This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Dannemiller Memorial Educational Foundation and MatureHealth Communications.  The Dannemiller Memorial Educational Foundation is accredited by the ACCME to provide continuing medical education for physicians.

The Dannemiller Memorial Educational Foundation designates this educational activity for up to 1 hour in category 1 credit towards the AMA Physician’s Recognition Award.  Each physician should claim only those hours of credit that he/she actually spent in the educational activity.

This program has been reviewed by Bernard M. Abrams, MD, Clinical Professor of Neurology, University of Missouri at Kansas City School of Medicine, Kansas City, Missouri. The Dannemiller Memorial Educational Foundation requires that the faculty participating in a continuing medical education activity disclose to participants any significant financial interest or other relationship (1) with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in an educational presentation, and (2) with any commercial supporters of the activity.  Dr. Bernard M. Abrams reported that he is the editor of "Progress in Neurology," which is sponsored by the Dannemiller Memorial Educational Foundation through an educational grant provided by Pfizer.

Rutgers, the State University of New Jersey, is approved by the American Council on Pharmaceutical Education (ACPE) as a provider of continuing education and complies with the criteria for continuing pharmaceutical education programming.  Pharmacists who successfully complete this program will receive 1.0 contact hour (0.10 CEU) of continuing education credit. “Management of Diabetic Complications:  A Focus on Diabetic Neuropathy (program number 038-999-00-052-H01)

The intended audience for this program is pharmacists, endocrinologists, and primary care physicians.

The program release date is October, 2000.  Please refer to the continuing education section of this internet activity for additional information.

Listed on this slide are the objectives of the program.

This program is approximately 1 hour in length.  A total of 35 slides are included.

Throughout this lecture, references will be made to diabetic neuropathy and its most common form, peripheral diabetic neuropathy (PDN).  Studies mentioned in this presentation will refer to diabetic neuropathy or to the specific forms of the disease.

The definition in the slide is the simplest day-to-day working definition for PDN.  It was first presented at a conference held in San Antonio, Texas, in February 1988 and is still being used today.  The conference was sponsored by the American Diabetes Association and American Academy of Neurology.  In attendance were experts in the fields of diabetes and neurology.¹

The inclusion of the word diabetes is important because approximately 10% of diabetic patients have neuropathies attributable to other causes, such as vitamin imbalances, hypothyroidism, and malnutrition.^2,3

Symptoms may or may not be present with diabetic neuropathy.  With the most common form of diabetic neuropathy, distal sensory polyneuropathy, or PDN, the patient generally presents with symptoms in the feet and hands.  These symptoms include decreased ability to feel hot or cold, burning sensations, shooting pains, numbness, and tingling.⁴

Diabetic neuropathy is not a single entity, but a group of disorders classified by the affected organ.  Several authors have proposed the scheme listed on the slide.  Others have proposed similar classifications.^5,6,7

Diffuse neuropathies can be located in many different organs, including the skin, bones, heart, and lungs.  Focal neuropathies occur within one specific organ system.^6,7

Distal symmetric sensorimotor polyneuropathy, more commonly referred to as peripheral diabetic neuropathy (PDN), is the most common type of diabetic neuropathy.  PDN starts in the long nerve fibers of the toes and fingertips.  Symptoms then move proximally into the legs, arms, and then trunk.  This can lead to alterations in normal sensations and predisposition to injury, ulceration, and chronic infection.⁶

Autonomic neuropathy is a common form of diffuse neuropathy, and is found in up to 40% of patients with insulin-dependent diabetes mellitus (IDDM).  The most common symptoms of autonomic neuropathy include patients with sexual dysfunction, diarrhea, bladder dysfunction, and loss of sweating in the feet.  Changes in heart rate and blood pressure may also be noted.^5,8

Symmetric proximal lower limb motor neuropathy is a syndrome prevalent in non-IDDM (NIDDM) patients between the ages of 50 and 60.  Significant weight loss and poor glucose control are associated with this syndrome.  Symptoms include severe leg pains, muscle atrophy, and leg weakness.^5,8

Focal neuropathies, also called mononeuropathies, may occur in the eye and result in vision loss.  This is due to effects on the cranial nerve that may result in oculomotor palsies. The cranial nerve controls most muscles that move the eye, including the pupil and the eyelid.  Other focal neuropathies involve the trunk and may result in chest or abdominal pain.  This type of neuropathy occurs most frequently in the elderly.  Focal lesions in peripheral nerves may result in carpal tunnel syndrome.  It should be noted that recovery is possible with many of these focal neuropathies if glycemic control is achieved.⁵

Diabetic neuropathy is a common complication of diabetes.  It is associated with a high rate of morbidity and can even be a complicating factor in some deaths.  With approximately 16 million people in the United States having diabetes and the prevalence of diabetic neuropathy over 60%, up to 10 million people have some form of diabetic neuropathy.^2,9

This lecture program presents information on the prevalence, diagnosis, management, and impact of diabetic neuropathy.

