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Diabetic neuropathy

T H E R A P Y U P D AT E

Diabetic neuropathy: An intensive review JEREMIAH JOHN DUBY, R. KEITH CAMPBELL, STEPHEN M. SETTER, JOHN RAYMOND WHITE, AND KRISTIN A. RASMUSSEN Purpose. The epidemiology, classification, pathology, and treatment of diabetic neuropathy are reviewed. Summary. Diabetic peripheral neuropathy is a common complication of diabetes that can cause significant morbidity and mortality. Some 30% of hospitalized and 20% of community-dwelling diabetes patients have peripheral neuropathy; the annual incidence rate is approximately 2%. The primary risk factor is hyperglycemia. Sensorimotor neuropathy is marked by pain, paresthesia, and sensory loss. Cardiac autonomic neuropathy (CAN) may contribute to myocardial infarction, malignant arrhythmia, and sudden death. Gastroparesis is the most debilitating complication of gastrointestinal autonomic neuropathy. Genitourinary autonomic neuropathy can cause sexual dysfunction and neurogenic bladder. The pathology of diabetic neuropathy involves oxidative stress, advanced glycation end products, polyol pathway flux, and protein kinase C activation; all contribute to microvascular disease and nerve dysfunc-

D

iabetic peripheral neuropathy is a common complication of diabetes that can affect virtually every tissue of the body and cause significant morbidity and mortality. Current understanding of the patho-

tion. For symptom management current evidence from clinical trials supports the use of desipramine, amitriptyline, capsaicin, tramadol, gabapentin, bupropion, and venlafaxine as preferred medications. Citalopram, nonsteroidal antiinflammatory drugs, and opioid analgesics may be used as adjuvant agents. Lamotrigine, oxcarbazepine, paroxetine, levodopa, and α-lipoic acid are alternative considerations. Evidence supporting the use of zonisamide, fluoxetine, mexiletine, dextromethorphan, and phenytoin is considered equivocal. Complementary therapies have also shown efficacy. The symptoms of CAN may be ameliorated with fludrocortisone, clonidine, midodrine, dihydroergotamine or caffeine, octreotide, and β-blockers. Gastroparesis may be treated with metoclopramide or erythromycin. The most promising disease-modifying therapy is ruboxistaurin, which is in Phase III trials. Glycemic control remains the foundation of prevention and the prerequisite of adequate treatment. Conclusion. Diabetic neuropathy is a

physiology is complicated and incomplete, but basic experimental research is on the threshold of producing the first disease-modifying therapies. The available treatments are modestly to moderately effective in

JEREMIAH JOHN DUBY, PHARM.D., is General Practice Resident, University of Arizona, Tucson. R. KEITH CAMPBELL, B.PHARM., M.B.A., CDE, FASHP, FAPhA, is Professor; STEPHEN M. SETTER, PHARM.D., D.V.M., is Assistant Professor; and JOHN RAYMOND WHITE is Associate Professor of Pharmacotherapy, Department of Pharmacotherapy, College of Pharmacy, Washington State University (WSU), Spokane. KRISTIN A. RASMUSSEN is a D.V.M. degree candidate, College of Veterinary Medicine, WSU. Address correspondence to Dr. Duby at 1347 N. Euclid Avenue,

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many-faceted complication of diabetes that can be managed symptomatically with an array of drugs. Index terms: Amitriptyline; Analgesics and antipyretics; Anticonvulsants; Antidepressants; Antiinflammatory agents; Antioxidants; Antiparkinson agents; Antitussives; Bupropion; Caffeine; Capsaicin; Cardiac drugs; Central nervous system stimulants; Citalopram; Classification; Clonidine; Desipramine; Dextromethorphan; Diabetic neuropathies; Dihydroergotamine; Enzyme inhibitors; Epidemiology; Erythromycin; Fludrocortisone; Fluoxetine; Gabapentin; Gastrointestinal drugs; Hypotensive agents; Lamotrigine; Levodopa; Macrolides; Metoclopramide; Mexiletine; Midodrine; Octreotide; Opiates; Oxcarbazepine; Paroxetine; Phenytoin; Ruboxistaurin; Steroids, cortico-; Sympatholytic agents; Sympathomimetic agents; Thioctic acid; Tramadol; Transcutaneous electric nerve stimulation; Venlafaxine; Zonisamide Am J Health-Syst Pharm. 2004; 61:160-76

relieving symptoms but are limited by adverse effects and drug interactions. The emphasis of management of diabetic neuropathy remains prevention by glycemic control. The purpose of this article is to review the epi-

Tucson, AZ 85719. This is article 204-000-04-003-H01 in the ASHP Continuing Education System; it qualifies for 2.0 hours of continuing-education credit. See the learning objectives, test questions, and instructions starting on page 175. Copyright © 2004, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/04/0102-0160$06.00.

THERAPY UPDATE

demiology, classification, pathology, and treatment of diabetic neuropathy. Epidemiology: Prevalence, incidence, and risk factors Diabetes is the leading cause of neuropathy in the Western world, and neuropathy is the most common complication and greatest source of morbidity and mortality in diabetes patients.1 It is estimated from a comprehensive collection of epidemiologic studies that the prevalence of neuropathy in diabetes patients is approximately 30% in hospital patients and 20% in community patients.2 The overall annual incidence of neuropathy was ~2% in the United Kingdom Prospective Diabetes Study (UKPDS) and the Diabetes Control and Complications Trial (DCCT).3 A commonly cited study in 1977 reported that roughly 7% of patients had neuropathy upon diagnosis of diabetes, and the incidence approached 50% for patients with diabetes for more than 25 years.4 However, it is impossible to accurately approximate the true prevalence of diabetic neuropathy, because the criteria for diagnosis vary, epidemiologic studies are limited to patients receiving medical care, and diabetes remains undiagnosed in a large population of diabetes patients. 5 Therefore, the frightening statistic that diabetic neuropathy is implicated in 50–75% of nontraumatic amputations is merely an exclamation point in the overall impact.1 The primary risk factor for diabetic neuropathy is hyperglycemia.2 As noted above, the annual incidence of diabetic neuropathy in the DCCT was approximately 2% in conventionally treated patients, but that rate dropped to 0.56% in intensively treated type 1 diabetes mellitus patients.3 The UKPDS failed to support a similar correlation between the incidence of neuropathy and glycemic control in type 2 diabetes patients, but the progression of diabetic neuropathy is dependent on glycemic

control in both type 1 and 2 diabetes patients, and the pathologies are considered similar.2,3,6 The duration of diabetes also increases the risk of neuropathy, but the association between duration and prevalence may depend in part upon patient age, which itself is a risk factor.2,7 Cigarette smoking, alcohol consumption, hypertension, height, and hypercholesterolemia are all considered independent risk factors for diabetic neuropathy.2,7,8 Classification and disease course Diabetic neuropathy affects sensory, autonomic, and motor neurons of the peripheral nervous system, which is to say that nearly every type of nerve fiber in the body is vulnerable. Moreover, every organ system in the body that relies on innervation for function is consequently subject to pathology. Therefore, diabetic neuropathy describes a number of unique syndromes that are primarily classified by the nerve fibers affected. As for the disease course, it is fortunate that only a minority of patients experience neuropathic pain but tragic that a majority do not report symptoms until the complications are severe or irreversible. It is beyond the scope of this article and the practice of pharmacy to formulate diagnoses; however, a practical understanding of the classification and course of neuropathy is an invaluable part of pharmaceutical care for diabetes patients. A simple classification and staging system is outlined in the appendix, and the disease courses for the most common diabetic neuropathies are detailed below. Sensorimotor neuropathy or distal symmetrical polyneuropathy. The excruciating, refractory pain that can accompany sensorimotor neuropathy is what most health care providers recognize as diabetic neuropathy; however, the damage typically develops insidiously as a painless loss or change of sensation that may be detected and quantified only by clinical tests. Sensorimotor neuropathy

