The Management of Diabetic Neuropathy in CKD

Article Outline

• Case Presentation
• Introduction
• Epidemiology
• Pathogenesis
• Cardiac Autonomic Neuropathy
  • Clinical Manifestations
  • Evaluation
    • Evaluation of Heart Rate Variability
    • Evaluation Using Scintigraphic and Other Techniques
• Diabetic Peripheral Neuropathy
  • Clinical Manifestations
  • Lower-Limb Amputation
  • Evaluation
• Therapeutic Strategies
  • Therapies to Interrupt Pathogenic Mechanisms
  • Management of Cardiac Autonomic Neuropathy
    • Therapies for Sympathetic Hyperactivity
    • Therapies for Orthostatic Hypotension
    • Effects of Dialysis on Measures of Cardiac Autonomic Neuropathy
  • Management of Painful Diabetic Peripheral Neuropathy
    • Calcium Channel α2-δ Ligands
    • Tricylic and Tetracyclic Antidepressive Agents
    • Selective Serotonin Reuptake Inhibitors
    • Selective Serotonin-Norepinephrine Reuptake Inhibitors
    • Anticonvulsants
    • Opioids
    • Combination Treatment
    • Topical Agents
    • Nonpharmacologic Treatment of Neuropathic Pain
• Case Review
• Acknowledgements
• References
• Copyright

Index Words: Diabetes mellitus, peripheral neuropathy, autonomic neuropathy, chronic kidney disease, management

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Case Presentation 

A 64-year-old man with a 15-year history of poorly controlled type 2 diabetes and a 10-year history of hypertension and hyperlipidemia had developed multiple diabetes-related complications within the last 5 years. He first developed albuminuria 5 years ago, and during the next several years, he experienced a fairly rapid decrease in kidney function, with an estimated glomerular filtration rate of 55 mL/min/1.73 m² noted 2 years ago. Proliferative retinopathy was diagnosed 5 years ago, and he underwent laser photocoagulation. Four years ago, he noted symptoms of peripheral neuropathy manifested as shooting pain and numbness with loss of light touch, thermal, and vibratory sensation in a stocking distribution. Last year, he developed a nonhealing ulcer on the plantar aspect of his left foot that was complicated by gangrene and resulted in a below-the-knee amputation of the left leg 1 year ago. He now reports new onset of weakness, lightheadedness, and dizziness on standing that affects his daily activities. He reports lancinating pain in his right lower extremity, worse in the evening. Medications include neutral protamine Hagedorn insulin twice daily and regular insulin on a sliding scale; metoprolol, 50 mg/d; lisinopril, 40 mg/d; atorvastatin, 80 mg/d; furosemide, 40 mg/d; and aspirin, 81 mg/d. Blood pressure is 127/69 mm Hg with a pulse rate of 96 beats/min while supine and 94/50 mm Hg with a pulse rate of 102 beats/min while standing. Strength is normal, but with complete loss of all sensory modalities to the knee in his remaining limb and up to the wrists in both upper extremities, and he is areflexic. Today's laboratory evaluations show a serum creatinine level of 2.8 mg/dL, estimated glomerular filtration rate of 24 mL/min/1.73 m², hemoglobin A_1c level of 7.9%, and urine protein excretion of 2.1 g/1 g of creatinine. What would be the most appropriate management for this patient?

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Introduction 

Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) requiring renal replacement therapy in the United States.¹ Progression of diabetes to advanced stages of chronic kidney disease (CKD) is associated with the progression of multiple other micro- and macrovascular complications of diabetes, including diabetic neuropathies.² Diabetic peripheral neuropathy is a common complication of diabetes associated with high morbidity, poor quality of life, and high risk of lower-extremity amputation. Similarly, cardiac autonomic neuropathy is associated with life-threatening consequences, such as silent myocardial ischemia and high mortality.³, ⁴, ⁵

In this review, we examine the characteristics of cardiac autonomic neuropathy and diabetic peripheral neuropathy in diabetic patients with stages 4-5 CKD or ESRD undergoing dialysis. We describe the evidence supporting the available therapeutic options and the challenges associated with providing adequate care for these patients and discuss future directions for investigation.

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Epidemiology 

In patients with diabetes and CKD or ESRD on dialysis therapy, cardiovascular events represent the leading cause of mortality,⁶, ⁷, ⁸ with a high incidence of sudden cardiac death. A recent study of the National Institute of Diabetes and Digestive and Kidney Diseases reported an annual death rate of 230 deaths/1,000 patient-years for US dialysis patients in 2004.⁹ Forty-three percent of all-cause mortality in hemodialysis and peritoneal dialysis patients was secondary to cardiovascular disease, with ∼60% of cardiac deaths secondary to arrhythmic mechanisms.⁹, ¹⁰ Moreover, an association between compromised autonomic function and sudden cardiac death in patients awaiting kidney transplant has been reported.¹⁰, ¹¹ The many comorbid conditions associated with diabetes-induced CKD and the presence of unique metabolic/physiologic alterations of the uremic state make the management of coronary artery disease and the prevention of sudden cardiac death challenging in patients with stages 4-5 CKD.

Available evidence shows that patients with stages 4-5 CKD caused by diabetic nephropathy also present with multiple neurologic complications of diabetes, including cardiovascular autonomic neuropathy¹² and diabetic peripheral neuropathy. Several studies using measures of heart rate variability for the evaluation of cardiac autonomic neuropathy have established abnormalities in up to 62% of dialysis patients.¹³, ¹⁴, ¹⁵ These abnormalities frequently occur in the absence of clinical symptoms of autonomic dysfunction and also were described in patients with stages 4-5 CKD before dialysis therapy.¹⁶ In nondiabetic patients, uremic neuropathy develops at glomerular filtration rates < 12 mL/min/1.73 m² and usually has an insidious onset progressing over months.¹⁷ However, in patients with diabetes, the presence of peripheral neuropathy may be detected at much earlier stages of decreased kidney function in those with type 1 diabetes and even at the time of diagnosis in those with type 2 diabetes.¹⁸ The prevalence of neuropathic pain in these patients varies, but was described in as much as 50% of all dialysis patients.¹⁸

The presence of cardiac autonomic neuropathy and diabetic peripheral neuropathy further increases morbidity and mortality risk and negatively impacts on the quality of life of individuals with late-stage CKD.

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Pathogenesis 

The full spectrum of mechanisms inducing neurotoxicity in diabetic patients with CKD is unclear. In patients with diabetes, the development of cardiac autonomic neuropathy and diabetic peripheral neuropathy is a function of complex interactions between the degree of hyperglycemia, disease duration, age-related neuronal attrition, and systolic and diastolic blood pressures.¹⁹, ²⁰ Hyperglycemia clearly has a key role in the development and progression of both cardiac autonomic neuropathy and diabetic peripheral neuropathy through activation of biochemical pathways related to the metabolic and/or redox state of the cell. Pathways that are driven mainly by metabolism are glucose flux through the polyol pathway; the hexosamine pathway; excess/inappropriate activation of protein kinase C isoforms; sodium-potassium (Na⁺-K⁺) pump dysfunction,²¹, ²² and accumulation of advanced glycation end products.²², ²³ Although each pathway may be injurious alone, collectively they cause an imbalance in the mitochondrial redox state of the cell and lead to excess formation of reactive oxygen species.²⁵, ²⁶ Increased oxidative stress within the cell leads to activation of the poly(ADP-ribose) polymerase (PARP) pathway, which regulates the expression of genes involved in promoting inflammatory reactions, microvascular deficits, and neuronal dysfunction²³ (Fig 1). Two articles recently reviewed this topic.²³, ²⁴

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• Figure 1. 