Diabetic neuropathy has been reported in more than 66% of patients with diabetes.²  The most commonly reported form of neuropathy is peripheral polyneuropathy, also called peripheral diabetic neuropathy.^2,4

Harris et al analyzed the 1989 National Health Interview Survey, which is a representative sample population in the United States.  Approximately 85,000 people were surveyed.  Of these, approximately 2,500 had diabetes-either IDDM or NIDDM.¹⁰

The study focused on peripheral neuropathy.  Patients with diabetes were asked if they noted any of the following symptoms:

• Numbness or loss of feeling in their hands or feet
• A sense of hands or feet falling asleep
• Painful sensation in hands or feet
• Decreased ability to feel hot or cold

The slide notes that the prevalence of neuropathy increased with the duration of diabetes.  The prevalence was 29.0% and 31.1% for men and women, respectively, at 2 to 4 years after diagnosis, and increased to 45.7% and 53.2% for men and women, respectively, at > 19 years after diagnosis.¹⁰

Harris et al also noted, as shown in the slide, that the prevalence of peripheral neuropathy in both men and women over age 65 was higher in those with NIDDM compared to those without diabetes (non-DM).  The prevalence of peripheral neuropathy in men aged 65 to 74 years was approximately 35% in the NIDDM group versus 13% in the non-DM group.  In the NIDDM group, the prevalence was lower in men more than 75 years old, but was still higher in the NIDDM group than the non-DM group (28% versus 18%, respectively).  Within both age groups of men, prevalence of neuropathy symptoms among NIDDM subjects was often three to four times that of non-DM subjects.¹⁰

The overall prevalence was higher in women with NIDDM.  The incidence of peripheral neuropathy in women aged 65 to 74 years was approximately 37% in the NIDDM group versus 15% in the non-DM group.  The prevalence was much higher in NIDDM group of women more than 75 years old compared to the non-DM group (42% versus 15%, respectively).  In women, similarly to men, the prevalence of neuropathy symptoms in NIDDM subjects was three to four times that in non-DM subjects.⁴

Regarding nationality and race, there was a trend toward blacks and Mexican Americans having a higher prevalence of neuropathy, but this was not statistically significant.¹⁰

Does tight control of blood glucose reduce the prevalence of diabetes-related complications?  This was studied in the Diabetes Control and Complications Trial (DCCT), which compared intensive therapy regimens versus conventional therapy to reduce the complications of diabetes.¹¹  The intensive therapy group of 711 patients received insulin three or more times per day via injection or insulin pump.  The goal of therapy was a preprandial blood glucose concentration of 70-120 mg/dL.  Self-monitoring of blood glucose was performed at least four times per day, with insulin dosage adjusted accordingly.

The conventional therapy group of 730 patients received one or two insulin (mixed and rapid-acting) injections per day.  This group also utilized daily self-monitoring of urine or blood glucose, and education about diet and exercise.  Patients were also initially divided into two groups: primary prevention-those with no current diabetes-related complications, and secondary intervention-those with mild-to-moderate diabetes complications.¹¹

Both groups were monitored an average of 6.5 years for complications related to diabetes, including retinopathy and peripheral neuropathy.  Ninety-nine percent of patients, 1441, competed the study.  A statistically significant difference in glycosylated hemoglobin was maintained after baseline between intensive therapy and conventional therapy groups (P < 0.001).  Mean glucose concentrations were also significantly different, with the intensive therapy group averaging 155 ± 30 mg/dL versus the conventional therapy group averaging 231 ± 55 mg/dL (P < 0.001).  The diagnosis of peripheral neuropathy was based on physical exam and nerve conduction studies.¹¹

As the slide shows, assessment at 5 years found that intensive insulin therapy in the primary prevention group reduced the prevalence of peripheral neuropathies by 69%—3% in intensive treatment versus 10% in conventional treatment (P = 0.006). At 5 years in the secondary intervention group, intensive insulin therapy reduced the prevalence of peripheral neuropathies by 57%—7% in intensive treatment versus 16% in conventional treatment (P < 0.001).¹¹

Adherence to the intensive insulin regimen resulted in a substantial decrease in glycosylated hemoglobin. Statistical significance was noted (P < 0.001), with the goal of 6.05% or less achieved at least once during the study. Unfortunately, less than 5% maintained an average in this range.¹¹

The authors concluded that an intensive insulin regimen in patients with IDDM delays onset and slows progression and may have the ability to prevent peripheral neuropathy from developing. On the basis of these results, the authors recommended that most patients with IDDM be treated with an intensive insulin regimen with the goal of maintaining glycemic status in a safe range.¹¹

There are many risk factors associated with the development of diabetic neuropathy.