Diabetic neuropathy

affects large and small afferent nerve fibers to varying degrees, resulting in mixed symptoms and sensory loss.1,9 Large afferent nerve fibers transmit proprioception (i.e., spatial limb location), cold, and vibration sensation. Small afferent fibers are responsible for conducting nociceptive stimuli, touch, and warmth sensation.1 The manifestations of sensorimotor neuropathy classically progress from the most distal extremities (the fingers and toes) in a symmetrical pattern that is generally described as a glove-and-stocking distribution.1,9,10 The positive symptoms are pain and paresthesia (abnormal sensations), and patients complain of burning, tingling, aching, cold sensation, lancinating (sharp) pain, numbness, or pain from normal touch (allodynia), such as clothing brushing the skin.1,9-11 Painful symptoms occur in a minority (11–32%) of neuropathy patients with diabetes and do not correlate with diminished nerve conduction velocity (NCV) or function.1,9,11 The negative symptoms of sensory loss are more common and occur throughout the course of diabetes.1 Patients may experience an inability to feel, identify, or manipulate smaller objects. They can gradually lose the capacity to judge temperature or sense even painful or threatening stimuli. 1,9,10 Further, the loss of innervation can lead to atrophy of essential pedal muscles, resulting in deformities (e.g., hammertoes) that predispose the patient to calluses and ultimately to ulceration.1,12 In fact, sensorimotor neuropathy is the primary risk factor for the development of diabetic foot ulcer, which is responsible for 85% of lower-extremity amputations in diabetes patients.12 Cardiovascular autonomic neuropathy (CAN). Sensorimotor neuropathy is the most common type of neuropathy, but there is an increasing awareness of the prevalence and impact of autonomic neuropathies. CAN is rapidly emerging as a key

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cause of morbidity and mortality in diabetes. The incidence of CAN appears to be around 15% in type 1 and 20% in type 2 diabetes patients. A conservative source determined the 10-year mortality rate for diabetic patients with CAN to be 27%, a remarkable 22 absolute percentage points higher than the mortality rate for diabetes patients without CAN.13 It is hypothesized that the comorbidity of CAN with coronary artery disease results in synergistic cardiovascular dysfunction, decreased myocardial infarction survival rates, and increased incidence of malignant arrhythmia and sudden death. 1,13,14 CAN affects both the sympathetic and parasympathetic innervation of the heart and coronary vessels.15 The hallmark symptoms are orthostatic hypotension and decreased heartrate variability, and CAN may contribute to left ventricular dysfunction, silent or asymptomatic myocardial infarction, and exercise intolerance.1,13-15 There is evidence that the disease process may begin early in the course of diabetes but remain asymptomatic until later stages.1,13,15 Gastrointestinal (GI) autonomic neuropathy. Gastroparesis is the GI complication most commonly associated with diabetes, but diabetic autonomic dysfunction can affect the entire GI system from the esophagus to the colon.16,17 Subclinical abnormalities are relatively common, and symptoms do not typically occur until later in the course of diabetes.16-18 The symptoms can range from mild discomfort to disabling impairment of daily activities. Gastroesophageal dysfunction manifests as gastroesophageal reflux disease (GERD) in roughly 30% of diabetes patients.16,17 Delayed gastric emptying and gastric retention, which are present in 25– 50% of patients with diabetes, can cause early satiety, cramping, bloating, epigastric pain (heartburn), nausea and vomiting, and loss of appetite to the point of anorexia.16-21 Gastroparesis can also complicate pharma-

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cotherapy by delaying the absorption of glucose or antidiabetic medication, for example.16,17 Colon abnormalities are symptomatic in approximately 25% of patients, resulting in severe constipation, diarrhea, and fecal incontinence.15,17 Genitourinary autonomic neuropathy. Male and female sexual function and urinary continence are fundamental quality-of-life issues that can be adversely affected by diabetes.22,23 Erectile dysfunction affects more than 50% of men with diabetes over the age of 50 years and three out of every four male diabetes patients who are 60 or older.17,24 The initiation of penile erection is directed by the autonomic nervous system, and neuropathic dysfunction may result in the gradual loss of rigidity to the point of complete impotence. Female sexual dysfunction may manifest as diminished libido as a result of vaginal dryness and pain during intercourse (dyspareunia).16,17 Neurogenic bladder or cystopathy may also be caused by diabetic autonomic neuropathy and can result in the inability to sense bladder fullness or initiate micturition, resulting in urinary retention, bladder enlargement, and overflow incontinence.15,17 Pathology Decades of research elucidating the pathophysiology of diabetic neuropathy have failed, thus far, to produce a treatment that prevents or reverses its development and progression. Recently, however, numerous competing or parallel pathological pathways have begun to intersect and complement each other, illuminating potential pharmacologic targets. The current foci of diabetic neuropathy research are oxidative stress, advanced glycation end products (AGEs), protein kinase C (PKC), and the polyol pathway. Figure 1 provides an overview of how these pathways may contribute to the pathophysiology. Microvascular factor. The diabetic pathologies of the peripheral ner-

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vous and microvascular systems are inseparably intertwined by their physiological codependence. In the simplest terms, blood vessels depend on neural regulation for normal function, and neurons depend on capillaries for nutrients. The selfperpetuating potential of microvascular and neural dysfunction in the development of diabetic neuropathy is supported by a number of persuasive studies. In fact, much of the literature refers to diabetic neuropathy as a microvascular complication or neurovascular disease. Diabetic neurovascular disease is a metabolic disorder, and the key to pathogenesis is that neither vascular nor nervous tissue requires insulin for the uptake of glucose. Therefore, hyperglycemia results in elevated intracellular glucose levels that drive secondary pathologies—oxidative stress, protein glycation—that are likely similar in both vascular and nervous tissue. Nevertheless, although the systems are codependent and may have analogous diabetic pathologies, they are unique, especially with respect to the challenges of treatment. Perhaps the first pathological change in the microvasculature is a physiological shift favoring vasoconstriction, evidenced by blunted vasodilation and elevated vasoconstrictor activity. 25 As the disease progresses, neuronal dysfunction correlates closely with the development of vascular abnormalities, such as capillary basement membrane thickening and endothelial hyperplasia, which contribute to diminished oxygen tension and hypoxia.26-28 Indeed, hemodynamic abnormalities, hypoperfusion, and neuronal ischemia are well-established characteristics of diabetic neuropathy.25,29 Finally, diabetic animal models have demonstrated that vasodilator agents (e.g., angiotensin-convertingenzyme [ACE] inhibitors, α 1 antagonists) and experimental drugs (e.g., aldose reductase inhibitors, PKC inhibitors) can lead to substan-

THERAPY UPDATE

Diabetic neuropathy

Figure 1. General overview of the pathophysiology of diabetic neuropathy. AGE = advanced glycation end product, RAGE = receptors for AGEs, ROSs = reactive oxygen species, TCA = tricarboxylic acid. Hyperglycemia Increased extracellular protein glycation AGE formation

Microvascular vasoconstriction, capillary basement membrane thickening, endothelial hyperplasia, hemologic abnormalities

Increased intracellular glucose in nerve and vascular tissue

RAGE activation

Neural hypoperfusion and ischemia

Sugar + ROSs

carbonyls Increased glycolysis and TCA cycle activity Carbonyls + proteins or Mitochondrial lipids glycoxidation or dysfunction lipoxidation products Increased superoxide

Increased diacylglycerol

Reduced NADPH + glutathione, NADH:NAD+ misbalance

Protein + glucose

Oxidative stress AGEs

Redox reaction: glucose sorbitol fructose

Protein kinase C

Polyol pathway flux

Nerve dysfunction and death

tial improvements in neuronal blood flow, with corresponding improvements in NCV. 25 Thus, microvascular dysfunction occurs early in diabetes, parallels the progression of neural dysfunction, and may be sufficient to support the severity of structural, functional, and clinical changes observed in diabetic neuropathy. Oxidative stress. Diabetes is, foremost, a hypermetabolic state that promotes elevated intracellular concentrations of glucose that can participate in a number of different pathological processes. Sugars can react with reactive oxygen species to form carbonyls that can further react with proteins or lipids to produce glycoxidation or lipoxidation compounds, respectively.30 Glucose and its metabolites can also create carbonyl complexes with proteins directly, producing AGEs that contribute to oxidative stress as well. Alternatively, glucose metabolism itself creates free-radical byproducts in the normal production of ATP. The presence of excessive glucose may lead to increased production of reducing agents (i.e., NADH and FADH2) through glycolysis and the