  Proposed paradigm of the mechanisms inducing neurotoxicity in diabetic patients with chronic kidney disease (CKD). Abbreviations: AGE, advanced glycation end products; GSH, glutathione; GSSG, oxidized glutathione; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced NADP; NF-κB, nuclear factor κB; PAI 1, plasminogen activator inhibitor 1; PARP, poly(ADP-ribose) polymerase; PKC, protein kinase C; PTH, parathyroid hormone; RNS, reactive nitrogen species; ROS, reactive oxygen species; SDH, sorbitol dehygrogenase; TCA, tricarboxylic acid; VEGF, vascular endothelial growth factor. Adapted and reproduced from Edwards et al²³ with permission of Elsevier.

The superimposed uremic state, with its constellation of unique metabolic/physiologic alterations, contributes to more rapid onset and progression of both cardiac autonomic neuropathy and diabetic peripheral neuropathy. Some evidence suggests that the presence of a variety of toxins, including parathyroid hormone and β₂-microglobulin (which have increased levels in patients with ESRD), may underlie the development of uremic neuropathy.²⁷, ²⁸, ²⁹ Older experimental evidence proposed that the neurotoxicity associated with the uremic state may be caused by alterations in membrane excitability induced by an inhibitory effect on the activity of the axonal Na⁺-K⁺ pump, which would abolish the direct contribution of the hyperpolarizing pump current to the membrane potential, leading to accumulation of extracellular potassium that causes further depolarization.³⁰ The Na⁺-K⁺ pump is of critical importance in maintaining normal ionic gradients, which are essential for axonal survival. More recent evidence in humans has shown that hyperkalemia, and not Na⁺-K⁺ pump dysfunction, is primarily responsible for uremic depolarization and likely a contributing factor to the development of neuropathy.³¹ However, an abnormal pattern of response to ischemia in dialysis patients was not fully explained by the hyperkalemic membrane depolarization, suggesting that some other factor, possibly hydrogen ions, affects nerve excitability in these patients, but that this factor becomes evident only during ischemia.³² Disruption of these various ionic gradients may affect the Na⁺/Ca²⁺ exchanger, leading to increased levels of intracellular calcium and axonal loss.³³ In this respect, several studies of patients with CKD progressing to ESRD have shown significant alterations in membrane potential before hemodialysis, with recovery in the postdialysis period.³¹, ³², ³⁴

Measures of motor and sensory nerve excitability have been assessed in relation to changes in serum levels of potential neurotoxins, including potassium, calcium, urea, uric acid, and middle molecules, such as parathyroid hormone and β₂-microglobumin. Predialysis excitability abnormalities become apparent with serum potassium concentrations in the high-normal range, much less than levels required to produce cardiac toxicity. These changes in nerve excitability are correlated strongly with serum potassium levels in all studies, suggesting that hyperkalemic depolarization may underlie the development of uremic neuropathy.³⁵ The abnormal excitability in dialysis patients is different from that noted in patients with diabetic peripheral neuropathy in the absence of uremia,³⁵ suggesting that abnormalities noted in dialysis patients are consequences of both structural changes and acute metabolic changes (Fig 1).

The development of cardiac autonomic neuropathy in patients with diabetes is characterized by early augmentation of sympathetic tone compared with healthy individuals. Sympathetic activation also may have a central role in the pathogenesis of CKD.³⁶, ³⁷, ³⁸ It is proposed that an imbalance between sympathetic and parasympathetic activities in diabetic dialysis patients is augmented further by the effects and consequences of uremia.³⁹ Enhanced cardiac sympathetic nervous system activity may contribute to myocardial injury.⁴⁰, ⁴¹ Abnormally high myocardial norepinephrine levels, reflecting sympathetic hyperactivity, result in abnormal norepinephrine signaling and metabolism,⁴⁰, ⁴² cytotoxic effects to the heart through increased mitochondrial reactive oxygen species production⁴¹, ⁴³ and calcium-dependent apoptosis.⁴⁴, ⁴⁵ Therefore, activation of the sympathetic adrenergic system, which is documented in patients with stages 4-5 CKD,³⁶, ³⁷ likely is involved in the pathogenesis of arrhythmias, cardiomyopathy, coronary artery disease, heart failure, and sudden death.

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Cardiac Autonomic Neuropathy 

Clinical Manifestations 

Clinically, cardiac autonomic neuropathy presents with abnormal heart rate variability, tachycardia at rest, exercise intolerance, decreased baroreflex sensitivity, and orthostatic hypotension (Box 1). In patients with CKD, cardiac autonomic neuropathy often manifests as exercise intolerance because of a decreased response in heart rate and blood pressure and blunted increases in cardiac output in response to exercise (Box 1).⁴⁶, ⁴⁷

Whereas abnormalities in heart rate variability usually are early findings of cardiac autonomic neuropathy, tachycardia at rest and a fixed heart rate are characteristic late findings in diabetic patients with vagal impairment.⁴⁸, ⁴⁹, ⁵⁰ However, heart rate may not provide a reliable diagnostic criterion for cardiac autonomic neuropathy in the absence of other causes unless it is increased by > 100 beats/min. It generally is accepted that a fixed heart rate that is unresponsive to moderate exercise, stress, or sleep indicates almost complete cardiac denervation.⁵¹

Orthostatic hypotension, defined by the American Autonomic Society and the American Academy of Neurology as a > 30-mm Hg decrease in systolic blood pressure or > 10-mm Hg decrease in diastolic blood pressure in response to a postural change from supine to standing,⁵² occurs in diabetic patients largely as a consequence of efferent sympathetic vasomotor denervation, causing reduced vasoconstriction of the splanchnic and other peripheral vascular beds. Symptoms associated with orthostatic hypotension include lightheadedness, weakness, faintness, dizziness, visual impairment, and syncope on standing. The contribution of autonomic dysfunction to the development of hypotension during dialysis is a matter of ongoing debate, with some studies suggesting a possible association⁵³, ⁵⁴ and others suggesting no significant relationship.⁵⁵

Another clinical manifestation of cardiac autonomic neuropathy with important prognostic implications is silent myocardial ischemia/cardiac denervation syndrome. Patients present with decreased appreciation for ischemic pain, which can impair timely recognition of myocardial ischemia or infarction and thereby delay appropriate therapy.⁵¹ It has been shown that diabetic patients with alterations in cardiac sympathetic innervation, tone, and/or responsiveness show abnormal myocardial blood flow regulation,⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹, ⁶⁰, ⁶¹ which may increase mortality associated with myocardial ischemia. Regional cardiac sympathetic imbalance may promote malignant arrhythmogenesis and cardiac death, particularly when accompanied by decreased parasympathetic tone and myocardial ischemia.⁶², ⁶³, ⁶⁴ Consequently, sudden cardiac death is the ultimate severe clinical consequence of cardiac autonomic neuropathy and is the single greatest cause of mortality in patients with CKD on dialysis therapy.¹⁰