Patients with neuropathy had a longer duration of diagnosed diabetes, along with a greater need for insulin.  In addition, those with neuropathy had higher glucose levels and reduced blood sugar control.  Within this group, those reported to have glycosuria were more than two times as likely to have neuropathy compared to those never reporting glycosuria.¹⁰

The duration of diabetes was a critical factor.  Patients having diabetes (glucose levels measured in blood and urine) for longer than 20 years were more than twice as likely to have neuropathy versus those with diabetes of 0 to 4 years duration.¹²

A medical history of cardiovascular disease increased the risk of neuropathy.  The diagnosis of hypertension was associated with a greater likelihood of symptoms of neuropathy compared to those without hypertension.^5,12

It is still questionable if common risk factors of diabetes, such as age, smoking, and obesity, are also risk factors for the development of diabetic neuropathies.  Harris et al noted no correlation with these risk factors, but Maser et al did note a correlation with smoking, age, and lower high-density cholesterol levels.^5,12

Increased blood glucose levels have dramatic effects throughout the body.¹¹ Research at the cellular level has shown that glucose is converted to sorbitol within the cell.  The increase in sorbitol results in decreased intracellular myo-inositol.^13,14  A reduction in myo-inositol inhibits ionic activity within the cell, resulting in a slowing of nerve conduction.¹⁵

Changes in the sorbitol pathway lead to reduced energy stores in the cell.  This produces oxidative stress, which produces vascular changes and reduced perfusion.^5,16

It is also theorized that high glucose levels, and subsequent conversion to sorbitol, may alter nerve cell proteins and deplete stores of necessary nutrients within the cell.  This makes the cell more vulnerable to damage and injury.⁵

As with most complications related to diabetes, insulin deficiency and hyperglycemia appear to initiate progression of diabetic neuropathy.

It is proposed that an abnormal vasa nervosum will cause local ischemia and poor nerve function.  In addition, insulin deficiency and hyperglycemia appear to result in increased glucose metabolism and increased aldose reductase activity.  This activity competes with nitric oxide synthetase for NADPH, which results in decreased nitric oxide and reduced blood flow.¹⁷

There also appears to be increased activity of the polyol pathway and decreased nerve myo-inositol.  This results in decreased nerve conduction.  myo-inositol is also decreased intracellularly through competitive inhibition with glucose, which results in decreased Na+-K+-ATPase activity and a reduction in nerve conduction.¹⁷

Hyperglycemia may also result in glycosylated neuronal proteins.  These proteins can cross-link, become dysfunctional, and slow axonal transport.¹⁷

Clinical studies have shown that the metabolism of linoleic acid is also altered.  This produces changes in prostaglandin metabolism and direct and indirect nerve ischemia.¹⁷

A last hypothesis is that neural antibodies are formed during diabetes.  These neural antibodies impair nerve integrity and function.¹⁷

Recently it has been noted that insulin resistance, not insulin deficiency, may have a role in development of peripheral neuropathy.  Lee and Dellon noted a group of eight patients that presented with peripheral neuropathy.  These patients had tightly controlled glucose (average 100.5 mg/dL), but were noted to have elevated fasting insulin levels (average 39.2 µU/mL).    The authors noted that there appears to be an association among insulin resistance, compensatory hyperinsulinism, and peripheral neuropathy.¹⁸

In summary, the major PDN-induced changes that appear to be taking place are alterations in nerve conduction and vascular structure.  These may lead to reversible and irreversible cellular changes.  Current research is focused on stopping or slowing those with pathophysiological changes.

Time may be the confounding factor in determining if complications are reversible or irreversible.  Pfeiffer and Schumer hypothesize that neuronal damage can be divided into metabolic and structural components.  The metabolic component, which is present during the early stages of neuropathy, is reversible with glucose control.  The structural component occurs later during disease progression and is generally permanent.  This is supported in trials that have taken place with neurotropic factors and pancreatic transplant.  In these studies, normalization of glucose has not completely reversed symptoms of neuropathy.¹⁷  This is also supported in the DCCT study, in which the greatest chance of reversing or limiting neuropathy occurred within the first year of treatment-when the greatest component of neuropathy was the metabolic component.¹¹

This slide lists the major symptoms of PDN; all symptoms are related to nerve damage.  It is common for these symptoms to be exacerbated at night.⁶

Because this is a disease of the periphery, the major symptoms are noted in the feet and hands.  These symptoms are initially mild, but can eventually become disabling.  The loss of sensation is particularly important because injuries may occur that are not noticed.  This results in a lack of treatment, leading to infections and amputations.^6,10,19

