Back-to-basics approach to diabetic neuropathy can prevent, relieve painful symptoms

Diabetic neuropathy remains one of the most common chronic complications of both type 1 and type 2 diabetes. According to the National Institute of Neurological Disorders and Stroke, about 60% to 70% of people with diabetes have mild to severe forms of nervous system damage that can affect sensory, motor and autonomic nerves.

Diabetic neuropathy can present in any number of painful ways: a superficial burning pain; needle-like pain; sharp and stabbing pain; or an increased sensitivity to any stimulus, known as hyperalgesia, according to Aaron Vinik, MD, PhD, FCP, MACP, FACE, professor of medicine, pathology and neurobiology and director of the research and neuroendocrine unit at Eastern Virginia Medical School.

“People will also experience numbness of the feet, and people think that numbness means a loss of sensation, but it doesn’t,” Vinik told Endocrine Today.

Potentially more dangerous still, Vinik said, is the loss of sensory perception that often accompanies the condition, putting patients at risk for falls and, potentially, fractures.

Aaron Vinik

“It’s like the difficulty in telling the difference between the brake of a car and the accelerator,” Vinik said. “You’re not aware.”

Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable with specific measures, according to a position statement released in January by the American Diabetes Association. For clinicians, Vinik said, it is important to take a careful patient history — including all medications the patient is taking —and do a proper foot exam without shoes and socks on to assess symptoms.

“The problem here is that neuropathy is a spectrum,” Andrew J.M. Boulton, MD, DSc (Hon), FACP, FICP, FRCP, professor of medicine at the University of Manchester, U.K., told Endocrine Today. “Up to 50% of all patients with type 2 diabetes will have significant neuropathy and loss of sensation, putting them at risk for foot ulcers. At the other end of the spectrum, you have patients who have some sensation preserved, but they have severe neuropathic pain. This affects quality of life, disturbs sleep and is difficult to describe because it’s not the sort of pain that all of us experience, like a toothache or a fracture.”

Still, other patients report feeling fine, but they have lost “the gift of pain,” Boulton said, leading them to walk around on a fracture, for example, and not know it.

“Half of the patients with neuropathy may have never experienced any symptoms at all, apart from the foot feeling a bit numb, but it’s so gradual that most patients won’t complain because we’re a symptom-driven society,” Boulton said. “Then you’ve got the other half of patients who have symptoms ... but none of these symptoms alter the natural history of neuropathy, which is a progressive loss of nerve fibers.”

Screening decisions

According to the ADA, patients with type 1 diabetes for at least 5 years and all patients with type 2 diabetes should be assessed annually for distal symmetric polyneuropathy, or DSPN, using medical history and simple clinical tests, such as a temperature or pinprick sensation and vibration sensation using a 128-Hz tuning fork.

More intensive screening methods, such as nerve conduction testing or quantitative sensory testing, are often marketed heavily to patients in the U.S., but are usually unnecessary, according to Boulton. Still, he said, controversy surrounds the use of such tests and whether they may be useful for detecting preclinical neuropathy, when symptoms may not be evident to patients.

“The question is: Should we be screening earlier?” Boulton said. “My answer is: Screening is costly. You should only do screening if it’s going to alter your management.”

Boulton compared diabetic neuropathy to diabetic kidney disease, which can be detected in its earliest stages in a simple urine test showing, for example, proteinuria.

“We don’t have an early test. All we’ve got are expensive, time-consuming tests that may show when you’ve got very early sensory loss, but it’s not clinically significant,” he said.

“And the thing is, the only treatment we’ve got that will prevent the progression of neuropathy in its early phase is good glycemic control, good blood pressure control, and we should be doing that anyway,” Boulton said.

Glycemic control varies

The benefit of good glycemic control on diabetic neuropathy can vary depending on the type of diabetes and the progression of nerve damage.

In the January position statement, the ADA wrote that enhanced glucose control in people with type 1 diabetes can lead to a 78% RR reduction in incidence of DSPN, whereas tight control in type 2 diabetes leads to only a 5% to 9% RR reduction.

“This discrepancy highlights the differences between type 1 and type 2 diabetes and emphasizes the point that many people with type 2 diabetes develop DSPN despite adequate glucose control,” the researchers wrote.