A meta-analysis of studies of diabetic patients concluded that mortality of subjects without cardiac autonomic neuropathy during 5.5 years of observation was 5%, but that this increased to 27% with the onset of cardiac autonomic neuropathy.⁶⁵ When impairment of cardiovascular autonomic function is combined with left ventricular hypertrophy, an independent risk factor for shortened survival in patients with CKD, as well as for cardiovascular disease,⁶⁶, ⁶⁷ the mortality of patients with CKD increased further.⁶⁸

Evaluation 

Variability in instantaneous beat-to-beat heart rate intervals is a function of sympathetic and parasympathetic activity that regulates the cardiac functional response to the body's level of metabolic activity. The autonomic nervous system transmits impulses from the central nervous system to peripheral organs and is responsible for controlling heart rate, blood pressure, and respiratory activity. In healthy individuals, heart rate has a high degree of beat-to-beat variability. Assessment of heart rate variability provides a noninvasive method for investigating autonomic input into the heart. It quantifies the amount by which the R-R interval or heart rate changes from one cardiac cycle to the next. Heart rate variability fluctuates with respiration: it increases with inspiration and decreases with expiration and is mediated primarily by parasympathetic activity.

Heart rate variability studies should be performed as a battery of autonomic tests (ie, R-R response to deep breathing, Valsalva maneuver, and R-R response to postural changes) and ideally under paced breathing (Box 2). Incorporating respiratory signal analysis enables one to independently measure each branch of the autonomic nervous system. These validated tests, described in detail in a Statement by the American Diabetes Association,⁷² are summarized in Box 2.

Heart rate variability also can be analyzed using different indices in the time and frequency domains. Time-domain analysis measures normal R-R intervals, and various measures are computed from these intervals, usually during a 24-hour electrocardiographic recording, although these measures can be computed from shorter recordings if necessary. The most commonly used measurements are listed in Box 2. Frequency-domain analysis splits the heart rate signal into constituent frequency components, mainly using fast Fourier transformation that decomposes the signal into a set of sine and cosine waves. The sympathetic system primarily generates the very low-frequency components (0.003-0.04 Hz), and the parasympathetic system primarily generates the high-frequency components (0.15-0.4 Hz; Box 2).

Quantitative scintigraphic assessment of sympathetic innervation of the human heart is possible using either [¹²³I]meta-iodobenzylguanidine (MIBG) or [¹¹C]meta-hydroxyephedrine (HED). Deficits of left ventricular [¹²³I]MIBG and [¹¹C]HED retention have been identified in type 1⁵⁸, ⁶¹, ⁷³, ⁷⁴, ⁷⁵, ⁷⁶, ⁷⁷, ⁷⁸ and type 2⁷⁹, ⁸⁰ diabetic individuals with⁵⁸, ⁷⁵, ⁷⁸ and without⁸¹ abnormal cardiovascular reflex test results. [¹¹C]HED undergoes highly specific uptake into sympathetic nerve varicosities through norepinephrine transporters (“uptake-1”).⁸² [¹¹C]HED is metabolically stable, and its neuronal retention requires intact vesicular storage.⁸² Therefore, [¹¹C]HED retention correlates with myocardial neuronal norepinephrine content and norepinephrine transporter density.⁸³, ⁸⁴ Evaluation of these scintigraphic techniques in patients with stages 4-5 CKD or dialysis patients has not yet been reported.

Microneurographic techniques are based on recording electrical activity emitted by peroneal, tibial, or radial muscle sympathetic nerves and identification of muscle sympathetic bursts, which reflect the centrally generated postganglionic sympathetic nerve activity toward the human skeletal muscle vasculature. Recently developed fully automated sympathetic neurographic techniques provide a rapid and objective method that is minimally affected by signal quality and preserves beat-by-beat sympathetic neurograms.⁸⁵

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Diabetic Peripheral Neuropathy 

Clinical Manifestations 

Diabetic peripheral neuropathy in patients with stages 4-5 CKD presents as a distal symmetrical polyneuropathy with greater lower-limb than upper-limb involvement. The most frequent clinical features of uremic neuropathy are those of large-fiber involvement, with paresthesias, impaired or absent deep tendon reflexes, impaired vibration sense, distal foot muscle wasting, and weakness.³⁵ However, in patients with diabetes on dialysis therapy, symptoms and signs of small-fiber involvement can dominate, with patients experiencing severe burning and shooting pains with impaired pain and temperature perception. Commonly, both large and small fibers can be affected in patients with CKD with diabetic peripheral neuropathy. Sensory deficits overshadow motor nerve dysfunction and appear first in the distal portions of the extremities and progress proximally in a “stocking-glove” distribution. In patients with CKD, the severity of diabetic peripheral neuropathy is correlated directly with duration of diabetes, degree of glycemic control, and degree of uremia.²³ In rare cases, diabetic peripheral neuropathy may present first with late complications, such as ulceration or neuroarthropathy (Charcot joints) of the foot; both these complications are more prevalent in patients with ESRD.⁸⁶

Lower-Limb Amputation 

The diabetic population with stages 4-5 CKD is at extremely high risk of lower-limb amputation. A prospective study reported that the rate of lower-limb amputation increased during a 4-year period of follow-up from 4.8/100 person-years to 6.2/100 person-years.⁸⁷ The rate in diabetic patients with stages 4-5 CKD was 10 times greater than in the diabetic population at large, and two-thirds died within 2 years after the first amputation.⁸⁷ In a cohort of 29,838 patients in DOPPS (Dialysis Outcomes and Practice Patterns Study) followed up from 1996 to 2004, diabetic patients on dialysis therapy had a > 9-fold greater incidence of new amputation, higher mortality risk, and shorter survival after their first amputation compared with nondiabetic dialysis patients.⁸⁸

Evaluation 

A consensus statement from the San Antonio Conference on Diabetic Neuropathy recommended that the diagnosis and classification of diabetic peripheral neuropathy for research and clinical trials be based on at least 1 standardized measure from each of the following categories: clinical symptoms, clinical examination, electrophysiology, and quantitative sensory testing.⁸⁹ It is important to note that the diagnosis of subclinical or clinical diabetic peripheral neuropathy requires that signs (eg, abnormal quantitative test results for neuropathy) and symptoms (for clinical neuropathy) are not attributable to a nondiabetic cause. Because there are no distinguishing features unique to diabetic peripheral neuropathy, all other possible causes of the observed neuropathic disorders must be ruled out using careful history and physical examination. Considering that the uremic state per se is associated with direct pathologic effects on peripheral nerve fibers, as mentioned, the neurologic deficits found in patients with diabetes are in general more advanced and include all types of fibers.