Not all diabetic neuropathies are easy to diagnose.  The disease may be subclinical, with the absence of abnormal clinical symptoms, but detectable by laboratory testing.  Some diabetics may also present with a neuropathic syndrome similar to peripheral neuropathy, such as cranial nerve problems.  Symptoms may also be similar to nondiabetic peripheral disease, such as nutritional illnesses, cancer, and collagen diseases.  In these situations, a thorough neurological exam should be conducted to rule out diabetic neuropathy.²⁰

Other symptoms and types of neuropathy may also be present.  Common symptoms related to other diffuse and focal neuropathies include severe localized pain in muscles such as the lower back or pelvis; chest pain; inability to focus; paralysis in the face; and hearing problems.  These kinds of symptoms are unpredictable and are often present in older people who have mild diabetes.^6,10

It is very important for the healthcare provider to frequently assess the patient with diabetes for signs and symptoms of neuropathy.  There are several methods used to determine the presence of neuropathy and the extent of severity.

Benow et al looked at the quality of life (QOL) associated with diabetic pain.²¹  Seventy-nine IDDM and NIDDM patients and 37 nondiabetic controls were assessed using the Nottingham Health Profile (NHP).  The NHP looks at six domains related to quality of life: emotional reaction, energy, pain, physical mobility, social isolation, and sleep.  Symptomatic pain was present in 41 diabetic patients. As noted in the above graphic, patients with neuropathic pain had significantly higher impairment scores in 5 of 6 NHP domains (the exception being social isolation) when compared to those without pain or diabetes.

Diabetes alone affects QOL.  The patient with diabetes but without pain also noted a significantly higher range of scores in four of six NHP domains compared to those without diabetes (energy, pain, physical mobility, and sleep).²¹

No significant relationships were noted among duration of either diabetes or pain, metabolic control (glycosylated hemoglobin), or body mass.

Benow et al stated that this study demonstrated that painful diabetic neuropathy has a considerable impact on QOL.²¹

Several tests for determining the presence and severity of neuropathy can be easily performed in the physician’s office or in a long-term care facility.

The first step in determining the presence of neuropathies is to assess symptoms. Preventing progression and complications is key to management.  It is important to remember that peripheral neuropathy is usually not detected until the patient complains of problems.

Several diagnostic neurological tests are available.  One of the most sensitive is the Neuropathy Impairment Score of the Lower Limbs plus Seven test (NIS-LL+7), which was validated by the Rochester Diabetic Neuropathy Study.  This test evaluates muscle weakness, reflexes, touch pressure, vibration detection, joint position sense, and sensation of a pin prick on the big toe.  Dyck et al. noted that only 10% of patients with a positive assessment by NIS-LL+7 complained of neuropathy symptoms.^5,20,22

Physical assessment can be done with simple tools.  A 10-g monofilament or pin employed at multiple sites in commonly affected areas such as the feet determines the level of sensitivity.  It should be noted that a positive test is likely to show advanced neuropathy.  This test lacks uniformity because different body sites may result in different sensitivities.  However, it is a simple, rapid, and inexpensive way to screen for neuropathy.²³

In vibration perception threshold testing, a handheld device that vibrates at a high frequency is held on the big toe to evaluate perception of vibration.  Multiple readings are taken to reduce errors.²³

Nerve conduction studies and biopsy tests can also detect neuropathies. Advantages of these tests include a high level of sensitivity and reproducibility. Unfortunately, the results of these tests do not correlate well with the severity of neuropathy. These tests measure effect on large nerves, not on the small nerves that may be producing the symptoms.

The exact indications for peripheral nerve biopsy have not been defined. Studies report that biopsy is useful only 50% of the time. Because of this, other options should be tried first. Currently, peripheral nerve biopsy is usually reserved for clinical research purposes.^20,24

Diabetes may cause damage in large and small nerve fibers. Generally, the lower limbs are first affected, with symptoms of pain and sensitivity noted.

There are a number of other diseases that may produce neuropathy; some of the more common ones are listed on this slide.  Diabetes as the cause of neuropathy is usually diagnosed by exclusion of other causes.  Differential diagnosis should include hereditary sensory neuropathies, vitamin deficiencies, syphilis, Lyme disease, and other autoimmune diseases.  In many situations, patients may have multiple sources of neuropathy.  It is important that a full assessment be performed to determine the likely underlying source of neuropathy.²⁵

Feldman et al combined the use of a questionnaire, the Michigan Neuropathy Screening Instrument (MNSI), along with the Michigan Diabetic Neuropathy Score (MDNS) to determine the diagnosis and extent of neuropathy.²⁴

The MNSI, which is shown on the slide, is designed to screen large numbers of patients for diabetic neuropathy in a routine clinical setting.  This questionnaire consists of 15 “yes” or “no” questions on foot sensation and other common PDN symptoms.  A physician, nurse, or other healthcare professional can administer this test.  In addition, a brief clinical exam should be performed to check for foot deformities, vibration sensation, and ankle reflexes.  If a patient screened positive with this questionnaire and exam, they were referred for administration of the MDNS.