tricarboxylic acid cycle.31 This surplus of electron donors may result in a dangerous imbalance in the mitochondrial electron transport chain that could accelerate the production of superoxide, a highly reactive free radical.31-33 In summary, oxidative stress describes an increase in substrate for AGEs, an increase in precursors for glycoxidation and lipoxidation products, and an acceleration in free-radical formation that may be accompanied or caused by a deficiency of antioxidant and detoxification pathways.30 Glycoxidation and lipoxidation products represent an extensive and diverse group of potentially deleterious compounds. Superoxide anion is capable of profound tissue damage and may contribute to the activation of PKC by inducing de novo synthesis of diacylglycerol.32 In fact, the existing evidence of oxidative stress supports a number of expert hypotheses, ranging from a unifying pathology to a universal consequence of disease itself.30,31 However, a principal role for oxidative stress in the pathology of diabetic neuropathy currently hinges on gaps in basic research and disappointing clinical

trials. Tissue concentrations of known carbonyl compounds are nearly negligible, and antioxidants have been shown to be of little benefit for the treatment of diabetic neuropathy or microvascular disease.29,30 AGEs. Glucose and other sugars can nonenzymatically form covalent bonds with proteins through the Maillard reaction to produce Schiff bases and Amodori products, which can further degrade or react to produce AGEs. This process occurs in euglycemic individuals and normally affects only longer-lived proteins, but hyperglycemia provides an excess of substrate (i.e., glucose) that may accelerate the reaction, with pathological consequences. The glycation of essential proteins could alter their structure and impair their function.34 There is scattered evidence linking AGEs to abnormalities in vascular tissue, lipid metabolism, and platelets that may be germane to the pathology of diabetic neuropathy.34,35 Receptors for AGEs have also been identified that can contribute to oxidative stress and activate signaltransduction pathways, such as PKC and mitogen-activated protein.31,34-36 Potent AGE cross-link inhibitors,

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such as aminoguanidine, have demonstrated efficacy in preventing diabetic vascular complications in animal models, but their lack of efficacy and dose-limiting toxicity have proven prohibitive in humans.29,31,34,35 Polyol pathway flux. The polyol pathway provides persuasive indications that the unifying feature of diabetes—chronic hyperglycemia— can induce and drive subordinate metabolic processes that promote intracellular instability and decay. It is essentially an alternative catabolic pathway that is activated and supplied by elevated intracellular glucose levels.31,37 The first redox reaction of the polyol pathway couples the reduction of glucose by the enzyme aldose reductase with the oxidation of NADPH to NADP+, producing sorbitol. Sorbitol is further oxidized to fructose by sorbitol dehydrogenase, which is coupled with the reduction of NAD+ to NADH. It was once believed that the accumulation of sorbitol resulted in osmotic stress that caused neuron damage, but it is generally accepted that sorbitol concentrations are relatively insignificant in the nerves and vascular tissue of patients with diabetes.29,31,37 The current hypothesis holds that a high rate of “flux” of glucose through the polyol pathway is pathogenic, primarily by increasing the turnover of cofactors— NADPH and NAD+. The reduction and regeneration of glutathione require NADPH, and depletion of glutathione could contribute to oxidative stress and the accumulation of toxic species.37 Also, an imbalance in the NADH:NAD+ ratio could ultimately result in increased production of AGEs and the activation of diacylglycerol and PKC. Aldose reductase inhibitors are effective in preventing the development of diabetic neuropathy in animal models. However, human trials have demonstrated disappointing results and dose-limiting toxicity. Investigators continue to search for a potent inhibitor with adequate tissue pene-

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tration and a tolerable adverse-effect profile.37 PKC. There is mounting evidence that PKC may be a critical conductor in the metabolic pathologies associated with diabetic neuropathy. The term “PKC” actually describes a superfamily of 12 isoenzymes that act in the transduction of intracellular signaling and are activated by phosphorylation and subsequent binding to the second messenger diacylglycerol.29,38 Elevated intracellular glucose has been linked to increased diacylglycerol and PKC levels in retinal, aortic, and renal tissues, but, surprisingly, neuronal concentrations of diacylglycerol and PKC appear to be largely unchanged or even decreased under diabetic conditions.29,38 However, studies have demonstrated that PKC inhibitors can improve Na+-K+ATPase activity, which is suppressed and could contribute to diminished NCV in diabetes.38 More important, β1- and β2-specific PKC inhibitors have been shown to be capable of preventing diminished neuronal blood flow and NCV in diabetic animal models. Treatment The treatment of diabetic neuropathy may be classified as primary prevention, symptom management, and disease modifying. The DCCT and the UKPDS demonstrated that the risk of neuropathy and other complications can be dramatically reduced or delayed by intensified glycemic control in patients with type 1 and 2 diabetes, respectively.3,6 These results are especially important in light of the fact that treatments directed at symptom management are polypharmacy nightmares fraught with adverse effects and are only moderately effective. Diseasemodifying agents, which target the underlying pathologies, have a disappointing history but remain the critical focus of secondary intervention and are a hope for the near future. Table 1 gives information on dosage

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adjustments, targeted dosages, drug interactions, and adverse effects. Sensorimotor neuropathy or distal symmetric polyneuropathy. Tricyclic antidepressants (TCAs). TCAs are commonly prescribed and are one of the most investigated classes of medications for the treatment of diabetic sensorimotor neuropathy.39 The analgesic effect of TCAs appears dependent on inhibition of the reuptake of norepinephrine and serotonin, which each agent does to various degrees. The sum of research on TCAs in diabetic neuropathy includes less than 200 patients and indicates only a modest improvement of symptoms versus placebo.40 The combined number needed to treat (NNT) for the six placebo-controlled trials of TCAs was 2.4 (2.0–3.0); however, the study designs were markedly different, especially with respect to dosing, patient populations, and pain evaluation methods.41 Desipramine, amitriptyline, imipramine, and clomipramine have demonstrated the best efficacy.40,42 One head-to-head comparison of desipramine with amitriptyline showed no difference in efficacy but suggested that desipramine was better tolerated.43 A second study comparing desipramine with placebo demonstrated improvement in a majority of patients who had previously failed to receive pain relief from amitriptyline or had discontinued taking it due to bothersome adverse effects.42 Clomipramine exhibited efficacy comparable to that of desipramine in a small crossover study.40 Consideration of nortriptyline, which is an active metabolite of amitriptyline, for the treatment of diabetic neuropathy is confounded by its combination with fluphenazine in both existing trials.44,45 The combination reduced pain and paresthesia by ≥50% in over 80% of the patients in one trial, but—as might be expected from the potential drug interaction—greater than 75% of patients (14/18) experienced adverse effects.44

20–60

150–375

200–400

Citalopram

Venlafaxine

Bupropion

200–600

600–1200

200–400

40–160

Apply to affected area 3–4 times daily

Lamotrigine

Mexiletine

Tramadol

Oxycodone

Capsaicin

20 mg every 12 hr, increase by 10 mg/wk ...

900 mg/day, increase by 300 mg/wk 50 mg/day, increase by 100 mg biweekly—do not ramp up or load dose 150 mg/day, increase by 150 mg/wk 150 mg/day, increase by 50 mg/wk

300 mg/day, increase by 300 mg/wk 100 mg/day, increase by 100 mg/wk

37.5 mg/day, increase by 37.5 mg/wk 100 mg/day, increase by 100 mg/wk 200 mg/day, increase by 200 mg/wk

10 mg/day, increase by 10 mg/wk

25 mg h.s., increase by 25 mg/wk 10 mg/day, increase by 10 mg/wk 10 mg/day, increase by 10 mg/wk 10 mg/day, increase by 10 mg/wk

DosageAdjustment Schedule Adverse Effects

Lidocaine, phenobarbitol, phenytoin, theophylline MAOIs, TCAs, SSRIs, phenytoin, carbamazepine, opioid analgesics CNS depressants, tramadol, TCAs None reported

cThis table outlines only suggested dosage schedules and is by no means a comprehensive source of adverse effects and drug interactions. MAOIs = monoamine oxidase inhibitors, TCAs = tricyclic antidepressants, SSRIs = selective serotonin-reuptake inhibitors, N/V = nausea and vomiting, CNS = central-nervous-system.