A simple neurologic examination usually is sufficient to diagnose diabetic peripheral neuropathy in patients with CKD or on dialysis therapy. The examiner carefully inspects the patient's feet, looking for evidence of dryness, fissures, or skeletal abnormalities, such as hammer toes, all of which suggest neuropathy. Small-fiber function is assessed using a 10-g monofilament, a pin, and a cotton wasp on the dorsum of the great toe and first forefinger. The 10-g monofilament also can be used on the plantar surface of the foot. Large-fiber function is assessed using a 256-Hz tuning fork to determine vibratory sensation on the dorsum of the great toe and forefinger; if altered, proprioception is assessed using small up/down movements of the distal joints of the toe and first finger. Reflexes are assessed, with special emphasis on the Achilles' reflex. A simple screening tool for the diagnosis of diabetic peripheral neuropathy, the Michigan Neuropathy Screening Instrument, is publicly available (www.pnrd.umich.edu) and incorporates these measures with a high degree of sensitivity and specificity.

More quantitative techniques exist to assess warm and cold perception thresholds and current perception thresholds. These techniques have been developed for research purposes, generally are time consuming, and require specialized equipment and thus are not used routinely in a clinical setting. In contrast, nerve conduction studies can be used to quantify the degree of nerve injury in diabetic peripheral neuropathy in patients with CKD and dialysis patients in an outpatient setting.⁹⁰ Although usually not required for diagnosis, nerve conduction studies can help the patient and physician monitor diabetic peripheral neuropathy progression during a long period, particularly if the patient is asymptomatic. Nerve conduction studies also are useful to identify superimposed mononeuropathies, for example, carpal tunnel syndrome, which also are a common problem in dialysis patients with diabetic peripheral neuropathy.

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Therapeutic Strategies 

In diabetic patients with CKD, as in all patients with diabetes, therapies for cardiac autonomic neuropathy and diabetic peripheral neuropathy may be divided into treatments that target the underlying pathogenic mechanisms and those aimed at relieving symptoms.²³, ²⁴, ⁷², ⁹¹

Therapies to Interrupt Pathogenic Mechanisms 

Despite significant efforts undertaken during the last few decades to develop effective agents targeting principal pathways in patients with diabetes that are involved in nervous system dysfunction, the only proven method currently available to prevent cardiac autonomic neuropathy and diabetic peripheral neuropathy or to slow their progression is strict glycemic control. Other than strict glycemic control, disease-modifying treatments for neuropathies presently are only experimental and as such are beyond the scope of this review. However, a recent review discusses this topic.²³

The benefits of strict glycemic control were shown in patients with type 1 diabetes by large randomized controlled trials, such as the DCCT (Diabetes Control and Complications Trial),⁹², ⁹³, ⁹⁴ and by observational clinical trials, such as EURODIAB.⁹⁵, ⁹⁶ Tight control of blood glucose levels is the optimal treatment for prevention of diabetic nephropathy, as well. The EDIC (Epidemiology of Diabetes Interventions and Complications), a prospective observational study of the DCCT cohort, has shown that differences in diabetic peripheral neuropathy and cardiac autonomic neuropathy between the intensive and conventional treatment groups observed at the end of the DCCT have persisted for a decade despite the loss of glycemic separation between the groups after the end of the DCCT.⁹⁷, ⁹⁸, ⁹⁹ However, there are no similar data showing benefit of tight glucose control on cardiac autonomic neuropathy or diabetic peripheral neuropathy outcomes in type 1 diabetic patients with significant CKD or those on renal replacement therapies. Thus, strict glycemic control should be pursued actively in patients with type 1 diabetes before they manifest a substantial decrease in glomerular filtration rate. However, it is unclear whether this remains a good strategy in patients with advanced CKD or on dialysis therapy.

The evidence linking good glycemic control with prevention or delay of progression of diabetic neuropathy is more limited in patients with type 2 diabetes. A randomized prospective 6-year study of 110 Japanese patients with type 2 diabetes showed that intensive insulin therapy prevents the progression of diabetic peripheral neuropathy.¹⁰⁰ In the UKPDS (UK Prospective Diabetes Study), intensive treatment significantly decreased the risk of an aggregate end point of microvascular complications comprising mainly retinopathy and nephropathy; however, there was only a trend for decrease in risk of amputation in the intensively treated patients.¹⁰¹ There was a significant decrease in risk of sudden death, in which it is possible that cardiac autonomic neuropathy has a role.¹⁰²

In the Veterans Administration Cooperative Study on Type 2 Diabetes, there was no improvement in clinical diabetic peripheral neuropathy or cardiac autonomic neuropathy in the intensive treatment group.¹⁰³ The Steno-2 Study compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease, including intensive treatment of hyperglycemia in patients with type 2 diabetes and microalbuminuria. After a mean follow-up of 7.8 years, patients receiving the intensive intervention had a significant decrease in risk of cardiac autonomic neuropathy.¹⁰⁴ However, the risk reduction was driven mainly by the decrease in systolic and diastolic blood pressure.¹⁰⁴

In summary, the interventional evidence targeting hyperglycemia to prevent diabetic peripheral neuropathy and cardiac autonomic neuropathy in patients with type 2 diabetes is less conclusive than that for patients with type 1 diabetes. However, in view of the strong associations between glucose control measured using hemoglobin A_1c level and the incidence, prevalence, and progression of neuropathy in all forms of diabetes, as well as the overwhelming evidence showing the beneficial effects of tight glucose control on diabetic nephropathy, aggressive treatment aiming for normalization of both fasting and postprandial glucose levels remains the first and most important step in treating cardiac autonomic neuropathy and diabetic peripheral neuropathy in patients with diabetes and earlier stages (1-3) of CKD.

Management of Cardiac Autonomic Neuropathy 

Activation of the sympathetic adrenergic system is well documented in patients with stages 4-5 CKD as outlined and likely is involved in the pathogenesis of cardiovascular events, including sudden death. Various pharmacologic approaches that modify sympathetic/parasympathetic balance have been shown to decrease the incidence of arrhythmias and consequently of cardiovascular death in several patient populations, including patients after myocardial infarction or those with congestive heart failure. Therefore, it would seem logical that use of agents that decrease sympathetic activity and interfere with the renin system would have beneficial effects. However, the clinical evidence in stages 4-5 CKD and dialysis populations is limited and somewhat controversial (Table 1).

Table 1. Management of Cardiac Autonomic Neuropathy in Stages 4-5 CKD

Class and Drug	Patient Population (N)	Design	Outcome	Evidence in CKD	Reference
ACE inhibitors/ARBs
Ramipril	Dialysis, diabetes (11)	Prospective pilot, not controlled, 4 wk	HRV	Worsening HRV	105
Telmisartan	Stages 4-5 CKD, diabetes (10)	Prospective pilot, not controlled, 12 mo	HRV	Progressive impairment in HRV	106
ACE inhibitor	Dialysis, diabetes (187)	Retrospective analysis	HRV	No effect	107
Enalapril	CKD, nondiabetic (21)	Randomized, control vs amlodipine	Muscle sympathetic activity	Muscle sympathetic activity improved with enalapril vs amlodipine	108
ACE inhibitor/ARB	CKD, nondiabetic (31)	Enalapril vs losartan vs eprosartan	Muscle sympathetic activity	Modest improvement in muscle sympathetic activity from baseline with all	109
β-Blocker
All agents	Dialysis, diabetic and nondiabetic (43,200)	Observational cohort	Cardiac arrest	Indirect; improved odds of survival	110
Carvedilol	Dialysis with cardiomyopathy, diabetic and nondiabetic (114)	Randomized controlled	2-y all-cause and cardiovascular mortality	Indirect; increased survival	111
β-Blockers	Dialysis, diabetic and nondiabetic (2,286)	Prospective observational cohort	All-cause mortality	Indirect; increased survival in nondiabetic, but not in diabetic	112
β-Blockers	Dialysis, diabetic and nondiabetic (11,142)	Prospective observational cohort	All-cause mortality	Indirect; increased survival overall	113
Human erythropoietin	Dialysis (27)	Prospective, not placebo controlled	HRV	No effect	114

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; HRV, heart rate variability.