The MDNS consists of a neurological exam and nerve conduction studies.  Its purpose is to diagnose and stage the extent of neuropathy.  The neurological exam can be performed by a primary care physician, and utilizes a tuning fork, pin, and 10-g filament.  This exam includes vibration testing and autonomic function tests. A nerve conduction study may also be required.  After all testing is complete, the patient is given a score and classification which can range from asymptomatic to disabling neuropathy.

The MNSI questionnaire showed high accuracy and sensitivity in predicting those patients with diabetic neuropathy.  In patients with a positive MNSI, a thorough neurological evaluation should take place.  The authors concluded that the MNSI is a simple and effective method to screen for diabetic neuropathy when time and resources are limited.  MDNS should be used to diagnose and define the extent of diabetic neuropathy.²⁴

There are several strategies that can be followed to reduce the prevalence and progression of PDN.  In early stages of disease, tight glucose control may be most effective in reducing progression.^4,11  Therefore when peripheral neuropathy is first noted, preventing disease progression and complications is key!

Diabetic patients need to understand the risks related to diabetes and how to self-care.

Drug therapy should be reserved as a last-line treatment if lifestyle adjustment, diet, and nutritional support are ineffective.⁵  Each of these options will be discussed in greater detail later in the presentation.

More than 15% of all diabetics will at some time develop a foot ulcer.  Approximately six out of every 1,000 diabetics will eventually require an amputation.  It is estimated that more than 75% of all amputations are caused by neuropathies and poor circulation.²⁶  The goal of treatment is to prevent ulcers and related complications.

It is imperative that feet get frequently checked by the caregiver and healthcare provider.

Listed on this slide is a series of “helpful hints” to prevent foot problems.  Compliance with these rules can be overseen by a designated healthcare provider within the long-term care facility, or by a family member or friend in the independent living setting.

It is also suggested that a physician or podiatrist be consulted periodically to perform an overall assessment of the condition of the diabetic’s feet.

Nutritionals may have clinical value in the prevention and management of PDN.  One proposed mechanism of diabetic neuropathy is through the blocking of essential fatty acids conversion.  This fatty acid deficiency results in a deficiency in prostacyclin and prostaglandin.  These two molecules have vasoprotective effects.  By blocking these effects, there is a reduction in red blood cells and oxygen transport, capillary generation, and nerve growth.

Several nutritional products are currently available that may produce vasoprotective effects.  One such product is gamma-linolenic acid (GLA).  GLA is the essential fatty acid required for production of prostacyclin and prostaglandin.  A recent multicenter, double-blind trial using GLA for 1 year showed significant improvement in blood flow.²⁷

Carnitine is an amino acid that may be useful in repairing neuron damage.  It appears to be effectve in reducing symptoms, however early clinical trials have not been encouraging.^25,28

It is important to remind healthcare providers that although these products are available “over-the-counter,” they can produce drug interactions and side effects.  Healthcare providers may need to discuss with patients the use of these agents as part of disease management.

No drugs currently marketed in the United States are FDA approved to prevent or stop the progression of diabetic PDN.  Agents are currently used to improve nerve function or alleviate symptoms, including pain.

Kingery identified and analyzed more than 66 controlled clinical trials on drugs used for the management of PDN.²⁹  The agents listed in the slide are the most common agents that have been studied.  The next section of the lecture will go into greater detail on some of the most commonly used agents in practice today.

There appears to be a lack of effective agents for pain control in PDN.  Kingery noted that in a survey of 188 physicians, only a minority rated pain relief properties of existing agents as good or excellent.²⁹ The percentage of physicians rating the following agents as good or excellent in pain relief were:

Antidepressants-40%
Anticonvulsants-35%
Opiates-30%
Simple analgesics-18%

Based on these findings, newer agents that show effectiveness in pain relief would be a valuable addition to the armamentarium of PDN care.

For relief of pain, tingling, and burning, NSAIDs may be recommended.  These agents are used in short courses to relieve the exacerbations of neuropathy.

Clinical trials have shown mixed results for the effectiveness of selected agents, such as ibuprofen 600 mg QID and sulindac 200 mg BID, in relieving the pain of neuropathy.  These studies reported effectiveness for up to 8 weeks.³⁰  Piroxicam 20 mg per day, however, was shown to be ineffective in a clinical trial.³¹

It is important to remember that NSAIDs have significant side effects that include gastrointestinal bleeding and nephrotoxicity.  These side effects are more prevalent in an older patient population.