Sedation, dizziness, N/V, dry mouth, constipation, urinary retention, respiratory depression Burning, itching, stinging, cough

Dyspepsia, dizziness, tremor, ataxia, insomnia, diarrhea, constipation, headache, nervousness, hepatotoxicity, arrhythmia Nausea, sedation, constipation, headache, dry mouth, urinary retention, confusion, tremor, seizures

Dry mouth, sedation, dizziness, confusion, orthostatic hypotension, constipation, urinary retention, confusion, blurred vision MAOIs Dry mouth, sedation, dizziness, confusion, orthostatic hypotension, constipation, urinary retention, confusion, blurred vision MAOIs Dry mouth, sedation, dizziness, confusion, orthostatic hypotension, constipation, urinary retention, confusion, blurred vision MAOIs, codeine, hydrocodone, Dry mouth, constipation, dizziness, sedation, insomnia, sexual dysfunction, phenytoin, TCAs, SSRIs, diarrhea tramadol, dextromethorphan MAOIs, codeine, hydrocodone, Dry mouth, constipation, dizziness, sedation, insomnia, sexual dysfunction, phenytoin, TCAs, SSRIs, diarrhea tramadol, dextromethorphan MAOIs, SSRIs, TCAs, tramadol Headache, nausea, sedation, constipation, diarrhea, dizziness, dry mouth, sexual dysfunction, hypertension, seizures MAOIs, SSRIs, TCAs, phenytoin Agitation, dry mouth, sedation, insomnia, headache, N/V, constipation, anorexia, seizures MAOIs, phenytoin, lamotrigine, Agitation, dry mouth, sedation, ataxia, N/V, blurred vision, confusion, fatigue, methadone, tramadol, TCAs, nystagmus, aplastic anemia theophylline, warfarin, antifungals Carbamazepine, phenytoin, Sedation, dizziness, confusion, N/V, ataxia, tremor, dyspepsia, nystagmus, lamotrigine, TCAs hyponatremia, leukopenia, thrombocytopenia Bupropion, carbamazepine, N/V, nystagmus, ataxia, dizziness, confusion, blurred vision, sedation, fentanyl, lamotrigine, constipation, headache, insomnia, gum hypertrophy, osteomalacia, blood tramadol, TCAs, SSRIs, dyscrasias, hypertrichosis theophylline, rifampin, amiodarone Antacids, CNS depressants Sedation, dizziness, ataxia, N/V, dry mouth, constipation, nystagmus, leukopenia Carbamazepine, Dizziness, ataxia, sedation, headache, blurred vision, diplopia, N/V, confusion, oxcarbazepine, phenytoin nystagmus, aplastic anemia, toxic epidermal necrolysis

MAOIs

Drug Interactions

aAdapted, with permission, from reference 39. bMcEvoy GK, ed. AHFS drug information 2002. Bethesda, MD: American Society of Health-System Pharmacists; 2002.

1800–3600

300–500

Gabapentin

Phenytoin

1200–2400

20–60

Paroxetine

Oxcarbazepine

75–150

Amitriptyline

1000–1600

75–150

Nortriptyline

Carbamazepine

75–200

Targeted Dosage (mg/day)

Desipramine

Medication

Dosage Adjustment, Targeted Dosages, Interactions, and Adverse Effects of Medications Commonly Used to Treat Diabetic Neuropathya,b,c

Table 1.

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The severity of adverse effects associated with TCAs is attributed to their relative affinities for muscarinic, histaminic (H1), and α1adrenergic receptors. Amitriptyline exhibits the greatest affinity for muscarinic receptors, followed by protriptyline, clomipramine, trimipramine, doxepin, imipramine, nortriptyline, and desipramine. 42 The anticholinergic adverse effects commonly associated with TCAs are dry mouth (xerostomia), constipation, dizziness, blurred vision, and urinary retention. The tertiary amine tricyclics (i.e., amitriptyline, imipramine, clomipramine, and doxepin) also have the greatest affinity for histamine and α1-adrenergic receptors, resulting in extreme sedation and orthostatic hypotension, respectively. Choosing a TCA should be based chiefly on individual patient tolerability and the risk of adverse drug reactions. Desipramine is a reasonable choice for diabetic sensorimotor neuropathy on the basis of efficacy data, relative tolerability compared with other TCAs, and cost. Tertiary TCAs, including amitriptyline, are considered second- or third-line agents in geriatric patients and should be used with extreme caution in this patient population. Selective serotonin-reuptake inhibitors (SSRIs). Clinical investigation of SSRIs for the treatment of diabetic sensorimotor neuropathy is limited to studies of paroxetine, fluoxetine, citalopram, and sertraline in a total of 98 patients. Paroxetine was compared with imipramine and placebo in a double-blind crossover study in 26 patients.46 The antidepressants proved comparable and better than placebo, but 70% of patients receiving placebo experienced a similar improvement on the neuropathic scale used. Perhaps the most notable result was the withdrawal of 7 of the 26 patients from imipramine treatment due to adverse effects, but none of the patients withdrew due to treatment-related reasons during the

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paroxetine or placebo phases. Citalopram was more effective than placebo in a similar crossover study in 18 patients; however, the overall relief of symptoms was slight, and 2 patients withdrew due to GI adverse effects.47 Fluoxetine proved to be no better than placebo in a trial of 46 patients with diabetic neuropathy.43 In general, SSRIs are considered better tolerated but less effective than TCAs, and they should not be considered for monotherapy of diabetic neuropathy.39 Other antidepressants. Extendedrelease bupropion demonstrated greater efficacy than placebo in a double-blind crossover study in 46 patients with neuropathic pain of mixed etiology.48 Nearly three out of four patients rated their pain as improved or much improved with bupropion, but placebo produced no significant change. Only two patients withdrew from the study; however, over half of patients taking bupropion experienced significant adverse effects, such as dry mouth, insomnia, and headache. Extended-release venlafaxine 150–225 mg/day (n = 82) was more effective than placebo (n = 81) and extended-release venlafaxine 75 mg/ day (n = 81) in a randomized trial in 244 patients with diabetic neuropathy.49 Those patients receiving venlafaxine 150–225 mg/day reported significantly lower pain intensity and greater pain relief than recipients of placebo and venlafaxine 75 mg/day. The Patient Global Scale and Physician Clinical Impression Scale also demonstrated parallel improvements. In a smaller study, venlafaxine produced a 75–100% reduction in pain without producing any adverse effects in 10 patients with severe sensorimotor neuropathy. 50 However, the trial was not blinded or placebo controlled and lasted only two weeks. Gabapentin. Gabapentin is an adjuvant anticonvulsant that is emerging as a first-line agent for

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the treatment of painful sensory neuropathy. 39 The first double-blind, placebo-controlled study of gabapentin for diabetic neuropathy enrolled 165 patients and was designed to establish high-dose tolerance and efficacy.51 Patients were initiated on 900 mg/day for the first week, and doses were rapidly increased to 3600 mg/day over the course of four weeks, followed by four weeks of maintenance at the highest dosage tolerated. Gabapentin was well tolerated, and 68% of the patients achieved the maximum dosage; however, roughly one out of four patients experienced dizziness and somnolence, and 8.3% of patients experienced confusion, versus 1.2% of those taking placebo. Gabapentin demonstrated statistically significant efficacy compared with placebo in reducing pain severity that was supported by clinically significant improvements in global impression scales and quality-of-life assessments. Gabapentin was compared with amitriptyline in a 12-week, doubleblind, crossover study in 25 veterans with diabetic neuropathy.52 The average tolerated dose of gabapentin was slightly less than 1600 mg/day compared with 59 mg/day for amitriptyline. The study demonstrated comparable efficacy and tolerability for both medications. Eleven (52%) of 21 patients taking gabapentin experienced moderate or greater pain relief, compared with 14 (67%) of 21 patients treated with amitriptyline. Sedation and dizziness were more common with gabapentin than amitriptyline, although dizziness rapidly diminished. Dry mouth occurred with twice the frequency during the amitriptyline phase and worsened with time. Two patients withdrew from amitriptyline treatment, versus one patient during the gabapentin phase. The remaining studies suggest that gabapentin is generally well tolerated, and 1600 mg/day or greater is necessary to achieve clinically signifi-

