s a growing body of literature that reveals the value of employing antioxidants in preventing, delaying or attentuating aberrations in nerve function, metabolism and morphology, as well as disturbances in nitric oxide release and production.6 Dr. Page adds that oxidative stress is accompanied by systemic inflammation as indicated by elevated C-reactive protein. Q: What are currently the most promising therapies for treating painful diabetic neuropathy? A: A strong proponent of evidence-based medicine, Dr. Boulton says the current evidence base favors tricyclic drugs as the top choice, followed closely by anti-epileptic medications such as gabapentin. While there are not a lot of new therapies he would call promising, Dr. Rosenblum notes that gabapentin has helped patients who previously did not benefit from analgesics alone. Dr. Boulton adds that controlled trials have shown the opiod-like drug tramadol to be “very useful” in managing neuropathic pain. In recent years, Dr. Page says there has been an increased focus on disease modifying agents such as aldose reductase inhibitors, nerve growth factors and antioxidants. However, Dr. Dellon points out that currently all double-blind prospective trials of drugs like aldose reductase inhibitors, myoinostol and insulin-like growth factors have failed to provide significant relief. Dr. Page says two promising agents, often referred to as “herbal remedies,” are alpha-lipoic acid and capsules containing gamma-linolenic acid, such as evening primrose oil or borage oil.7-9 He also notes that antioxidants, such as vitamins C, E and B complex, and micronutrients, like magnesium and selenium, may have value.6 Dr. Rosenblum says the effectiveness of topical isosorbide dinitrate spray has been described in the literature. While Dr. Rosenblum has not been “entirely impressed” with the results of peripheral nerve surgery, he says surgery may play more of a role in patients with pain than it might in restoring protective sensation to the diabetic foot. Dr. Dellon says surgical decompression, an approach he has developed over the past 20 years, offers “the most hope for the diabetic with symptomatic neuropathy.” Q: What is your algorithm for treatment of painful diabetic neuropathy? A: Drs. Boulton and Rosenblum agree that you first need to confirm whether the neuropathy is caused by diabetes.10 Dr. Rosenblum emphasizes ruling out other possible neurogenic causes of pain during your initial patient evaluation. Dr. Boulton points out that 5 percent of neuropathy among diabetes patients is of non-diabetic etiology. All of the panelists agree that achieving stable glycemic control is essential before proceeding with treatment. Dr. Rosenblum adds that persistent hyperglycemia plays a significant role in perpetuating all diabetic complications, including neuropathy, and may incite episodic pain. Dr. Page believes it is helpful to determine whether the patient’s complaints of pain are superficial or deep. If the complaints are superficial and mild (such as minor burning and tingling), Dr. Page says using a topical counter irritant may be sufficient. Dr. Rosenblum adds that he has seen some anecdotal cases in which patients were able to achieve improvement with topical agents such as capsaicin. Dr. Rosenblum says he would proceed to consider acetaminophen or one of the nonsteroidal antiinflammatory agents. If this doesn’t provide symptomatic relief and prior to considering narcotic analgesics, Dr. Rosenblum says he will consider using a tricyclic antidepressant or gabapentin. Dr. Boulton says first-line drugs would include the tricyclic medications such as amitriptyline. However, he cautions that many patients cannot tolerate the significant side effect profile of tricyclic drugs. In this scenario, he suggests using gabapentin or tramadol. A number of patients may initially benefit from using a tricyclic antidepressant or an anticonvulsant for symptomatic relief, according to Dr. Page. However, Dr. Page believes disease modifying agents may provide a better alternative. To that end, he recommends that these patients begin taking evening primrose oil capsules three times a day and alpha lipoic acid 600 mg t.i.d. Dr. Boulton says there are other agents, such as lamotragine, topirimate, mexilitene and possibly carbamazepine, that have demonstrated proven efficacy in controlled trials. If the patient is under the best possible glycemic control he or she is capable of, has had a trial of neuropathic drugs and still remains symptomatic, Dr. Dellon says he will consider the patient as a candidate for surgical decompression of peripheral nerves. If the patient’s complaints of pain are severe or involve a deeper stabbing or lancinating pain, Dr. Page often recommends physical therapy including electrical stimulation or infrared treatment. Q: What about non-traditional methods of treating painful diabetic neuropathy? A: While Dr. Dellon is not opposed to patients attempting non-traditional methods, he says he is not aware of any that offer “consistent relief.” Dr. Dellon says he has seen many patients who have tried to obtain relief via magnets or acupuncture, but to no avail. Dr. Rosenblum has seen some limited success with acupuncture or acupressure, but he believes a larger study is necessary to confirm the effectiveness of these therapies. Non-traditional methods may be useful, according to