“Once it’s established, in type 1 and type 2 diabetes, glycemic control doesn’t do a great deal to slow the progression or reverse neuropathy,” Vinik said. “Most of what is done is to manage the symptoms — I call it band-aid therapy. It doesn’t address the underlying issues.”

For many patients with diabetes struggling with neuropathic pain, Boulton said, the key may not be tight glucose control, but rather a steady glucose level without high and low excursions.

“Glycemic control probably does matter — not the level, but the stability,” he said. “People with diabetic neuropathic pain have more unstable control. Blood sugar swinging from high to low — and continuous glucose monitoring may help identify this — may worsen neuropathic pain.”

Boulton also cautioned against trying to optimize glucose management quickly and suddenly, noting the risk for worsening neuropathic pain or a condition known as insulin neuritis.

Management of symptoms, comorbidities

The pain associated with diabetic neuropathy presents in a way that is opposite from arthritic pain and ischemic limb pain, getting worse during the day and often keeping people awake at night, according to Vinik. Comorbidities, such as anxiety and depression, often accompany the pain symptoms, he said, and treating those issues can improve pain management.

The key is to make a proper diagnosis.

“People make a lot of mistakes with pain,” Vinik said. “For example, people think that the pain should get worse when you walk, and that’s not true. That type of pain is usually claudication, and it’s usually a vascular problem. Or, people think that if you have pain, you don’t need to know about its distribution, and that’s a mistake too, because the people who have entrapment, for example, like carpal tunnel, the pain is in the first three fingers, and that means you have another form of intervention as opposed to the gross neuropathic pain.”

Additionally, Vinik said, about 30% of people with diabetes will have some form of entrapment neuropathy.

“There is a cadre of things that masquerade as neuropathic pain, and so, people may apply the principles of managing neuropathy incorrectly to the condition that is a misdiagnosis on the part of the practitioner,” he said.

Despite advances in the understanding of the pathogenesis of diabetic neuropathy, there remains a lack of treatment options to target or reverse established neuropathy.

In its position statement, the ADA recommends pregabalin (Lyrica, Pfizer) or the antidepressant duloxetine as an initial approach to neuropathic pain in diabetes, although Boulton cautioned that many patients cannot tolerate the side effects of antidepressants, and drowsiness can be marked. Gabapentin may also be used as an initial approach, considering potential drug interactions.

The use of opioids, including tapentadol (Nucynta, Depomed) or tramadol, is not recommended as first- or second-line agents to treat pain associated with diabetic neuropathy.

“One of the things that is neglected in neuropathic pain is there are a cadre of people who have very bad pain ... that requires immunotherapy,” Vinik said. “It occurs in about 12% of people with diabetes. If you recognize it, it is easy to treat. If you don’t recognize it, you do all the wrong things.”

Risks of no pain

For patients with diabetic neuropathy, Vinik said, many risks come with a loss of the presence of pain, but clinicians must put the most important risks into perspective.

“A lot of people think that neuropathy is conducive to a foot ulcer, and a foot ulcer will go on to osteomyelitis and that contributes to the 96,000 amputations we have every year in the U.S. for diabetic neuropathy,” Vinik said. “But, if you think about the loss of peripheral sensation or protective sensation, which leads to the loss of position sense and the loss of balance and coordination, this is conducive to falls and fractures. That’s well over 96,000. We’re talking over 200,000 people a year, and 20% of those falls result in traumatic brain injury.”

Adults aged at least 65 years have a 1 in 3 chance of falling every year, Vinik noted, adding that the risk increases 15-fold in the older patient with diabetes.

“A major risk factor in falling is the presence of pain,” he said. “It distracts you. You don’t focus on what you need to do not to fall. There is a need to make people aware of this, and the protective things that you can do to reduce the rate of falling.” – by Regina Schaffer

Disclosures: Vinik reports he has financial ties with Impeto Medical Research, Intarcia, Ionis, NeuroMetrix, Novo Nordisk, Pamlab Pharmaceuticals, Pfizer, Sanofi-Aventis, VeroScience and ViroMed. Boulton reports he has received consulting or speaking fees from Eli Lilly, Pamlab and Pfizer; and has received grants for clinical research from Eli Lilly.