THERAPY UPDATE

cant pain relief.53-55 The obvious disadvantages of gabapentin are the relative cost and the divided (threetimes-a-day) dosing needed in most patients. For elderly patients, gabapentin has the advantage of very few drug interactions. In summary, the current evidence demonstrates that gabapentin is effective for diabetic sensorimotor neuropathy, and its use requires no less consideration and vigilance than more traditional medications, especially in elderly diabetes patients.39,51,53-55 Carbamazepine and oxcarbazepine. Carbamazepine is chemically related to the TCAs, and its anticonvulsant and analgesic mechanisms of action are thought to depend on neuron stabilization by inhibition of ionic conductance.54 The NNT for sensorimotor neuropathy was 3.3 in two placebo-controlled crossover studies.41,54,56,57 The first study, published in 1969, demonstrated relief of symptoms in 28 of 30 patients within two weeks of initiation of treatment.54,56 The results of the second trial were equivocal, because carbamazepine failed to demonstrate efficacy versus placebo in the first arm of the study but proved superior to placebo in the second.54,57 A more recent trial compared the efficacy and tolerability of carbamazepine and nortriptyline–fluphenazine in a double-blind crossover study.39 Patients treated with carbamazepine experienced a clinically significant improvement in pain and paresthesia from baseline. There was no significant difference in symptom improvement between the two medications, but patients reported more adverse effects for nortriptyline– fluphenazine than carbamazepine. The adverse effects of carbamazepine (e.g., somnolence, dizziness, and ataxia) tend to limit its use in clinical practice. Oxcarbazepine is chemically related and has a mechanism of action similar to that of carbamazepine, and it was recently proposed that it may

have a much better adverse-effect and drug interaction profile. 39,41 There are no published studies examining oxcarbazepine for the treatment of diabetic neuropathy, but it has demonstrated efficacy comparable to that of carbamazepine in the treatment of trigeminal neuralgia.39,58 Other anticonvulsants: Phenytoin, lamotrigine, and zonisamide. Evidence of the efficacy of phenytoin in the treatment of diabetic sensorimotor neuropathy would have to be considerable to justify the clear risk of adverse effects and drug interactions. The results of two doubleblind studies in neuropathy patients with diabetes provide conflicting results that substantiate the hazard but fail to satisfy the consequent burden of efficacy.39,54,59 Conversely, lamotrigine was relatively well tolerated in an eight-week, double-blind, placebo-controlled study in 59 patients with diabetic neuropathy.60 The 27 patients randomized to lamotrigine experienced a lower rate of adverse effects than for placebo at dosages of up to 400 mg/day. Pain severity was moderately reduced from an average of 6.4 on the Numerical Pain Scale to 4.2, but there were no significant changes in any of the global pain assessment scales or questionnaires. Nearly a third of the patients taking lamotrigine considered it highly efficacious, which raises hope for a subset of patients with intractable chronic pain.58 Patients were immediately withdrawn from the study if they developed a rash of any kind; toxic epidermal necrolysis is a current concern. In an open-label study of zonisamide, less than half of the patients completed the eight-week trial, 10 patients withdrew due to adverse effects, and there were no significant changes in pain or global assessment scores.61 Opioid analgesics, tramadol, and nonsteroidal antiinflammatory drugs (NSAIDs). The nature and chronicity of neuropathic pain complicate the

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use of opioid analgesics for diabetic sensorimotor neuropathy. There have been very few trials evaluating the long-term safety and efficacy of opioids in neuropathic pain, and it is generally accepted that these drugs provide only marginal relief at the risk of severe adverse effects and physical dependence.41 In fact, no published studies have formally examined the treatment of diabetic neuropathy with an opioid. One eight-week, double-blind, placebocontrolled, crossover trial examined controlled-release oxycodone in the treatment of 38 patients with postherpetic neuralgia.62 Reductions in the intensity of steady pain, brief pain, and allodynia were statistically and clinically significant versus placebo. Despite the predictable occurrence of constipation, sedation, and nausea, the patients preferred oxycodone to placebo 67% to 11%. Of course, the introduction of opioids to a patient’s drug regimen should be considered only on an individual basis. Periodic follow-up is necessary to adjust the dosage, ensure tolerance of adverse effects, and taper the dosage at the conclusion of treatment. Tramadol has opioid analgesic and serotonergic properties that theoretically make it an attractive medication for neuropathic pain. There have been two key studies of the safety and efficacy of tramadol in the treatment of neuropathy. A randomized, double-blind study in 131 diabetes patients with neuropathy demonstrated a clinically and statistically significant reduction in pain intensity compared with placebo; the NNT was 3.1.41,63,64 Nausea and constipation occurred in over 20% of patients, and headache and dyspepsia were also more common than in placebo recipients. The second doubleblind study compared tramadol with placebo for the treatment of pain, paresthesia, and touch-evoked pain associated with polyneuropathies. Tramadol 200–400 mg/day proved to be more effective than placebo; how-

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ever, although the difference was statistically significant, the clinical improvement was fairly modest, and the NNT for >50% pain relief was 4.3.41,62 The major adverse effects— tiredness, dizziness, and dry mouth—were reported by roughly half of the patients during the tramadol phases, and constipation occurred in over 40%, versus 12% for placebo. Adverse effects were generally reported by patients as absent to mild. In conclusion, tramadol is a safe and effective medication for diabetic sensorimotor neuropathy, and the dosage required for therapeutic effect is relatively high. The use of NSAIDs in diabetes patients must be prefaced with the caution that they can impair renal function in vulnerable individuals by inhibiting prostaglandin synthesis; also, long-term use, especially in the elderly, can cause GI bleeding. Both ibuprofen (600 mg four times daily) and sulindac (200 mg twice daily) demonstrated statistically significant reductions in paresthesia scores compared with placebo in a 24-week, single-blind study in 18 veterans with diabetic neuropathy.65 The paresthesia scale is no longer commonly used, and only those patients with “moderate pain” experienced relief. However, there were no major adverse effects or changes in renal variables in the 16 weeks that the patients received the ibuprofen and sulindac. NSAIDs should not be considered for monotherapy of diabetic neuropathy.64 They may have a limited, adjuvant role for short-term pain relief in patients at low risk of renal dysfunction and GI bleeding who receive adequate education and monitoring. Mexiletine and lidocaine. Information on the use of mexiletine, a type Ib antiarrhythmic medication, for painful diabetic neuropathy is based on a study demonstrating moderate pain relief with intravenous lidocaine.66,67 Mexiletine is the oral analogue of lidocaine and is thought to

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exert its analgesic and antiarrhythmic effects by membrane-stabilizing Na+-channel antagonism. Four welldesigned studies failed to show a statistically significant improvement in pain, paresthesia, or global assessment compared with placebo.66,68-70 One trial suggested that a subset of patients with burning or stabbing pain or those with a high degree of pain benefitted from higher dosages of mexiletine.68 The studies did show that mexiletine is very well tolerated in dosages up to 675 mg/day; however, patients with heart disease were generally excluded. In the absence of clinical data demonstrating efficacy, mexiletine can be recommended only as an alternative agent for patients with extreme, refractory symptoms and no cardiac risk. Levodopa. One double-blind, placebo-controlled study in 25 patients with sensorimotor neuropathy demonstrated a statistically significant reduction in pain.71 The study was too small to make any conclusions about clinical significance, but no adverse effects were observed with the 100-mg dose of levodopa given. Dextromethorphan. Dextromethorphan is a partial antagonist of the N-methyl- D -aspartate receptor, which has been implicated in the mediation of neuropathic pain in animal models. In a double-blind, crossover study in 13 patients, dextromethorphan led to a 24% reduction in pain compared with placebo (p = 0.014), with an average dosage of 381 mg/day.72 In fact, 7 of the 13 patients described their pain relief as “a lot” or “moderate” while taking dextromethorphan. Every patient experienced adverse effects while receiving dextromethorphan (e.g., sedation and dizziness). Clinically, the extremely high average dosage required and the adverse effects all but prohibit use. Topicals: Capsaicin cream and isosorbide dinitrate spray. Capsaicin is extracted from capsicum peppers and produces a dose-dependent de-

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sensitization of type C nociceptive fibers by depleting the neurotransmitter substance P.73,74 The largest published study of an analgesic treatment for diabetic sensorimotor neuropathy was conducted by the Capsaicin Study Group.74 The multicenter study involved 252 patients with painful symptoms severe enough to interfere with daily activities. Patients were randomized to either 0.075% capsaicin or vehicle cream (placebo) for six weeks. Capsaicin proved significantly more effective than placebo in providing pain relief (58.4% versus 45.3%), decreasing pain intensity (38.1% versus 27.4%), and improving global assessment scores (58.4% versus 45.3%) (p < 0.05), although placebo produced very high response rates as well. Burning was the most commonly reported adverse effect, affecting 87 of the 135 patients in the capsaicin group, compared with 23 of the 49 patients in the placebo group; however, the reports of burning tended to diminish and pain relief increased as therapy progressed. Coughing, irritation, and rash were reported by approximately 10% of patients receiving capsaicin. There are several practical considerations in the clinical use of capsaicin cream. First, it must be applied three or four times daily to the affected area, which may be quite large. Second, application results in temporary burning, which is intolerable for many patients already in pain. Finally, as demonstrated by this and other trials, several weeks of diligent use may be needed for capsaicin to have an effect. The recommendation of capsaicin to a patient must be accompanied by practical instructions about handling, adverse effects, and expected results. A pilot study of isosorbide dinitrate spray for diabetic neuropathy demonstrated safety and efficacy in 22 patients with refractory pain and burning.75 In the 12-week, doubleblind, placebo-controlled, crossover