The benefits of β-blockers in patients with normal kidney function and increased cardiovascular risk have been amply shown.¹¹³, ¹¹⁵, ¹¹⁶, ¹¹⁷ However, the benefits of β-blockade in patients with stages 4-5 CKD or patients on renal replacement therapy are unclear. Concerns for potential higher rates of adverse effects, including hypotension during dialysis, hyperkalemia, and glycemic abnormalities, have somewhat limited their use, although there is no clear evidence that the risk is greater than with other antihypertensive agents. A few small studies of short duration have shown improvement in heart rate variability with propranolol in nondiabetic dialysis patients.¹¹⁸ However, studies directly evaluating the effects of β-blockers on cardiac autonomic neuropathy and sympathetic overactivity in diabetic patients with stages 4-5 CKD are lacking. A recent review argued that the “old” β-blockers, such as propranolol, are a source of concern because they decrease insulin sensitivity and may worsen glucose control and aggravate dyslipidemia, with negative effects on both nerve and kidney function.¹¹⁵ The combined α/β-blocker carvedilol is metabolically neutral, has beneficial effects on kidney perfusion, and could be used in diabetic patients.¹¹⁵ In addition to being a potent β₁-adrenergic receptor blocking agent, carvedilol blocks β₂- and α₁-receptors at therapeutic doses and slightly decreases cardiac adrenergic drive with a more “comprehensive” degree of adrenergic inhibition.¹¹⁹ A prospective study of 114 dialysis patients with cardiomyopathy randomly assigned to receive either carvedilol or placebo in addition to standard therapy showed that carvedilol significantly increased 2-year survival and decreased both all-cause and cardiovascular mortality.¹¹¹ A recent study evaluating the association between β-blocker use and all-cause mortality in a large cohort from Japan-DOPPS showed highly significant associations between treatment with β-blockers and lower risk of all-cause mortality after adjustment for multiple risk factors.¹¹² Furthermore, in a prospective observational analysis of the US Renal Data System Dialysis Morbidity and Mortality Study, Foley et al¹¹³ found that β-blockers were the only class of antihypertensive agents associated with a significant decrease in all-cause mortality after adjustment for multiple comorbid conditions. A benefit from β-blockade in improving the odds ratio for survival also is reported in an observational study of 729 cases of cardiac arrest in 43,200 prevalent dialysis patients between 2002 and 2005.¹¹⁰ Although most of these studies did not directly assess changes in heart rate variability using β-blockers, sympathetic hyperactivity has increased susceptibility to increased cardiovascular complications, such as arrhythmias and sudden cardiac death.¹²⁰, ¹²¹ Thus, on the basis of current evidence, it is likely that β-blockers provide some degree of protection from cardiovascular events to patients with advanced CKD and dialysis patients and that their beneficial survival effects are caused in part by the attenuation of sympathetic hyperactivity and subsequent improvement in electrocardiographic abnormalities.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have improved heart rate variability in asymptomatic patients with diabetes or patients with heart failure.⁵¹ In contrast, the evidence available for patients with stages 4-5 CKD suggests no or opposite effects on heart rate variability (Table 1). A retrospective study analyzing determinants of heart rate variability in 187 dialysis patients found no associations with the use of ACE inhibitors.¹⁰⁷ A more recent study evaluating the effects of 4 weeks of treatment with the ACE-inhibitor ramipril on dialysis patients described a deleterious shift in several major time-domain measures of heart rate variability that were consistent with increased cardiac sympathetic tone with the use of ramipril in this patient population.¹⁰⁵ Another small study evaluating the effects of telmisartan, an ARB, on blood pressure in patients with diabetes and stages 4-5 CKD found deterioration in heart rate variability with an increase in sympathetic tone after 12 months of treatment despite a significant decrease in blood pressure.¹⁰⁶ Conversely, treatment with ACE inhibitors or ARBs decreased muscle sympathetic nerve activity assessed using nerve microneurography in nondiabetic patients with CKD and hypertension.¹⁰⁸, ¹⁰⁹ It is possible that in patients with both diabetes and CKD, the decrease in muscle sympathetic nerve activity induced by ACE inhibitors and ARBs induces a baroreflex-mediated increase in sympathetic activity that may explain the changes described in heart rate variability. Use of ACE inhibitors and ARBs is standard of care in patients with CKD. Because the few prospective studies evaluating their direct effect on heart rate variability were small and not controlled, studies evaluating longer term implications of the described changes in heart rate variability on cardiovascular events in this patient population are needed.

The benefits and risks of recombinant human erythropoietin (rHuEPO) administration in dialysis patients in general are well known and beyond the scope of this review. A small collection of studies have reported that some patients with severe symptomatic cardiac autonomic neuropathy from type 1 diabetes have normocytic anemia associated with erythropoietin deficiency before the point at which they develop significant CKD. In these patients, treatment with rHuEPO rapidly corrects their anemia and improves their symptoms.¹²², ¹²³, ¹²⁴ However, only a few investigators have evaluated the effects of rHuEPO on measures of heart rate variability in patients with stages 4-5 CKD. One study using the standard battery of cardiovascular reflex tests (deep breathing, Valsalva maneuver, handgrip exercise, heart rate response to standing, post-Valsalva increase in blood pressure, and postural decrease in blood pressure) randomly assigned 2 groups of patients on maintenance hemodialysis therapy to rHuEPO for either 1 or 2 years of treatment and compared these patients with an untreated group. Results of tests were compared before and after correction of anemia using rHuEPO in each group. There was no improvement in heart rate variability with rHuEPO in these patients despite correction of anemia.¹¹⁴

Treatment of orthostatic hypotension is challenging in patients with CKD. Nonpharmacologic treatments include avoidance of sudden changes in body posture to the head-up position; avoiding medications that aggravate hypotension, such as tricyclic antidepressants and phenothiazines; eating small frequent meals to avoid postprandial hypotension; and avoiding activities that involve straining because increased intra-abdominal and intrathoracic pressure decrease venous return.⁵¹ In addition, adjusting doses of diuretics and the timing and doses of ACE inhibitors and ARBs need to be considered.

