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Despite its prevalence and potential for foot injury, infection, and amputation, diabetic peripheral neuropathy (DPN) remains grossly underdiagnosed.
A large cohort study with data on 7,378 patients revealed that physicians miss the diagnosis of DPN in 61% of patients. Even severe neuropathy goes undetected in about one-third of cases, the study showed.1
About half of diabetic patients eventually will develop peripheral neuropathy, and 13% of patients with type 2 show signs of it upon diagnosis.2 DPN places patients at risk of foot injury; those who lack sensation in their feet are particularly susceptible.
"The problem is, up to half of all patients with DPN will be completely asymptomatic," says Andrew Boulton, MD, professor of medicine at University of Manchester, U.K., and the University of Miami. "Most doctors assume that if there are no complaints, there can't be much wrong."
ADA ON SCREENING FOR DPN
The most recent American Diabetes Association (ADA) recommendations advise physicians to screen all patients with type 2 diabetes for DPN upon diagnosis of diabetes, and at least annually thereafter.3
ADA screening guidelines advise clinicians to examine sensory function in feet and check ankle reflexes. The ADA recognizes testing of sensory function via pinprick, temperature and vibration perception (using a 128Hz tuning fork), or pressure sensation (using a 10-g monofilament pressure sensation at the distal halluces).3
For those patients who experience spontaneous pain but, upon clinical evaluation, show minimal signs of neuropathy, skin biopsies have proven effective for diagnosis.4 Minimally invasive skin biopsies can diagnose even small-fiber sensory neuropathy.
"When there's a question of whether a patient has DPN, a skin biopsy that takes just 3 mm of skin to look at the nerves will answer it," says neurologist Christopher Gibbons, MD, of the Beth Israel Deaconess Medical Center in New York.
Screening devices, however sophisticated, cannot supplant a thorough foot examination (DOC News, September 2005). "You can't diagnose DPN without examining the foot," Boulton says, emphasizing the importance of being thorough and diligent.
The same principles apply to managing DPN. For patients, that means consistently aiming for stable and optimal glycemic control, plus doing daily self-checks of the feet. Still, about 20% of patients have symptoms of pain that require treatment, Boulton says.
NEW DRUGS TO TREAT PAIN
To date, medical management of DPN consists primarily of medicine for pain. The ADA's 2005 statement on diabetic peripheral neuropathy includes management recommendations in order of priority, starting with glycemic control (see sidebar above). The ADA also suggests using both a tricyclic antidepressant and an anticonvulsant drug if one or the other doesn't bring relief on its own.3
The Food and Drug Administration (FDA) recently approved two drugs specifically for treating painful DPN.
Duloxetine (Cymbalta, Lilly), originally developed as an antidepressant, works by interacting with serotonin and norepinephrine, chemicals believed to play a role in pain. Its efficacy was established most recently in a 12-week study involving 457 patients with either type 1 or type 2 diabetes. Subjects who received 60 or 120 mg duloxetine showed statistically significant improvements on the 24-h Average Pain Score, compared with those taking a placebo. Improvements were reported as early as the first week of treatment and remained throughout the study.5 Most patients taking duloxetine for DPN-related pain are prescribed 60 mg once daily. The most commonly reported side effects include nausea, sleepiness, dizziness, constipation, dry mouth, increased sweating, decreased appetite, and fatigue.
Pregabalin (Lyrica, Pfizer), an anticonvulsant, reduces the pain of DPN by binding to a protein within "over-excited" nerve cells. This binding action prevents the nerve cells from firing too many signals, thereby decreasing the pain that over-firing causes.
In the most recent 12-week study demonstrating pregabalin's efficacy, subjects on either a flexible dosage schedule of pregabalin or a fixed dosage schedule of 300 mg/day for 1 week followed by 600 mg/day for 11 weeks reported significant reductions in pain scores and pain-related sleep interference, compared with a placebo group.6 Most patients start with an initial dosage of 150 mg/day, but incremental increases up to 600 mg/day can be prescribed safely.7 Possible side effects include dizziness, sleepiness, weight gain, and edema.
Despite their FDA stamp of approval, duloxetine and pregabalin are just two in a cadre of pain medicines prescribed for symptom relief, and experts are reluctant to call these drugs superior.
"Most people recognize that many medications are equally effective," Gibbons says. "They don't necessarily have to be FDA-approved" specifically for DPN. But the newer drugs approved for DPN pain may be better tolerated, he adds.
"It's often, `let's see what works for you,'" says Martin J. Abrahamson, MD, acting chief medical officer at Joslin Diabetes Center.
NONPHARMACOLOGICAL TREATMENTS
Drugs continue to be the most widely used treatments for the pain of DPN, but some alternative therapies show promise.