It is important that any patient started on NSAIDs for PDN be closely monitored for complications.

Morphine or codeine products can be used in small amounts (e.g., oxycodone 5 to 10 mg every 4 hours).  These agents are not recommended for chronic use in patients with a history of chemical dependence.^28,32  Anticholinergic side effects such as constipation and dry mouth are also common with opiate usage.

Tramadol is an analgesic drug that appears to have low incidence of long-term tolerance and dependence and a low abuse liability.  Two studies reported the drug to be effective in reducing the pain associated with PDN.  In these studies, almost 80% of patients preferred tramadol to placebo for relief of pain.³³

Antidepressants have been used for many years to manage neuropathic pain. McQuay et al performed a meta-analysis on studies published in recent years.³⁴  The analysis reviewed the effectiveness and safety of antidepressants in neuropathic pain.  Drugs analyzed included the tricyclic antidepressants (TCAs)-amitriptyline, imipramine, and desipramine-and the selective serotonin-reuptake inhibitors (SSRIs)-paroxetine and fluoxetine.  A total of 21 placebo-controlled treatments in 17 randomized controlled trials were included involving 10 antidepressants.  It has been noted by several authors that the newer SSRIs appear to be less effective than TCAs in managing diabetic neuropathy.³⁵

The TCAs were effective in reducing pain by more than 50% in 30 out of 100 patients.  There was no difference noted among the TCAs.³⁵  The effect on neuropathy relief does not appear to be correlated with antidepressant effects. Adverse effects varied greatly, with 6% to 86% of patients reporting minor adverse effects.  Drug-related withdrawals were noted in 8% of patients on TCAs.  The incidence appears to be lower in patients receiving SSRIs.³⁵

Dosing of a TCA should be started very low, such as nortriptyline or amitriptyline 10 mg or 25 mg at bedtime.⁵  The dose is then increased to effect or adverse reaction.  It is very important that anticholinergic side effects, such as urinary retention, dry eye, dry mouth, orthostatic hypotension, and arrhythmias, be monitored-this is especially true in an older patient population.

Phenytoin and carbamazepine have been studied in the treatment of neuropathy.  Doses of phenytoin used were 100 mg administered three or four times per day; carbamazepine was administered at 600 to 1000 mg per day.^36,37  Both drugs were effective in producing pain relief and reducing paresthesias.  The level of effectiveness was not correlated with drug concentrations.

Unfortunately, there is a high incidence of adverse effects with these drugs.  Ataxia, blurred vision, dizziness, rash, nausea, and vomiting were noted in clinical studies.^36,37

Topiramate has been studied in doses up to 400 mg per day or maximum tolerated dose.  Topiramate was found to reduce diabetic neuropathic pain compared to placebo when the Short-Form McGill Pain Questionnaire and visual analog scale were used (P = 0.039 and P = 0.007, respectively).  Topiramate was generally well tolerated, with fatigue and dry mouth being the most common adverse reactions.³⁸

A newer agent, gabapentin, appears to be efficacious, with a much lower incidence of adverse effects.  Starting dosage for gabapentin is generally 300 mg per day, with the dosage increased up to a range of 2400 to 3600 mg per day.^5,39,40

Gabapentin, which is related to GABA, a neurotransmitter that plays a role in pain transmission and modulation, has been studied in the management of neuropathy.  Because of its low adverse reaction profile, gabapentin may be a promising candidate for management of diabetic neuropathy.⁴⁰

Backonja et al studied gabapentin 900 mg to 3600 mg per day versus placebo for the management of diabetic neuropathy pain.  The study was conducted over an 8-week period-4 weeks of dose titration and a 4-week fixed-dose period.  Gabapentin dosage was initiated at 900 mg per day and titrated up to 3600 mg per day or tolerability.

Pain was measured using four different pain scales or questionnaires. Quality of Life (QOL) was also measured using the Profile of Mood States (POMS) and Short Form-36 Quality of Life Questionnaire (SF-36 QOL).

