The efficacy of pregabalin for treating pain associated with diabetic peripheral neuropathy in subjects with type 1 or type 2 diabetes mellitus.

OBJECTIVE: The objective of this study was to compare the efficacy and safety of pregabalin for painful diabetic peripheral neuropathy (pDPN) in subjects with type 1 (T1DM) or 2 diabetes mellitus (T2DM). METHODS: Pooled data from 10 randomized clinical trials (pregabalin-treated T1DM and T2DM subjects with pDPN) were analyzed for change from baseline (CFB) scores (pain and sleep disturbance) using mixed model repeated measures (MMRM) through Week 12 and last observation carried forward (LOCF). Adverse events (AEs) were recorded. RESULTS: Pregabalin-treated (T1DM 156 [8.7%]; T2DM 1632 [91.3%]) and placebo subjects (T1DM 92 [9.6%]; T2DM 868 [90.4%]) had comparable baseline demographic characteristics between treatment groups within the same diabetes type. T2DM (vs. T1DM) subjects were ∼10 years older. With pregabalin and placebo, respectively, mean ± SD baseline pain (T1DM: 6.2 ± 1.4 and 6.5 ± 1.6; T2DM: 6.5 ± 1.5 and 6.4 ± 1.5) and sleep scores (T1DM: 5.2 ± 2.4 and 5.2 ± 2.7; T2DM: 5.3 ± 2.5 and 5.1 ± 2.5) were comparable. Using MMRM, mean CFB treatment differences (pregabalin minus placebo) were significantly different for pain and sleep with either diabetes types (all weeks p < .05). With LOCF, pregabalin's odds ratios (ORs) of achieving 30% pain reduction were similar with T2DM (OR, 1.91, 95% CI [1.61, 2.27]) and T1DM (2.01 [1.18, 3.44]) (both p ≤ .01). Pregabalin's ORs of 30% improvement in sleep quality were 1.81 (95% CI, 1.06, 3.09) with T1DM and 2.01 (1.69, 2.39) with T2DM (both p < .05). AEs were consistent with the known safety profile of pregabalin. CONCLUSIONS: Pregabalin significantly improved pain and sleep quality, without a clinically meaningful difference between diabetes types. ClinicalTrial.gov registration: NCT00156078, NCT00159679, NCT00143156, NCT00553475.

Alternative Quantitative Tools in the Assessment of Diabetic Peripheral and Autonomic Neuropathy.

Here we review some seldom-discussed presentations of diabetic neuropathy, including large fiber dysfunction and peripheral autonomic dysfunction, emphasizing the impact of sympathetic/parasympathetic imbalance. Diabetic neuropathy is the most common complication of diabetes and contributes additional risks in the aging adult. Loss of sensory perception, loss of muscle strength, and ataxia or incoordination lead to a risk of falling that is 17-fold greater in the older diabetic compared to their young nondiabetic counterparts. A fall is accompanied by lacerations, tears, fractures, and worst of all, traumatic brain injury, from which more than 60% do not recover. Autonomic neuropathy has been hailed as the "Prophet of Doom" for good reason. It is conducive to increased risk of myocardial infarction and sudden death. An imbalance in the autonomic nervous system occurs early in the evolution of diabetes, at a stage when active intervention can abrogate the otherwise relentless progression. In addition to hypotension, many newly recognized syndromes can be attributed to cardiac autonomic neuropathy such as orthostatic tachycardia and bradycardia. Ultimately, this constellation of features of neuropathy conspire to impede activities of daily living, especially in the patient with pain, anxiety, depression, and sleep disorders. The resulting reduction in quality of life may worsen prognosis and should be routinely evaluated and addressed. Early neuropathy detection can only be achieved by assessment of both large and small- nerve fibers. New noninvasive sudomotor function technologies may play an increasing role in identifying early peripheral and autonomic neuropathy, allowing rapid intervention and potentially reversal of small-fiber loss.

Phenotyping animal models of diabetic neuropathy: a consensus statement of the diabetic neuropathy study group of the EASD (Neurodiab).

NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy. The discussion was divided into five areas: (1) status of commonly used rodent models of diabetes, (2) nerve structure, (3) electrophysiological assessments of nerve function, (4) behavioral assessments of nerve function, and (5) the role of biomarkers in disease phenotyping. Participants discussed the current understanding of each area, gold standards (if applicable) for assessments of function, improvements of existing techniques, and utility of known and exploratory biomarkers. The research opportunities in each area were outlined, providing a possible roadmap for future studies. The meeting concluded with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence of statistically different values between diabetic and control animals in 2 of 3 assessments (nocifensive behavior, nerve conduction velocities, or nerve structure). The participants propose that this framework would allow different research groups to compare and share data, with an emphasis on data targeted toward the therapeutic efficacy of drug interventions.

Relation between risk of falling and postural sway complexity in diabetes.

For older individuals with diabetes, any decline in balance control can be especially problematic since it is often a precursor to an increased risk of falling. This study was designed to evaluate differences in postural motion dynamics and falls risk for older individuals with type 2 diabetes (T2DM) classified as fallers/non-fallers and, to assess what impact exercise has on balance and falls risk. The results demonstrated that the risk of falling is greater for those older individuals with multiple risk factors including diabetes and a previous falls history. The postural motion features of the high-risk individuals (T2DM-fallers) were also different, being characterized by increased variability and complexity, increased AP-ML coupling, less overall COP motion and increased velocity. One suggestion is that these individuals evoked a stiffening strategy during the more challenging postural tasks. Following training, a decline in falls risk was observed for all groups, with this effect being most pronounced for the T2DM-fallers. Interestingly, the COP motion of this group became more similar to controls, exhibiting decreased complexity and variability, and decreased velocity. The reciprocal changes in COP complexity support the broader view that age/disease-related changes in physiological complexity are bi-directional. Overall, these results show that, even for older T2DM individuals at greater risk of falling, targeted interventions can positively enhance their postural dynamics. Further, the finding that the pattern of postural motion variability and complexity was altered highlights that a decline in physiological complexity may not always be negatively associated with aging and/or disease.