THERAPY UPDATE

study, isosorbide dinitrate spray consistently produced a statistically and clinically significant reduction in pain and burning. The treatment, which consisted of spraying the affected area before bedtime, was extremely well tolerated, with only two patients complaining of transient headache. Relief was provided throughout the night and subsequent day until the next treatment. The study was relatively brief and small, but the results suggest great potential benefit with little risk for severely afflicted patients. Isosorbide dinitrate is not currently available in the United States. Complementary and alternative therapies. Electrostimulation has been shown to provide temporary relief of pain associated with diabetic sensorimotor neuropathy, but the feasibility and efficacy of maintenance therapy remain controversial. A study of transcutaneous electrotherapy randomized 31 patients with diabetic peripheral neuropathy to take a portable electrotherapy machine home for one week of selfadministration.76 Patients were assigned to therapy with either active or inactive electrodes. The therapy for both groups consisted of placing electrodes as instructed and administering electrical shock for 30 minutes every day. Active therapy improved neuropathic symptoms in 15 (83%) of the 18 patients, compared with 5 (38%) of 13 patients receiving sham therapy. No major adverse effects were observed in either group. The therapy had a very low residual effect, and patients’ pain returned within one week of stopping treatment. In a related study, percutaneous electrical nerve stimulation (PENS) was examined for value in the treatment of painful diabetic neuropathy.77 Therapy consisted of using 10 32-gauge “acupuncture-like” needles to puncture the soft tissue and muscle of the foot and leg to a depth of 1– 3 cm and applying alternating frequencies of electrical shock. The

crossover design randomized 50 patients to either electrical stimulation or acupuncture alone, which was considered sham treatment. Patients on active therapy experienced profound reduction in lower-extremity pain (56% versus 14%), increased physical activity (48% versus 13%), and improved sleep quality (41% versus 13%) compared with the sham treatment. Ninety-two percent of patients preferred the active therapy, and a similar majority reported an improved sense of well-being and willingness to pay “extra” for PENS. In theory, electrostimulation could produce analgesia by inducing the release of endogenous opioid-like chemicals, and these trials seem to support a role for electrotherapy. However, there are obvious weaknesses in the study designs and practical obstacles to clinical use. It is almost impossible to compare electrostimulation with a true sham or placebo therapy. In addition, PENS, for all its absence of reported adverse effects, remains relatively invasive. Further, both studies had very strict and extensive exclusion criteria that would prohibit a large fraction of the diabetic population from participating. The results are generally considered preliminary and difficult to imitate and maintain in a clinical setting.39 Thioctic acid, or α-lipoic acid, is an alternative therapy that has recently received attention for use in the treatment of symptomatic sensorimotor neuropathy. In a multicenter, double-blind study in 328 patients with diabetic neuropathy, intravenous infusions of α-lipoic acid proved safe and effective for the short-term relief of pain, paresthesia, and burning.78 Overall, the 600-mg dose produced the optimal statistically and clinically significant pain relief compared with other doses and placebo, and 93% of patients receiving the 600-mg infusions rated their tolerance as either good or very good. The obvious limitation to duplicat-

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ing this success in clinical practice is the requirement for daily 30-minute i.v. infusions, which also presents certain risks. Many herbal manufacturers are now promoting α-lipoic acid for diabetes patients without studies proving effectiveness. The half-life of α-lipoic acid is two to four minutes, making oral products suspect for treatment of neuropathy. Cardiovascular autonomic neuropathy (CAN). Prevention of CAN is essential, because there are very few effective treatments. There is persuasive evidence that the risk of diabetic CAN may be reduced by 68% through the management of hyperglycemia, hyperlipidemia, and hypertension and the use of ACE inhibitors and antioxidants.1,15 Further, effective glycemic control may reverse CAN in the early stages of development. The symptoms of postural hypotension may be reduced by nonpharmacologic measures, such as increasing water consumption and using body stockings.1 Fludrocortisone effectively increases blood pressure, but consideration must be given to the risk of triggering or exacerbating heart failure, edema, and hypertension. Antihypertensives may produce a paradoxical increase in blood pressure by activating or antagonizing α1-, α2-, and β-adrenergic receptors that are inappropriately expressed due to autonomic denervation or dysfunction.1,5,14-16 Clonidine should be initiated with extreme care in this patient population. Midodrine, dihydroergotamine or caffeine, and octreotide have been suggested for the treatment of severe, refractory CAN.1,16 Finally, imbalances in sympathetic and parasympathetic activities may be stabilized or improved with ACE inhibitors and β-blockers such as atenolol, metoprolol, and propranolol.1,15,16 GI autonomic neuropathy. The primary treatment for diabetic GI autonomic neuropathy is glycemic control. Hyperglycemia has been shown to directly reduce and retard

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gastric contractions and the GI emptying rate, and the sensation of premature satiety and fullness is also related to elevated blood glucose levels.20,79,80 Studies have shown that short-term reduction of preprandial hyperglycemia does not lead to a resolution of symptoms, but GI symptoms are much more prevalent in patients with poor glycemic control.19,20,80 Nonpharmacologic treatments are directed at dietary changes, and it is recommended that symptomatic patients reduce the fat content and increase the fiber content of their meals.1,20,80 Perhaps the most frustrating factor is that GI dysfunction itself makes glycemic control extremely challenging, because it becomes virtually impossible to time nutrient absorption with antidiabetic therapy.19 Despite the high prevalence of GERD, constipation, and diarrhea in patients with diabetes, there are conflicting reports about whether the incidence is greater than that in the general population.79,80 Further, there are no unique treatment algorithms for the symptoms of diabetic GERD, constipation, or diarrhea, except that clonidine is suggested for severe cases of diabetic diarrhea to reduce stool volume.1 The current focus of research is the use of prokinetic agents in the treatment of gastropathy and gastroparesis, which have been shown to be much more prevalent in diabetes patients than the general population.1,20,79,80 The most recent development is the failure of the motilin agonist ABT-229 to show greater efficacy than placebo in Phase II FDA trials. Cisapride, metoclopramide, and domperidone have been shown to be effective for the treatment of diabetic gastropathy. The market availability of cisapride is restricted because of the risk of QT-interval prolongation and arrhythmia, to which diabetics with autonomic neuropathy are susceptible.80 Furthermore, the known risk of using cisapride in patients

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with diabetic gastropathy cannot be justified by the relatively insignificant improvement in symptoms demonstrated by clinical trials.79,80 Metoclopramide has been shown to be significantly more effective than cisapride; however, its long-term use carries a risk of CNS adverse effects. 19,79 Domperidone has been found to be as effective as metoclopramide for the relief of symptoms of diabetic gastropathy.18 Domperidone and metoclopramide are both dopamine antagonists, but domperidone does not penetrate the blood– brain barrier to the extent that metoclopramide does, which may account for its more favorable adverse-effect profile.18-20,79 (Domperidone is not currently available in the United States.) Erythromycin is a macrolide antibiotic that directly interacts with motilin receptors; however, the stimulation of GI motility rapidly diminishes with oral administration and duration of use.15,19 Erythromycin can be recommended only for short-term therapy for gastroparesis and should not be administered concurrently with cisapride.19,80 The effect of erythromycin is reduced by hypoglycemia, a critical observation to the study and use of other prokinetic agents.80 In conclusion, the GI transit rate does not correlate with symptoms, and accelerating gastric emptying does not necessarily reduce or resolve symptoms.20 The existing prokinetic agents are only modestly efficacious in symptom relief, and their use is greatly limited by associated adverse effects and rapidly developing tachyphylaxis.20,80 Genitourinary autonomic neuropathy. Neurogenic bladder does not generally respond well to pharmacologic treatments. Bethanechol and doxazosin may reduce urinary retention but may not be sufficient to induce complete bladder voiding, which represents a high risk factor for recurrent urinary-tract infection.1,16 Patients may be able to use