Midodrine is a peripheral-selective α₁-adrenoreceptor agonist and the only US Food and Drug Administration (FDA)-approved agent for the treatment of orthostatic hypotension. It is used widely for dialysis-associated hypotension. Dosing regimens ranging from 2.5-10 mg of midodrine given 15-30 minutes before dialysis are safe and effective in these patients. A recent review of the literature for the use of midodrine in the treatment of intradialytic hypotension suggested a beneficial effect in improving symptoms and signs, although the investigators noted that most studies were not randomized and had small sample sizes.¹²⁵ In addition, there have been no randomized trials examining the effects of maintenance midodrine therapy during interdialytic periods, and concerns exist regarding possible adverse effects due to supine hypertension.¹²⁶ There have been no reported trials of midodrine for cardiac autonomic neuropathy in patients with stages 4-5 CKD.

Sertraline hydrochloride was reported to improve hemodynamic parameters in patients with dialysis-induced hypotension (DIH). A small study evaluated measures of heart rate variability response to tilt-table testing in dialysis patients with and without DIH and healthy control. Four-week treatment with 50 mg of sertraline daily induced a paradoxical decrease in indices of sympathetic modulation and sympathovagal balance in patients with DIH, whereas there was an increase in these indices in patients without DIH and healthy controls, suggesting that the effects of sertraline on DIH might be related to improvement in regulation of the autonomic response to hypovolemia.¹²⁷ There have been no reported trials of sertraline for cardiac autonomic neuropathy in patients with stages 4-5 CKD.

The effects of hemodialysis therapy on heart rate variability parameters in diabetic patients during the 24-hour period surrounding dialysis are still a matter of debate. Some investigators have not observed a change in autonomic function as a result of hemodialysis treatment,¹²⁸, ¹²⁹ whereas others have found significant improvement.¹³⁰, ¹³¹ Rubinger et al¹³⁰ compared dialysis patients who presented with intradialytic hypotension with patients who maintained stable blood pressure during hemodialysis and found that during dialysis, R-R variation increased in both stable and unstable patients, and both groups of patients showed a decrease in sympathetic activity. They also noted that sympathetic/parasympathetic balance was significantly lower in women compared with men.¹³⁰ Tong and Hou¹³¹ studied 35 dialysis patients and noted significant decreases in some measurements of heart rate variability during dialysis, which recovered 2 hours after dialysis to values similar to the predialytic period.¹³¹ They reported that the ratio between low- and high-frequency power assessed using spectral analysis of heart rate variability negatively correlated with ultrafiltration rate and positively correlated with Kt/V, suggesting that better dialysis adequacy can improve heart rate variability.

In a study comparing heart rate variability parameters in diabetic patients with nondiabetic patients immediately before, during, and after dialysis, Giordano et al⁴⁷ found that diabetic patients showed cardiac sympathetic hyperactivity in the predialytic period compared with nondiabetic patients. During the dialytic period, sympathetic tone increased further in diabetic patients, although it also increased in nondiabetic patients. Postdialysis, in the nondiabetic group, sympathetic activity decreased significantly, so that cardiac autonomic balance shifted toward a parasympathetic predominance, whereas in the diabetic group, sympathetic activity decreased to only the predialytic level.⁴⁷

Some studies reported that beneficial effects of hemodialysis on heart rate variability appear to be most pronounced during the first day of the interdialytic period, persisting for up to 24 hours after dialysis in nondiabetic patients.¹³¹ Other long-term studies showed a persistent effect. A longitudinal study comparing 20 dialysis patients (13 on hemodialysis and 7 on continuous peritoneal dialysis therapy) with 15 healthy controls found significant improvement in time-domain indices of heart rate variability after 12 months of dialysis therapy, suggesting that longer term dialysis therapy may improve autonomic dysfunction in these patients.¹³²

Others have explored the effects of dialysate sodium concentration, an important determinant of interdialytic weight gain and fluid balance, on blood pressure and heart rate variability. A longitudinal study comparing dialysis patients who underwent increased sodium profiling during dialysis with those who underwent conventional dialysis found that sodium modeling may be associated with increased blood pressure and abnormal heart rate variability over time, suggestive of increased sympathetic activity.¹³³

Management of Painful Diabetic Peripheral Neuropathy 

Pain may be managed through the use of nonopioids, opioids, and adjuvants (Table 2).¹⁴⁵ The treatment effect usually is assessed using reduction in pain intensity on a visual analogue scale or an 11-point numerical rating scale ranging from “no pain” to “worst possible pain.” This measure often is supplemented with the degree of pain relief on similar scales.¹⁴⁶ Various measures of life quality and the patient's/assessor's impression of change can be added.

Table 2. Pharmaceutical Therapies for Painful Diabetic Peripheral Neuropathy

Class and Drug	No. of Participants	Design	Outcome	Evidence in CKD	Reference
TCAs
Amitriptyline	29	Crossover, 2 × 6 wk, amitriptyline > placebo	50% Pain reduction	No, requires dose adjustment	134
Desipramine	20	Crossover, 2 × 6 wk, desipramine > placebo	Pain reduction	No, requires dose adjustment	135
SSRI
Paroxetine	29	Randomized crossover, 2 × 2 × 2 wk, paroxetine (40 mg) > imipramine > placebo	Pain reduction	No, requires dose adjustment	136
SNRIs
Duloxetine	457	Parallel, 12 wk, duloxetine (60 & 120 mg) vs placebo	50% Pain reduction	No, requires dose adjustment	137
Duloxetine	348	Parallel, 12 wk, duloxetine (60 & 120 mg) vs placebo	50% Pain reduction	No	138
Duloxetine	334	Parallel, 12 wk, duloxetine (60 & 120 mg) vs placebo	50% Pain reduction	No	139
Calcium channel α2-δ agonists
Gabapentin	165	Parallel, 8 wk, gabapentin vs placebo	50% Pain reduction	No, requires dose adjustment	140
Pregabalin	146	Parallel, 8 wk, pregabalin vs placebo	50% Pain reduction	No, requires dose adjustment	141
Pregabalin	338	Parallel, 5 wk, pregabalin (300 & 600 mg) vs placebo	50% Pain reduction	No, requires dose adjustment	142
Pregabalin	246	Parallel, 6 wk, pregabalin (600 mg) vs placebo	50% Pain reduction	No, requires dose adjustment	143
μ Receptor agonists
Tramadol	127	Parallel, 6 wk, tramadol vs placebo	50% Pain reduction	No dose adjustments required	144

Abbreviations: CKD, chronic kidney disease; TCA, tricyclic and tetracyclic antidepressants; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Adapted and reproduced from Edwards et al²³ with permission of Elsevier.

However, for patients with stages 4-5 CKD or on dialysis therapy, dosages and dosing intervals often need to be adjusted, and side-effect profiles can be distinct and severe. In addition, clinical evidence regarding the effects of the agents discussed next to treat painful diabetic peripheral neuropathy in patients on dialysis therapy and those with stages 4-5 CKD is virtually nonexistent. Therefore, in selecting the drug regimen for painful diabetic peripheral neuropathy in dialysis patients and those with stages 4-5 CKD, recommendations should take into account the specific dosing restrictions for each agent, as well as the constellation of potential side effects of these agents.