This slide shows that gabapentin significantly reduced pain compared to placebo (P < 0.05) for all 8 weeks of the study.  At the end of 8 weeks, 26% of patients on gabapentin and 15% of those on placebo gave a rating of no pain (P = 0.001).  Sixty percent of gabapentin versus 33% of placebo patients had moderate improvement in pain reduction.⁴⁰

QOL from the patient’s perspective was evaluated using the Patient Global Impression of Change (PGIC) scale in pain and sleep.  The healthcare provider also monitored changes in QOL with the use of the Clinical Global Impression of Change (CGIC) scale in pain and sleep.⁴⁰

As the slide shows, there was a statistically significant difference in the improvement of patient’s overall status since the beginning of the study with the gabapentin group (P = 0.001).  Gabapentin was noted to have a positive (lowering) effect on scores for anger/hostility (P = 0.02), vigor/activity (P = 0.01), and total mood (P = 0.03).⁴¹

A total of seven patients in the gabapentin group (8%) withdrew from the study because of a total of 13 adverse effects.  This was greater than the five patients (6%) who withdrew due to eight adverse events reported in the placebo group.  Adverse effects reported more frequently in the gabapentin group included dizziness, somnolence, and confusion.⁴⁰

The authors concluded that gabapentin appears to be efficacious as monotherapy in reducing pain and improving sleep in those with pain related to diabetic neuropathy.  In addition, gabapentin had positive effects on mood and QOL.⁴⁰

Morello et al compared the efficacy and safety of the current “standard” TCA for the management of diabetic neuropathic pain, amitriptyline, with gabapentin.  In this double-blind study, a total of 25 patients were initially enrolled, with 21 patients completing both study drugs at dosages of: gabapentin 900 to 1800 mg per day and amitriptyline 25 to 75 mg per day.  Patients were initiated on one of the two drugs and the dose was titrated up until a maximum dose was achieved or until pain relief.  After 6 weeks on a medication, a 1-week washout was done, then the patient was switched to the other drug.  To preserve the double blind, placebo was used to maintain TID dosing.⁴¹

Pain was measured using the Pain Scale Rating System and Global Rating Scale.  Patients completed a daily pain diary in which they could choose 13 words to describe pain intensity.  The researcher asked patients to make a global rating of overall pain relief at the end of each treatment arm.⁴¹

This slide shows that in both treatment groups, pain scores steadily declined with the use of both agents, with pain returning during the washout period.  There was a statistically significant difference in pain score reduction in patients treated with gabapentin (P < 0.001) and amitriptyline (P < 0.001) compared to baseline.  Mean score diary analysis showed pain relief between gabapentin and amitriptyline was not statistically different (P = 0.26).  Moderate or greater pain relief was experienced in 11 of 21 (52%) of gabapentin patients and 14 of 21 (67%) amitriptyline patients.⁴¹

Seventeen patients in the amitriptyline group and 18 patients receiving gabapentin experienced adverse reactions.  There was no statistical difference between the two groups for adverse reactions.⁴¹

The authors concluded that both gabapentin and amitriptyline appear to be effective in providing pain relief in PDN.⁴¹

Two agents that have been studied for the management of diabetic neuropathy are mexiletine and capsaicin.

Mexiletine, a derivative of lidocaine, is an antiarrhythmic agent that has been studied in small populations for the management of diabetic neuropathy.^42,43  Oskarsson studied 126 patients using dosages of 225 to 675 mg per day of mexiletine over a 21-day period.⁴²

The study noted a significant reduction in pain (P = 0.029) and sleep disturbances (P = 0.046) at the mexiletine 675 mg dose versus placebo.  Dosages less than 675 mg per day showed no statistical significance.  No deaths or serious adverse effects were reported.  Minor adverse effects, such as dizziness, diarrhea, and tiredness, were noted in several patients at various dosages.  The authors postulate that the mechanism of action for mexiletine is similar to that of lidocaine, which inhibits spontaneous activity of regenerating nerve fibers.⁴²

Capsaicin is a topical agent approved for the treatment of neuralgia.  The Capsaicin Study Group looked at the use of capsaicin cream 0.075% administered four times a day to the affected area over an 8-week period.  A vehicle cream was used as placebo.  Two hundred and seventy-seven patients were entered, with 219 completing the study.⁴⁴

Patients in the capsaicin 0.075% group showed a statistically significant improvement in pain status (P = 0.012), ability to work (P = 0.019), ability to sleep (P = 0.036), ability to walk (P = 0.029), and participation in recreational activities (P = 0.037) at up to 8 weeks.⁴⁴

A high number of adverse events was noted in the capsaicin 0.075% group, including a higher incidence of burning at the site.  This was reported in 63% of the capsaicin group versus 17% in the placebo group.  Eighteen patients in the capsaicin 0.075% group withdrew from the study due to side effects.  A small number of patients also appeared to have a problem with medication compliance. It should also be noted that this agent may take several weeks to show efficacy.  The authors concluded that capsaicin 0.075% appears to be effective in the management of pain related to diabetic neuropathy.⁴⁴

Transcutaneous electrical nerve stimulation (TENS) has been used for several years in the management of general chronic pain.  There have been conflicting results on the effectiveness of TENS in management of PDN.  Wunderlich reported the effective use of nocturnal stimulation with TENS to manage diabetic neuropathy.  The adverse effects noted with pharmacologic therapy were not noted with the TENS system.⁴⁵

Aldose reductase inhibitors block the conversion of glucose to sorbitol, thereby increasing myo-inositol within the cell and blocking nerve cell damage.  Unfortunately, clinical trials to date have not shown these agents to be effective in reducing neuropathy.⁴⁶  As a result, there have been no aldose reductase agents approved in the United States.  Several, though, are currently in development.