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abdominal massage techniques, such as the Credé method, to initiate micturition, but many eventually require catheterization.1,16 The treatment of diabetic sexual dysfunction must begin with glycemic control. Erectile dysfunction has been shown to directly correlate with hemoglobin A1c levels.81 This correlation of poor glycemic control with severity of sexual dysfunction was not supported in two separate studies of diabetic women; however, both trials demonstrated that the incidence of dysfunction was higher in diabetic women than in the general population.82-84 The next step is to evaluate the patient’s current medications for agents that are known to cause sexual dysfunction (e.g., β-blockers, antidepressants, spironolactone). Female diabetic sexual dysfunction has not been adequately studied, and treatments are virtually unknown. Vaginal dryness and dyspareunia may respond well to the use of water-based lubricants.85 Studies evaluating the effect of phosphodiesterase inhibitors for female sexual dysfunction have not yet been published; however, these agents are generally well tolerated and may provide some benefit in the absence of contraindications.1,16,86 Diabetic erectile dysfunction can be caused by a complex interplay of vascular and neural organic factors and psychological factors; however, it is generally recommended that patients be given a trial of oral medication (i.e., sildenafil, tadalafil, or vardenafil) to improve penile blood supply as much as possible, barring contraindications.24,87-89 Patients may also try intraurethral suppositories or intracavernosal injections of prostaglandin E1 (alprostadil); however, the use of intracavernosal injections is poorly tolerated, with penile pain and fibrotic changes occurring in roughly 10% of patients.24 Men with severe dysfunction may also try vacuum-constriction devices, which are better tolerated than intracavernosal injections.

THERAPY UPDATE

Future treatments. Ruboxistaurin mesylate (LY333531) is a protein kinase Cβ inhibitor in Phase III FDA trials for the treatment of diabetic neuropathy. A year-long, doubleblind, placebo-controlled, Phase II study demonstrated clinically and statistically significant improvement of objective and subjective neurologic endpoints, including overall neurologic examination and patient global assessment.90 Perhaps more important, ruboxistaurin was extremely well tolerated. Three aldose reductase inhibitors are currently in Phase III trials (zenarestat, minalrestat, and zopolrestat). Numerous clinical trials have failed to demonstrate clinically significant changes in symptoms, and their future use may be as preventive treatment. Discussion Diabetic peripheral neuropathy is a common and diverse complication that adversely affects the quality of life and life expectancy of diabetes patients. The key to the pathology is hyperglycemia, but the cascades that bridge the metabolic state with the secondary pathological changes still represent boundless challenges to basic research and clinical intervention. Symptom management typically requires careful use of a combination of agents. Current evidence from clinical trials supports the use of desipramine, amitriptyline, capsaicin, tramadol, gabapentin, bupropion, and venlafaxine as preferred medications for the treatment of diabetic sensorimotor neuropathy. Citalopram, NSAIDs, and opioid analgesics may be used as adjuvant agents. Lamotrigine, oxcarbazepine, paroxetine, levodopa, and α-lipoic acid are alternative considerations. The evidence supporting the use of zonisamide, fluoxetine, mexiletine, dextromethorphan, and phenytoin is considered equivocal, and their risks are generally better defined than their benefits. Transcutaneous elec-

trotherapy and percutaneous electrical nerve stimulation are alternative therapies that have demonstrated efficacy and may represent a hope for patients with severe, refractory pain. Diabetic autonomic neuropathy is extremely difficult to treat, and the risks and adverse effects frequently outweigh the benefits of most pharmacologic therapies. The symptoms of CAN may be ameliorated with fludrocortisone, clonidine, midodrine, dihydroergotamine or caffeine, octreotide, ACE inhibitors, and β-blockers. Gastroparesis may be improved with metoclopramide or erythromycin, but glycemic control is perhaps the best long-term treatment. Erectile dysfunction may respond to phosphodiesterase inhibitors, vacuum-constriction devices, and intracavernosal injections. It is critical that all clinical recommendations be based on a thorough patient review to minimize potentially severe adverse effects. Further, all medications should be initiated at low dosages and adjusted to individual efficacy and adverse effects. Ruboxistaurin represents the current hope for future disease-modifying therapies. Glycemic control remains the foundation of prevention and the prerequisite of adequate treatment of diabetic neuropathy.

5. 6.

7.

8.

9. 10.

11. 12. 13.

14. 15. 16. 17.

Conclusion Diabetic neuropathy is a manyfaceted complication of diabetes that can be managed symptomatically with an array of drugs.

18.

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1999; 33:996-1000. 43. Max MB, Lynch SA, Muir J et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992; 326:1250-5. 44. Gomez-Perez FJ, Choza R, Rios JM et al. Nortriptyline-fluphenazine vs carbamazepine in the symptomatic treatment of diabetic neuropathy. Arch Med Res. 1996; 27:525-9. 45. Gomez-Perez FJ, Rull JA, Dies H et al. Nortriptyline and fluphenazine in the symptomatic treatment of diabetic neuropathy: a double-blind, cross-over study. Pain. 1985; 23:395-400. 46. Sindrup SH, Gram IF, Brosen K et al. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain. 1990; 42:135-44. 47. Sindrup SH, Bjerre U, Dejgaard A et al. The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther. 1992; 52:527-52. 48. Semenchuk MR, Sherman S, Davis B. Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology. 2001; 57:1538-88. 49. Kunz NR, Goli V, Entsuah AR et al. Effect of venlafaxine extended release on diabetic neuropathic pain. Paper presented at Annual Meeting of the American Psychiatric Association. Chicago, IL; 2000 May. 50. Davis JL, Smith RL. Painful peripheral diabetic neuropathy treated with venlafaxine HCl extended release capsules. Diabetes Care. 1999; 22:1909-10. 51. Backonja M, Beydoun A, Edwards KR et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus. JAMA. 1998; 280: 1831-6. 52. Morello CM, Leckband SG, Stoner CP. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathic pain. Arch Intern Med. 1999; 159:1931-7. 53. Hemstreet B, Lapointe M. Evidence for the use of gabapentin in the treatment of diabetic peripheral neuropathy. Clin Ther. 2001; 23:520-31. 54. Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for neuropathic pain syndromes. Drugs. 2000; 60:102952. 55. Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther. 2003; 25:81-104. 56. Rull JA, Quibrera R, Gonzalez-Millan H et al. Symptomatic treatment of peripheral diabetic neuropathy with carbamazepine (Tegretol): double-blind, crossover trial. Diabetologia. 1969; 5:2158. 57. Beydoun A, Kutluay E. Oxcarbazepine. Expert Opin Pharmacother. 2002; 3:59-71. 58. Wilton T. Tegretol in the treatment of diabetic neuropathy. South Afr Med J. 1974; 27:869-72.

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59. Saudek CD, Werns S, Reidenberg MM. Phenytoin in the treatment of diabetic symmetrical polyneuropathy. Clin Pharmacol Ther. 1977; 22(2):196-9. 60. Eisenberg E, Lurie Y, Braker C et al. Lamotrigine reduces painful diabetic neuropathy. Neurology. 2001; 57:505-9. 61. Backonja MM. Use of anticonvulsants for treatment of neuropathic pain. Neurology. 2002; 59(suppl 2):S14-7. 62. Watson CPN, Babul J. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology. 1998; 50:1837-41. 63. Sindrup SH, Anderson G, Madsen C et al. Tramadol relieves pain and allodynia in polyneuropathy: a randomized, doubleblind, controlled trial. Pain. 1999; 83:8590. 64. Harati Y, Gooch C, Swenson M et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998; 50: 1842-6. 65. Cohen KL, Susanne H. Efficacy and safety of nonsteroidal anti-inflammatory drugs in the therapy of diabetic neuropathy. Arch Intern Med. 1987; 147:1442-4. 66. Stracke H, Meyer UE, Schumacher HE et al. Mexelitine in the treatment of diabetic neuropathy. Diabetes Care. 1992; 15: 1550-5. 67. Kastrup J. Clinical note: intravenous lidocaine infusion—a new treatment of chronic painful diabetic neuropathy? Pain. 1987; 28:69-75. 68. Dejgard A, Petersen P, Kastrup J. Mexiletine for treatment of chronic painful diabetic neuropathy. Lancet. 1988; 2:9-11. 69. Wright JM, Oki JC, Graves L. Mexiletine in the symptomatic treatment of diabetic peripheral neuropathy. Ann Pharmacother. 1997; 31:29-33. 70. Oskarsson P, Ljunggren JG, Lins PE. Efficacy and safety of mexiletine in the treatment of painful diabetic neuropathy. Diabetes Care. 1997; 20:1594-7. 71. Ertas M, Sagduyu A, Arac N et al. Use of levodopa to relieve pain from painful symmetrical diabetic polyneuropathy. Pain. 1998; 75:257-9. 72. Nelson KA, Park KM, Robinovitz E et al. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology. 1997; 48:1212-8. 73. Tandan R, Lewis GA, Krusinski PB et al. Topical capsaicin in painful diabetic neuropathy. Diabetes Care. 1992; 15:8-13. 74. Capsaicin Study Group. Treatment of painful diabetic neuropathy with topical capsaicin: a multicenter, double-blind, vehicle-controlled study. Arch Intern Med. 1991; 151:2225-9. 75. Yuen KC, Baker NR, Rayman G. Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray. Diabetes Care. 2002; 25:1699-703. 76. Kumar D, Marshall HJ. Diabetic peripheral neuropathy: amelioration of pain with transcutaneous electrostimulation. Diabetes Care. 1997; 20:1702-5.