Dr. Boulton. He refers to an uncontrolled trial in which he and his colleagues showed that the use of acupuncture in patients with significant neuropathy may achieve “good pain relief in up to 80 percent of cases.”11 According to Dr. Boulton, this pain relief may last up to six months and may reduce the need for pain medication.11 While Dr. Dellon says the word is still out on infrared wavelength treatment, Dr. Page notes that some researchers have recently shown promising results with this modality.12Q: What about peripheral nerve surgery? A: Dr. Dellon first published his findings on performing decompression of lower extremity peripheral nerves to treat symptomatic diabetic neuropathy back in 1992.13 That study, which ended in 1989, included patients with a seven-year follow-up and a mean follow-up of 3.5 years, according to Dr. Dellon. The observations from that study were confirmed by a subsequent 1995 study from a general surgery group at the University of Kentucky.14 Dr. Dellon notes that they included primarily painful neuropathy patients and those who had a previous ulcer and a negative Tinel sign. Another study on this subject by a plastic surgery group at the University of Florida included patients with a negative Tinel sign and some who had a previous amputation.15 Dr. Dellon also co-authored a small series study (designed as a prospective, blinded study) on this subject in 2000.16 He adds that another study on this subject (and currently pending publication) shows similar results.17 The results of the aforementioned studies on decompression of lower extremity peripheral nerves to treat symptomatic diabetic neuropathy can be summarized, “in their most conservative form, as demonstrating that 70 percent of patients will recover good sensibility and 85 percent will have good relief of pain,” according to Dr. Dellon. In his own practice, Dr. Dellon maintains that no patient who has had this surgery has had an ulcer or an amputation or been admitted to the hospital for foot infection or sustained a hip fracture from a fall. These findings, which were summarized in the September 2002 issue of Ostomy-Wound Management, also revealed that the difference in ulcers and amputations in a patient subgroup who had the surgery on one side but not the other was significant at the p<.002 level.18 Dr. Page believes that neurolysis is of “significant benefit,” especially for patients who have a deeper, lacinating type of pain. In his opinion, Dr. Page doesn’t feel it is necessary to have an abnormal nerve conduction velocity to justify peripheral nerve surgery. Raising Questions About Peripheral Nerve Surgery However, Dr. Boulton maintains that diabetic peripheral sensory motor neuropathy is not an entrapment neuropathy and knows of “no good controlled trial data to support peripheral nerve release.” In one study of patients with severe ulnar neuropathy, Dr. Boulton and his colleagues reported that classical entrapment may not be present in many patients with advanced neuropathy and that the lesion may be axonal.19 Therefore, releasing peripheral nerves such as the ulnar nerve would not be helpful in treating such conditions, according to Dr. Boulton. He adds that distal sensory motor neuropathy involves multiple nerves and does not usually respond to peripheral nerve release. Dr. Boulton does note that occasional localized pain may be due to tarsal tunnel syndrome. In these situations, he says performing a peripheral release may be useful. While Dr. Rosenblum believes the data on peripheral nerve surgery is “sketchy,” he says this treatment approach may be utilized in recalcitrant cases. Dr. Rosenblum advises surgeons to direct their attention to all of the nerves in the foot and ankle, and not solely the tarsal tunnel. As he noted earlier, Dr. Rosenblum is more impressed with this intervention’s possible ability to relieve pain as opposed to the claim of returning protective sensation. Dr. Rosenblum does caution that patients with severe ischemia would not be candidates for this procedure. When treating these patients, Dr. Rosenblum says you need to be certain that the pain is not secondary to arterial insufficiency. In addition, he says healing the surgical wound is another important consideration for ischemic patients. Dr. Armstrong is the Director of Research and Education within the Department of Surgery, Podiatry Section, within the Southern Arizona Veterans Affairs Medical Center in Tuscon, Ariz. He is a Visiting Senior Lecturer of Medicine in the Department of Medicine at the Manchester Royal Infirmary at the University of Manchester in the United Kingdom. Dr. Boulton is a Professor of Medicine at the University of Manchester in the United Kingdom. He is a Visiting Professor of Medicine within the Division of Diabetes at the University of Miami School of Medicine. Dr. Dellon is a Professor of Plastic Surgery and Neurosurgery at Johns Hopkins University and is a Professor of Plastic Surgery within the Department of Surgery at the University of Arizona. Dr. Page is the Associate Chairman of the Podiatry Section at the Carl T. Hayden Veterans Affairs Medical Center in Phoenix, Ariz. Dr. Rosenblum is an Assistant Clinical Professor of Surgery at Harvard Medical School and is the Director of Podiatric Residency Training at the Beth Israel Deaconess Medical Center in Boston.
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