Pregabalin is 1 of the 2 agents currently approved for the treatment of pain associated with diabetic peripheral neuropathy and acts by binding to the α2-δ subunit of L-type voltage-gated calcium channels and decreasing calcium influx. As shown in 4 randomized placebo-controlled trials, 300-600 mg/d of pregabalin is significantly more effective in alleviating diabetic peripheral neuropathy than placebo.¹⁴¹, ¹⁴², ¹⁴³ Unlike gabapentin, pregabalin has better gastrointestinal absorption and can be administered twice daily. Its linear pharmacokinetics provide a rapid (<2 weeks) onset of maximal pain relief.¹⁴⁷ A recent review of the Cochrane database found that the number-needed-to-treat benefit for at least 50% pain relief for 600 mg of pregabalin versus placebo is 5.0 (95% confidence interval, 4.0-6.6).¹⁴⁸ The same review found that a 150-mg/d dose generally was ineffective. However, side effects, such as dizziness, ataxia, sedation, euphoria, ankle edema, and weight gain, may limit its use. Pregabalin dosage adjustment should be considered for patients with creatinine clearance (CCr) < 60 mL/min. A 50% decrease in pregabalin daily dose is recommended for patients with CCr of 30-60 mL/min compared with those with CCr > 60 mL/min.¹⁴⁹ Daily doses should be decreased further by an additional 50% for each additional 50% decrease in CCr.¹⁴⁹ Pregabalin is cleared rapidly by hemodialysis. Supplemental pregabalin doses should be given after each hemodialysis treatment to patients on maintenance hemodialysis therapy to maintain steady-state plasma pregabalin concentrations within desired ranges. It was shown that each 4-hour hemodialysis session removes ∼50% of the drug from the body; therefore, 50 mg will need to be replaced after each dialysis session.¹⁴⁹

Gabapentin probably is the most commonly prescribed drug for painful diabetic neuropathy because of its effectiveness and low side-effect profile. Gabapentin produces analgesia also through binding to the α2-δ site of L-type voltage-gated calcium channels. In general, gabapentin dosage ≤ 2,400 mg/d is effective in treating diabetic peripheral neuropathy in patients with normal kidney function, according to data obtained in several randomized controlled clinical trials.¹⁴⁰, ¹⁵⁰ However, because gabapentin is cleared solely by renal excretion and is not bound to plasma proteins, in patients with stages 4-5 CKD, dosing restrictions apply based on CCr.¹⁵¹ It is recommended that total dose is not > 1,400 mg/d given in 2 doses for CCr of 30-60 mL/min, 700 mg/d given in 1 or 2 doses for CCr of 16-29 mL/min, and 300 mg/d given in 1 dose for CCr of 15 mL/min. For patients with CCr < 15 mL/min, the dose should be decreased in proportion to the decrease in CCr. It is recommended that patients on maintenance dialysis therapy receive an initial 300-400–mg gabapentin loading dose and then maintain plasma concentrations by receiving 200-300 mg after every 4 hours of hemodialysis.¹⁵¹ Titration to the maximal dose should be gradual to avoid side effects, which include dizziness, ataxia, sedation, euphoria, ankle edema, and weight gain.¹⁵² Risks of myoclonus and altered consciousness due to gabapentin are increased in patients with stages 4-5 CKD and in dialysis patients.¹⁴⁷, ¹⁵³, ¹⁵⁴ Myoclonus in these individuals is more disabling than in patients with normal kidney function, and when it occurs, discontinuation of gabapentin therapy is mandatory.¹⁴⁷

In clinical practice, often the tricylic and tetracylic antidepressants (TCAs) are the first-line treatment for neuropathic pain. They are inexpensive and effective. Their therapeutic actions are mediated by inhibition of the reuptake of norepinephrine and serotonin, and these agents therefore control pain and pain-related symptoms, such as insomnia and depression. Pooled data from several small placebo-controlled trials suggests that approximately 1 in 3 patients experience at least 50% relief from pain by using these drugs.¹⁵⁵ However, use of TCAs is limited by their important side effects.¹⁵⁶ Overall, secondary amines (nortriptyline and desipramine) are better tolerated than tertiary amines (amitriptyline and imipramine); however, TCAs are not well tolerated in older patients.¹⁴⁷, ¹⁵⁶ TCAs should be used with great caution (or avoided altogether) in patients with cardiac arrhythmias, congestive heart failure, orthostatic hypotension, and urinary retention, which further limits their use in dialysis patients. An electrocardiogram is mandatory before the initiation of treatment. In addition, their analgesic effects require several weeks to develop, which limits their utility for acute pain. TCAs are contraindicated in patients using monoamine oxidase inhibitors. The usual dosage schedule for TCAs is 10-25 mg at bedtime initially, titrating as tolerated to 100 or 150 mg as a single bedtime dose, and no dose adjustments are needed in dialysis patients or patients with CKD.

Selective serotonin reuptake inhibitors (SSRIs) are newer antidepressants that have largely replaced TCAs for the treatment of depression because they are better tolerated. However, in contrast to TCAs, the effects of SSRIs on neuropathic pain associated with diabetic peripheral neuropathy are limited. Although most studies specifically evaluating diabetic peripheral neuropathy pain as a primary outcome were small and short in duration, pooled data for SSRI treatment of diabetic peripheral neuropathy shows no significant difference between SSRIs and placebo.¹⁵⁵

Duloxetine, a serotonin-norepinephrine reuptake inhibitor, is the only other agent besides pregabalin that has been approved by the FDA for treating painful diabetic peripheral neuropathy. In 3 large randomized placebo-controlled trials,¹³⁷, ¹³⁸, ¹³⁹ duloxetine, 60 and 120 mg/d, provided significant relief from diabetic peripheral neuropathy. The higher dose, 120 mg/d, provides greater relief from diabetic peripheral neuropathy pain, but is associated with increased side effects, including orthostatic hypotension, tremor, anxiety, and increased blood pressure. The presence of kidney impairment requires a lower starting dose of 30 mg and more gradual titration, with a maximum suggested dose of 60 mg/d. The use of duloxetine is not recommended for patients with CCr < 30 mL/min.

Anticonvulsants control neuronal excitability by blocking sodium and/or calcium channels.¹⁵⁷ Originally developed for preventing seizures, they are in broad use for the treatment of neuropathic pain. Phenytoin and carbamazepine primarily block the voltage-gated sodium channel. At doses of 200-600 mg/d, both decrease the pain associated with diabetic peripheral neuropathy compared with placebo. However, because of serious side effects and newer improved therapies, we do not recommend use of these compounds in patients with stages 4-5 CKD or those on renal replacement therapies.

Opioids inhibit noxious transmission through multiple mechanisms, including peripheral, presynaptic, and postsynaptic-located opioid receptors in the dorsal horn and at sites in the brain. Several randomized controlled trials have shown that opioids are effective in relieving pain in patients with painful diabetic peripheral neuropathy.¹⁴⁶ The most common side effects are constipation, cognitive side effects, and nausea. The risk of drug abuse and immunologic side effects is a limiting factor for using these drugs in patients with nonmalignant pain. There is no general agreement about how opioids should be dosed; however, these drugs usually are dosed with short-acting opioids every 4-6 hours, followed by a switch to long-acting opioids after 1-2 weeks.