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77. Hamza MA, White PF, Craig WF et al. Percutaneous electrical nerve stimulation: a novel analgesic therapy for diabetic neuropathic pain. Diabetes Care. 2000; 23:365-9. 78. Reljanovic M, Reichel G, Rett K et al. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alphalipoic acid): a two year multicenter randomized double-blind placebocontrolled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy. Free Radic Res. 1999; 31:171-9. 79. Talley NJ. Diabetic gastropathy and prokinetics. Am J Gastroenterol. 2003; 98: 264-71. 80. Horowitz M, O’Donovan D, Jones KL et al. Gastric emptying in diabetes: clinical significance and treatment. Diabet Med. 2002; 19:177-94. 81. Romeo JH, Seftel AD, Madhun ZT et al. Sexual function in men with diabetes type 2: association with glycemic control. J Urol. 2000; 163:788-91. 82. Enzlin P, Matheiu C, van den Bruel A et al. Sexual dysfunction in women with type 1 diabetes. Diabetes Care. 2002; 25: 672-7. 83. Kolodney RC. Sexual dysfunction in diabetic females. Diabetes. 1971; 20:557-9. 84. Jovanovic L. Finally, it is our turn! Diabetes Care. 25:787-8. Editorial. 85. Buvat J, Lemaire A. Sexuality of the diabetic woman. Diabetes Metab. 2001; 27(4, pt. 2):S67-75. 86. Boyce EG, Umland EM. Sildenafil citrate:

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a therapeutic update. Clin Ther. 2001; 23: 2-23. Goldstein I, Young JM, Fischer J et al. Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a multicenter, double-blind, placebocontrolled, fixed-dose study. Diabetes Care. 2003; 26:777-83. De Tejada S, Anglin G, Knight JR et al. Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care. 2002; 25:2159-64. Stuckey GA, Jadzinsky MN, Murphy JL et al. Sildenafil citrate for treatment of erectile dysfunction in men with type 1 diabetes. Diabetes Care. 2003; 26:279-84. Vinik AI. New developments in the treatment of neuropathy. www.medscape. com/viewarticle/438361 (accessed 2002 Aug 5).

Appendix—Diabetic neuropathy classification and staging5,a I. Subclinical neuropathy A. Abnormal electrodiagnostic tests 1. Decreased nerve conduction velocity 2. Decreased amplitude of evoked muscle or nerve action potentials B. Abnormal neurologic examination 1. Vibratory and tactile tests 2. Thermal warming and cooling tests 3. Other C. Abnormal autonomic function tests

Diabetic neuropathy

1. Abnormal cardiovascular reflexes 2. Altered cardiovascular reflexes 3. Abnormal biochemical responses to hypoglycemia II. Clinical neuropathy A. Diffuse somatic neuropathy 1. Sensorimotor or distal symmetrical sensorimotor polyneuropathy a. Primarily small-fiber neuropathy b. Primarily large-fiber neuropathy c. Mixed B. Autonomic neuropathy 1. Cardiovascular autonomic 2. Abnormal pupillary function 3. Gastrointestinal autonomic neuropathy a. Gastroparesis b. Constipation c. Diabetic diarrhea d. Anorectal incontinence 4. Genitourinary autonomic neuropathy a. Bladder dysfunction b. Sexual dysfunction C. Focal Neuropathy 1. Mononeuropathy 2. Mononeuropathy multiplex 3. Amyotrophy a American Diabetes Association and American Academy of Neurology. Consensus statement report and recommendations of the San Antonio Conference on Diabetic Neuropathy. Diabetes Care. 1988; 11:592.

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CONTINUING EDUCATION

Continuing Education Diabetic neuropathy: An intensive review

9. Which of the following is a tricyclic antidepressant (TCA) that has demonstrated good efficacy in treating diabetic neuropathic pain?

Article 204-000-04-003-H01 (see page 160) Qualifies for 2.0 hours of CE credit

Learning objectives

After studying this article, the reader should be able to 1. Explain the epidemiology, classification, and disease course of diabetic neuropathy. 2. Compare and contrast the types of diabetic neuropathy. 3. Describe the pathology of diabetic neuropathy. 4. Explain appropriate treatments for diabetic neuropathy. Self-assessment questions

For each question there is only one best answer. 1. Which of the following is the primary risk factor for diabetic neuropathy? a. b. c. d.

Hypertension. Hypercholesterolemia. Hyperglycemia. Smoking.

2. A majority of diabetic patients experience neuropathic pain. a. True. b. False. 3. The first symptoms of sensorimotor neuropathy are experienced in what parts of the body? a. b. c. d.

Arms and legs. Fingers and toes. Head and neck. Neck and back.

4. Negative symptoms are more common than positive symptoms in diabetic neuropathy? a. True. b. False. 5. Which of the following is a hallmark symptom of cardiovascular autonomic neuropathy (CAN)? a. b. c. d.

Orthostatic hypotension. Left ventricular dysfunction. Silent myocardial infarction. Exercise intolerance.

6. Erectile dysfuntion affects what percentage of diabetic men over the age of 50 years? a. b. c. d.

10%. 25%. 50%. 75%.

7. Vasodilator agents have been shown to effect substantial improvements in neuronal blood flow. a. True. b. False. 8. All of the following describe oxidative stress except a. Increase in substrate for advanced glycation end products (AGEs). b. Decrease in substrate for AGEs. c. Increase in precursors for glycoxidation and lipoxidation products. d. Acceleration in free-radical formation.

a. b. c. d.

Sertraline. Bupropion. Citalopram. Amitriptyline.

10. Selective serotonin-reuptake inhibitors are better tolerated than TCAs and are, therefore, recommended as effective monotherapy for diabetic neuropathy. a. True. b. False. 11. Anticholinergic adverse effects commonly associated with TCAs include all of the following except a. b. c. d.

Constipation. Dizziness. Dry mouth. Itching.

12. Isosorbide dinitrate spray is not available in the United States because of its ineffectiveness and significant adverse effects. a. True. b. False. 13. Effective glycemic control may reverse CAN in the early stages of development. a. True. b. False. 14. Which of the following is a promising disease-modifying therapy for diabetic neuropathy? a. b. c. d.

Desipramine. Capsaicin. Ruboxistaurin. Alpha-lipoic acid.

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AJHP continuing education AJHP CE process

The continuing-education (CE) test for this article can only be taken online through ASHP’s CE Testing Center. If you score 70% or better on the test, you will be able to immediately print your own CE statement for your records. You will have two opportunities to pass the CE test, and you may stop and return to the test at any time before submitting your final answers. ASHP will keep a record of the credits you have earned from this and other CE activities, and you will be able to view your own transcript through the online CE service.

176

To view the list of available AJHP CE articles, go to http://www.ashp.org/ceselfstudy/ajhp-ce.cfm. Article: Diabetic neuropathy: An intensive review ACPE #: 204-000-04-003-H01 CE credit: 2.0 hours Expiration date: January 15, 2007 Instructions

ASHP members may go directly to www.ashp.org/ce/, select “Register for Test,” and then select the article for which CE credit is desired. AJHP CE is free to members.

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Nonmembers must go to the ASHP Shopping Cart (www.ashp.org/productsservices), select “Browse Online Catalog,” select “Products” in the navigation bar, and select “Continuing Education.” The fee for non-ASHP members is $30.95 per test. Questions? Call ASHP Customer Service at 301-657-4383. The American Society of HealthSystem Pharmacists is approved by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.