Diabetic neuropathy remains one of the most common chronic complications of both type 1 and type 2 diabetes. According to the National Institute of Neurological Disorders and Stroke, about 60% to 70% of people with diabetes have mild to severe forms of nervous system damage that can affect sensory, motor and autonomic nerves.

Diabetic neuropathy can present in any number of painful ways: a superficial burning pain; needle-like pain; sharp and stabbing pain; or an increased sensitivity to any stimulus, known as hyperalgesia, according to Aaron Vinik, MD, PhD, FCP, MACP, FACE, professor of medicine, pathology and neurobiology and director of the research and neuroendocrine unit at Eastern Virginia Medical School.

“People will also experience numbness of the feet, and people think that numbness means a loss of sensation, but it doesn’t,” Vinik told Endocrine Today.

Potentially more dangerous still, Vinik said, is the loss of sensory perception that often accompanies the condition, putting patients at risk for falls and, potentially, fractures.

Aaron Vinik

“It’s like the difficulty in telling the difference between the brake of a car and the accelerator,” Vinik said. “You’re not aware.”

Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable with specific measures, according to a position statement released in January by the American Diabetes Association. For clinicians, Vinik said, it is important to take a careful patient history — including all medications the patient is taking —and do a proper foot exam without shoes and socks on to assess symptoms.

“The problem here is that neuropathy is a spectrum,” Andrew J.M. Boulton, MD, DSc (Hon), FACP, FICP, FRCP, professor of medicine at the University of Manchester, U.K., told Endocrine Today. “Up to 50% of all patients with type 2 diabetes will have significant neuropathy and loss of sensation, putting them at risk for foot ulcers. At the other end of the spectrum, you have patients who have some sensation preserved, but they have severe neuropathic pain. This affects quality of life, disturbs sleep and is difficult to describe because it’s not the sort of pain that all of us experience, like a toothache or a fracture.”

Still, other patients report feeling fine, but they have lost “the gift of pain,” Boulton said, leading them to walk around on a fracture, for example, and not know it.

“Half of the patients with neuropathy may have never experienced any symptoms at all, apart from the foot feeling a bit numb, but it’s so gradual that most patients won’t complain because we’re a symptom-driven society,” Boulton said. “Then you’ve got the other half of patients who have symptoms ... but none of these symptoms alter the natural history of neuropathy, which is a progressive loss of nerve fibers.”

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Screening decisions

According to the ADA, patients with type 1 diabetes for at least 5 years and all patients with type 2 diabetes should be assessed annually for distal symmetric polyneuropathy, or DSPN, using medical history and simple clinical tests, such as a temperature or pinprick sensation and vibration sensation using a 128-Hz tuning fork.

More intensive screening methods, such as nerve conduction testing or quantitative sensory testing, are often marketed heavily to patients in the U.S., but are usually unnecessary, according to Boulton. Still, he said, controversy surrounds the use of such tests and whether they may be useful for detecting preclinical neuropathy, when symptoms may not be evident to patients.

“The question is: Should we be screening earlier?” Boulton said. “My answer is: Screening is costly. You should only do screening if it’s going to alter your management.”

Boulton compared diabetic neuropathy to diabetic kidney disease, which can be detected in its earliest stages in a simple urine test showing, for example, proteinuria.

“We don’t have an early test. All we’ve got are expensive, time-consuming tests that may show when you’ve got very early sensory loss, but it’s not clinically significant,” he said.

“And the thing is, the only treatment we’ve got that will prevent the progression of neuropathy in its early phase is good glycemic control, good blood pressure control, and we should be doing that anyway,” Boulton said.

Glycemic control varies

The benefit of good glycemic control on diabetic neuropathy can vary depending on the type of diabetes and the progression of nerve damage.

In the January position statement, the ADA wrote that enhanced glucose control in people with type 1 diabetes can lead to a 78% RR reduction in incidence of DSPN, whereas tight control in type 2 diabetes leads to only a 5% to 9% RR reduction.

“This discrepancy highlights the differences between type 1 and type 2 diabetes and emphasizes the point that many people with type 2 diabetes develop DSPN despite adequate glucose control,” the researchers wrote.