Another approach to increasing myo-inositol levels is through direct administration. myo-inositol supplements appear to improve neuropathy, but a treatment period of more than 6 months may be required to demonstrate significant effects.¹⁶

In diabetes, the metabolism of linolenic acid is impaired, which affects blood and nerve cell growth.  Several studies have noted clinical and electrophysiologic improvement in peripheral nerve function with exogenous administration of linolenic acid.²⁷  Studies that combine linolenic acid and existing therapies are ongoing.

Mixed results have been noted with dextramethorphan.  It appears that the drug’s effectiveness is related to the dose administered.  A recent study reported that in diabetic patients, there was no difference between good and poor responders with respect to pain.³³

In preclinical studies, nerve growth factors/neuropeptides have been shown to protect neurons from injury; they may also regenerate nerves.⁴⁷  Unfortunately, results from recent clinical trials failed to show significant improvement in diabetic neuropathy.  A final determination on the role of nerve growth factors/neuropeptides in the management of diabetic neuropathy is still to be determined.

Using the information presented in this lecture kit, a diagnosis and treatment algorithm can be proposed.  This algorithm is presented over the next three slides.

The first step is to diagnose PDN and rule out other precipitating factors.  A neuropathy screening instrument, such as the MNSI, is a simple, easy-to-use tool that can be used in the clinical setting.  Use of a foot inspection and screening instrument such as a vibration test is essential.  A nerve-conduction test may be required, but should be reserved if other diagnostic tests are unsuccessful.

Upon diagnosis of PDN, the first step, as per the DCCT study, is to control blood glucose.  This may require lifestyle or diet changes, or drug therapy.  It is essential that the underlying condition, diabetes, be treated.

If controlling the underlying diabetes is ineffective in reducing symptoms, pharmacologic therapy would be the next step.  A first choice would be topical therapy because of its lack of systemic effects and potential for complications.  Initiation of capsaicin 0.075% four times a day has shown effectiveness in reducing the symptoms of PDN.

Unfortunately, capsaicin may not be effective or may produce intolerable side effects.  Should this occur, a logical next step would be systemic drug therapy.

With initiation of systemic drug therapy, it is important to look at a patient’s underlying conditions.  TCAs would be the agents of choice, but because these agents have anticholinergic and proarrhythmic side effects, they should not be used in those patients with benign prostatic hypertrophy, heart disease, urinary retention, or glaucoma.  If a TCA is used, treatment should be initiated at a very low dose.  This dose should be given at bedtime to reduce side effects.

If a TCA is contraindicated, gabapentin would be the agent of choice.  Gabapentin should be initiated at 300 mg and titrated up to response.

Should a TCA or gabapentin not be effective, NSAIDs, antiepileptics, or mexiletine would be the next choice.  The agent selected should be based on an underlying history of gastrointestinal (GI) bleeding or ulcers; a history of GI bleeding or ulcers precludes use of an NSAID.

NSAIDs that have been effective in treating PDN include ibuprofen and sulindac.

If an antiepileptic agent is initiated, as previously stated, gabapentin is the first choice.  Phenytoin, carbamazepine, and topiramate have also been shown to be effective, but have a higher incidence of adverse effects compared to gabapentin.

Mexiletine has shown effectiveness in controlling the symptoms of PDN and should be tried only after other agents have failed.  Mexiletine is an antiarrhythmic and can produce serious and lethal side effects if not monitored closely. Another option includes combination therapy until effectiveness is reached or side effects are produced.

If these agents prove ineffective, the patient should be reevaluated for other conditions that may be mimick PDN.

It is essential that diabetic patients be monitored for neuropathy.  Symptoms are most common at night, therefore, patients who complain of pain at night or have difficulty in sleeping should be assessed for neuropathy.

Prevention is key to reducing complications.  The DCCT study showed that controlling glucose is the first step in prevention and management of diabetic neuropathy.  If intensive monitoring is not feasible, close monitoring should be attempted.  Lifestyle and nonpharmacologic care (i.e., foot care) are essential to slowing the progression of PDN.

No drugs are currently approved for the management of PDN, but several agents used for other disease states have been studied, including gabapentin, capsaicin, and tricyclic antidepressants.  These agents have been shown to relieve pain, but do not stop the progression of the disease.

Long-term monitoring is essential. Healthcare professionals caring for diabetic patients should monitor and track the prevalence and progression of PDN in all healthcare settings.

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