The Anodyne Therapy System, an infrared medical device approved by the FDA in 1994, purportedly increases circulation and decreases the pain of DPN. Results of a 2004 study published in Diabetes Care found it an effective method of restoring sensation, reducing pain, and improving balance for some patients.8 The sham-controlled, double-blind study noted improvements in these areas among subjects who were sensitive to the 6.65 Semmes-Weinstein monofilament at baseline. However, subjects with the greatest sensory impairment did not achieve significant improvements.
Surgery to decompress the lower-extremity peripheral nerves in patients with DPN is another relatively new therapy.
"Decompression surgery relieves pain and restores sensation in patients with symptomatic diabetic neuropathy," explains A. Lee Dellon, MD, professor of plastic surgery and neurosurgery at Johns Hopkins University, who developed the surgery. "Currently, no medication is available for the symptoms of sensory loss—they all treat pain."
In a retrospective analysis of 50 patients 4.5 years after they had undergone surgical decompression of the tibial and peroneal nerves, no ulcers or amputations had occurred.9 In presenting this data, researchers emphasize that, typically, 15% of patients with DPN eventually will experience ulceration and/or amputation.
Dellon says decompression surgery is a viable option for candidates who meet these stringent criteria: "someone whose blood sugar is under the best control it can be, who has failed medical treatment for pain, who weighs <300 lb, has no cardio or renal edema, [has] adequate circulation to heal, and a palpable pulse or ankle or brachial index >0.75."
Some remain skeptical. "Any surgery is a potential disaster for these patients," Gibbons says. "Many have impaired wound healing, and any surgical complications can have severe implications." He advocates surgical procedures for DPN patients "only when they're absolutely necessary." According to Gibbons, this includes patients with clearly identified local areas of compression. In these instances, he says, "Surgery can be a terrific improvement."
Although options to reverse nerve damage are limited, hope runs high for future treatments to protect against nerve damage.
"There are a number of medications in the pipeline for nerve
protection, and they may be available in the next few years," Gibbons
says. "Nerve protection is going to be the next phase of treatment. For
now, we are limited to pain relief. Hopefully we'll soon be able to prevent
the progression of the disease." 
How to Talk to Patients About DPN
Convincing patients to participate in managing their diabetic peripheral neuropathy (DPN) is critical to control. Some advice from the experts:
Determine the correct dosage of information. "You can really overload [patients] on that first visit. I try to break it down into the most important things," says Cheryl Hodgins, RN, NP, CDE, a nurse educator with Harbor Hospital Diabetes Center in Baltimore, Md.
"Explain what the damage is, and what it means," says Andrew Boulton, MD, professor of medicine at University of Manchester, U.K., and the University of Miami. If patients understand that the condition may result in a loss of sensation in their feet, they may be more apt to take the recommended precautions.
Use terms the patient understands. Boulton tells patients the nerve damage caused by DPN is "like a lightbulb, and some of the wires are frayed."
Make sure the patient knows that maintaining consistent glycemic control is critical to managing DPN. Patients who are motivated by scientific data can be told that neuropathic symptoms improve by avoiding extreme fluctuations in blood glucose.1
Drive home the importance of inspecting feet daily and general foot care. "I tell [patients] that if they see any changes in their feet, they should notify their doctor immediately and insist they be seen," Hodgins says. "I tell them, `Be assertive. Don't take no for an answer.'"
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References
2. Nathan DM: Some answers, more controversy, from UKPDS: U.K. Prospective Diabetes Study. Lancet 12: 832–833, 1998.
3. American Diabetes Association: Standards of medical care in
diabetes—2006 (Position Statement). Diabetes
Care 29 (Suppl. 1):S4
–S42, 2006.
4. Periquet MI, Novak V, Collins MP, et al.: Painful sensory
neuropathy: Prospective evaluation using skin biopsy.
Neurology 53:1641–1647, 1999.
5. Goldstein DJ, Lu Y, Detke MJ, et al.: Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 116: 109–118, 2005.[Medline]
6. Freynhagen R, Strojek K, Griesing T, et al.: Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain 115:254–263, 2005.[Medline]
7. Frampton J, Scott L: Pregabalin: In the treatment of painful diabetic peripheral neuropathy. Drugs 64: 2813–2820, 2004.[Medline]
8. Leonard DR, Farooqi MH, Myers S: Restoration of sensation, reduced
pain, and improved balance in subjects with diabetic peripheral neuropathy: A
double-blind, randomized, placebo-controlled study with monochromatic
near-infrared treatment. Diabetes Care 27: 168–172, 2004.
9. Aszmann O, Tassler PL, Dellon AL: Changing the natural history of diabetic neuropathy: Incidence of ulcer/amputation in the contralateral limb of patients with a unilateral nerve decompression procedure. Ann Plast Surg 53:517–522, 2004.[Medline]
1. Boulton AJ, Vinik AI, Arezzo JC, et al.: Diabetic neuropathies: A
statement by the American Diabetes Association. Diabetes
Care 28:956–962, 2005.
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