“Once it’s established, in type 1 and type 2 diabetes, glycemic control doesn’t do a great deal to slow the progression or reverse neuropathy,” Vinik said. “Most of what is done is to manage the symptoms — I call it band-aid therapy. It doesn’t address the underlying issues.”

For many patients with diabetes struggling with neuropathic pain, Boulton said, the key may not be tight glucose control, but rather a steady glucose level without high and low excursions.

PAGE BREAK

“Glycemic control probably does matter — not the level, but the stability,” he said. “People with diabetic neuropathic pain have more unstable control. Blood sugar swinging from high to low — and continuous glucose monitoring may help identify this — may worsen neuropathic pain.”

Boulton also cautioned against trying to optimize glucose management quickly and suddenly, noting the risk for worsening neuropathic pain or a condition known as insulin neuritis.

Management of symptoms, comorbidities

The pain associated with diabetic neuropathy presents in a way that is opposite from arthritic pain and ischemic limb pain, getting worse during the day and often keeping people awake at night, according to Vinik. Comorbidities, such as anxiety and depression, often accompany the pain symptoms, he said, and treating those issues can improve pain management.

The key is to make a proper diagnosis.

“People make a lot of mistakes with pain,” Vinik said. “For example, people think that the pain should get worse when you walk, and that’s not true. That type of pain is usually claudication, and it’s usually a vascular problem. Or, people think that if you have pain, you don’t need to know about its distribution, and that’s a mistake too, because the people who have entrapment, for example, like carpal tunnel, the pain is in the first three fingers, and that means you have another form of intervention as opposed to the gross neuropathic pain.”

Additionally, Vinik said, about 30% of people with diabetes will have some form of entrapment neuropathy.

“There is a cadre of things that masquerade as neuropathic pain, and so, people may apply the principles of managing neuropathy incorrectly to the condition that is a misdiagnosis on the part of the practitioner,” he said.

Despite advances in the understanding of the pathogenesis of diabetic neuropathy, there remains a lack of treatment options to target or reverse established neuropathy.

In its position statement, the ADA recommends pregabalin (Lyrica, Pfizer) or the antidepressant duloxetine as an initial approach to neuropathic pain in diabetes, although Boulton cautioned that many patients cannot tolerate the side effects of antidepressants, and drowsiness can be marked. Gabapentin may also be used as an initial approach, considering potential drug interactions.

The use of opioids, including tapentadol (Nucynta, Depomed) or tramadol, is not recommended as first- or second-line agents to treat pain associated with diabetic neuropathy.

“One of the things that is neglected in neuropathic pain is there are a cadre of people who have very bad pain ... that requires immunotherapy,” Vinik said. “It occurs in about 12% of people with diabetes. If you recognize it, it is easy to treat. If you don’t recognize it, you do all the wrong things.”

PAGE BREAK

Risks of no pain

For patients with diabetic neuropathy, Vinik said, many risks come with a loss of the presence of pain, but clinicians must put the most important risks into perspective.

“A lot of people think that neuropathy is conducive to a foot ulcer, and a foot ulcer will go on to osteomyelitis and that contributes to the 96,000 amputations we have every year in the U.S. for diabetic neuropathy,” Vinik said. “But, if you think about the loss of peripheral sensation or protective sensation, which leads to the loss of position sense and the loss of balance and coordination, this is conducive to falls and fractures. That’s well over 96,000. We’re talking over 200,000 people a year, and 20% of those falls result in traumatic brain injury.”

Adults aged at least 65 years have a 1 in 3 chance of falling every year, Vinik noted, adding that the risk increases 15-fold in the older patient with diabetes.

“A major risk factor in falling is the presence of pain,” he said. “It distracts you. You don’t focus on what you need to do not to fall. There is a need to make people aware of this, and the protective things that you can do to reduce the rate of falling.” – by Regina Schaffer

Disclosures: Vinik reports he has financial ties with Impeto Medical Research, Intarcia, Ionis, NeuroMetrix, Novo Nordisk, Pamlab Pharmaceuticals, Pfizer, Sanofi-Aventis, VeroScience and ViroMed. Boulton reports he has received consulting or speaking fees from Eli Lilly, Pamlab and Pfizer; and has received grants for clinical research from Eli Lilly.