Tramadol is a weak μ-receptor agonist that inhibits reuptake of serotonin. A few small, double-blind, randomized, placebo-controlled trials have shown that tramadol (200-400 mg/d) during short periods of time significantly decreased pain scores in patients with diabetic peripheral neuropathy.¹⁴⁴, ¹⁵⁸ Tramadol is well tolerated with a modest side-effect profile that includes nausea, constipation, headache, and dyspepsia. In patients with stages 4-5 CKD, it is recommended that treatment start at a lower dose and carefully titrate to a maximum of 200 mg/d, with a dosing interval of 12 hours. Because only 7% of an administered dose is removed by hemodialysis, dialysis patients can receive their regular dose on the day of dialysis.

Short-term clinical trials report that 20-80 mg/d of slow release oxycodone relieves pain associated with diabetic peripheral neuropathy.¹⁵⁹ Although opioids are an effective alternative against diabetic peripheral neuropathy pain, their long-term use often results in side effects, including constipation, urinary retention, impaired cognitive function, impaired immune function, and issues associated with tolerance and addiction. In general, lower doses of opiates should be used in patients with CKD and dialysis patients, although a maximal daily dose is not yet well established for oxycodone.

The dynamic and plastic nature of the pain system suggests participation of several mechanisms in the generation and maintenance of chronic pain.¹⁴⁶ In neuropathic pain, the pain-signaling system is distorted and plastic changes become increasingly complex. Hence, multifaceted treatment of these pains is a reasonable approach, but surprisingly few attempts have been made to address this issue. A recent trial showed that a combination of an opioid and gabapentin in patients with painful diabetic peripheral neuropathy resulted in improved pain relief in comparison to treatment with either agent alone, allowing for successful decreasing of opiate dosing.¹⁶⁰ Another more recent randomized crossover trial evaluated the effects of oral treatment with the TCA nortriptyline, gabapentin, and their combination at maximum tolerated doses in participants with chronic pain associated with painful diabetic neuropathy.¹⁶¹ Results showed that pain intensity and pain-related sleep disturbance were lower with combined treatment than with each drug alone.¹⁶¹ Although no patients with stages 4-5 CKD were included in these trials, use of combination therapy in the management of pain could help achieve beneficial effects on pain reduction in this patient population.

Capsaicin is an extract of capsicum peppers. Capsaicin binds to the transient receptor potential cation channel, subfamily V, member 1 (TRPV1) receptor and exhausts substance P in the peripheral nerves to achieve its analgesic effects. In the study published by the Capsaicin Study Group, 0.075% capsaicin cream applied 3 times daily for 6 weeks was more effective in alleviating diabetic peripheral neuropathy than placebo.¹⁶² Burning was the most common side effect, which tended to decrease as therapy was continued. However, therapeutic effects of capsaicin are modest and usually manifest weeks after the cream application. Recently, a patch containing high-concentrated capsaicin has shown promising effects in treating painful diabetic peripheral neuropathy.

Topical 5% lidocaine patches have been reported by several studies to relieve diabetic peripheral neuropathy. Lidocaine blocks voltage-gated sodium channels, and topical application is believed to silence ectopic discharges on small afferent fibers by blocking sodium channels unspecifically.¹⁴⁶ In an open-label study, up to 4 patches of 5% lidocaine applied for up to 18 hours daily are well tolerated in patients with painful diabetic peripheral neuropathy. Lidocaine patches significantly improved pain and quality-of-life ratings and may allow tapering of concomitant analgesic therapy. However, data from randomized controlled trials in patients with painful diabetic peripheral neuropathy and CKD are not available.

Botulinum toxin, which has been shown to inhibit vanilloid receptors to inhibit release of glutamate and substance P, also has had a pain-relieving effect in 1 randomized trial of patients with painful diabetic peripheral neuropathy.¹⁶³ However, no data are available for patients with stages 4-5 CKD.

Because drug treatment is associated with numerous side effects and may be ineffective in many patients with CKD and hemodialysis patients, nonpharmacologic strategies, such as electrotherapy, are a potential recourse. Of the various forms of electrostimulation, high-tone external muscle stimulation may be a promising alternative treatment for patients with stages 4-5 CKD and dialysis patients with symptomatic diabetic peripheral neuropathy. A recent small pilot study of 25 patients on maintenance dialysis therapy with a diagnosis of symptomatic diabetic peripheral neuropathy showed that high-tone external muscle stimulation can ameliorate the discomfort and pain associated with both diabetic and uremic neuropathy and could be a valuable supplement in the treatment of pain and neuropathic discomfort in these patients.¹⁶⁴ Finally, coordinated programs to screen and provide regular foot care for patients at high risk because of diabetic peripheral neuropathy, combined with guidelines for treatment and referral of ulceration, are needed and will assist in amputation prevention and improving quality of life.

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Case Review 

The patient discussed in the opening vignette has stage 4 CKD secondary to diabetic nephropathy and presents with painful diabetic peripheral neuropathy and new-onset autonomic neuropathy manifested as orthostatic hypotension. Several therapeutic interventions are recommended. First, his insulin regimen should be changed to a basal/bolus algorithm with insulin glargine or detemir and a short acting insulin analogue, such as aspart or lispro, based on carbohydrate counting. Pharmacokinetic profiles of these insulin analogues and the use of carbohydrate counting for calculation of prandial insulin requirements ensure superior blood glucose control with a lower incidence of hypo- and hyperglycemic peaks. Second, to decrease symptomatic orthostasis, the dose of furosemide should be decreased as tolerated, and lisinopril should be used at bedtime with a possible decrease in dose to 20 mg/d. In case of persistent symptomatic orthostatic hypotension, midodrine, 5-10 mg, could be added up to 3 times daily. However, careful monitoring of supine blood pressure should be performed because supine hypertension is a possible side effect of this agent. Additional interventions to decrease orthostatic hypotension include elevating the head of the bed while sleeping and wearing compression stockings. Finally, to treat his painful neuropathy, he should be started on gabapentin therapy with slow titration of dosage up to 700 mg twice daily. If he tolerates this maximum dose but is still experiencing pain, duloxetine could be added beginning at 20 mg/d, slowly titrating up to 60 mg/d. Careful foot care will be critical.

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Acknowledgements 

Support: Dr Pop-Busui is supported by grants from the American Diabetes Association (1-08-CR-48), the Juvenile Diabetes Research Foundation (1-2008-1025 and 4-200-421, for the study of complications of diabetes), and the Michigan Diabetes Research and Training Center (National Institutes of Health [NIH] 5P60-DK020572). Dr Feldman is supported by grants from the Michigan Diabetes Research and Training Center (NIH 5P60-DK020572), Animal Models of Diabetic Complications Consortium (NIH U01-DK076160), the Taubman Institute, and the Program for Neurology Research and Discovery. Dr Pennathur is supported by a Clinician Scientist Development Award from the Doris Duke Foundation and NIH grants HL092237 and HL092237-02S109.

Financial Disclosure: The authors declare that they have no relevant financial interests.

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