Painful diabetic peripheral neuropathy: consensus recommendations on diagnosis, assessment and management.

Painful diabetic peripheral neuropathy (DPN) is common, is associated with significant reduction in quality of life and poses major treatment challenges to the practising physician. Although poor glucose control and cardiovascular risk factors have been proven to contribute to the aetiology of DPN, risk factors specific for painful DPN remain unknown. A number of instruments have been tested to assess the character, intensity and impact of painful DPN on quality of life, activities of daily living and mood. Management of the patient with DPN must be tailored to individual requirements, taking into consideration the co-morbidities and other factors. Pharmacological agents with proven efficacy for painful DPN include tricyclic anti-depressants, the selective serotonin and noradrenaline re-uptake inhibitors, anti-convulsants, opiates, membrane stabilizers, the anti-oxidant alpha-lipoic acid and topical agents including capsaicin. Current first-line therapies for painful DPN include tricyclic anti-depressants, the serotonin and noradrenaline re-uptake inhibitor duloxetine and the anti-convulsants pregabalin and gabapentin. When prescribing any of these agents, other co-morbidities and costs must be taken into account. Second-line approaches include the use of opiates such as synthetic opioid tramadol, morphine and oxycodone-controlled release. There is a limited literature with regard to combination treatment. In extreme cases of painful DPN unresponsive to pharmacotherapy, occasional use of electrical spinal cord stimulation might be indicated. There are a number of unmet needs in the therapeutic management of painful DPN. These include the need for randomized controlled trials with active comparators and data on the long-term efficacy of agents used, as most trials have lasted for less than 6 months. Finally, there is a need for appropriately designed studies to investigate non-pharmacological approaches.

Autonomic imbalance: prophet of doom or scope for hope?

It has long been recognized that cardiac autonomic neuropathy increases morbidity and mortality in diabetes and may have greater predictive power than traditional risk factors for cardiovascular events. Significant morbidity and mortality can now be attributable to autonomic imbalance between the sympathetic and parasympathetic nervous system regulation of cardiovascular function. New and emerging syndromes include orthostatic tachycardia, orthostatic bradycardia and an inability to use heart rate as a guide to exercise intensity because of the resting tachycardia. Recent studies have shown that autonomic imbalance may be a predictor of risk of sudden death with intensification of glycaemic control. This review examines an association of autonomic dysregulation and the role of inflammatory cytokines and adipocytokines that promote cardiovascular risk. In addition, conditions of autonomic imbalance associated with cardiovascular risk are discussed. Potential treatment for restoration of autonomic balance is outlined.

Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting.

BACKGROUND: Despite the relatively high prevalence of gastroparesis and functional dyspepsia, the aetiology and pathophysiology of these disorders remain incompletely understood. Similarly, the diagnostic and treatment options for these two disorders are relatively limited despite recent advances in our understanding of both disorders. PURPOSE: This manuscript reviews the advances in the understanding of the epidemiology, pathophysiology, diagnosis, and treatment of gastroparesis and functional dyspepsia as discussed at a recent conference sponsored by the American Gastroenterological Association (AGA) and the American Neurogastroenterology and Motility Society (ANMS). Particular focus is placed on discussing unmet needs and areas for future research.

Treatment of gastroparesis: a multidisciplinary clinical review.

This clinical review on the treatment of patients with gastroparesis is a consensus document developed by the American Motility Society Task Force on Gastroparesis. It is a multidisciplinary effort with input from gastroenterologists and other specialists who are involved in the care of patients with gastroparesis. To provide practical guidelines for treatment, this document covers results of published research studies in the literature and areas developed by consensus agreement where clinical research trials remain lacking in the field of gastroparesis.

Effect of early addition of rosiglitazone to sulphonylurea therapy in older type 2 diabetes patients (>60 years): the Rosiglitazone Early vs. SULphonylurea Titration (RESULT) study.

AIM: To compare the efficacy, safety and tolerability of adding rosiglitazone (RSG) vs. sulphonylurea (SU) dose escalation in older type 2 diabetes mellitus (T2DM) patients inadequately controlled on SU therapy. METHODS: A total of 227 T2DM patients from 48 centres in the USA and Canada, aged > or =60 years, were randomized to receive RSG (4 mg) or placebo once daily in combination with glipizide 10 mg twice daily for 2 years in a double-blind, parallel-group study. Previous SU monotherapy was (1/4) to (1/2) maximum recommended dose for > or =2 months prior to screening with fasting plasma glucose (FPG) > or =7.0 and < or =13.9 mmol/l. Treatment options were individualized, and escalation of study medication was specifically defined. RESULTS: Disease progression (time to reach confirmed FPG > or =10 mmol/l while on maximum doses of both glipizide and study medication or placebo) was reported in 28.7% of patients uptitrating SU plus placebo compared with only 2.0% taking RSG and SU combination (p < 0.0001). RSG + SU significantly decreased HbA(1c), FPG, insulin resistance, plasma free fatty acids and medical care utilization and improved treatment satisfaction compared with uptitrated SU. CONCLUSIONS: Addition of RSG to SU in older T2DM patients significantly improved glycaemic control and reduced disease progression compared with uptitrated SU alone but without increasing hypoglycaemia. These benefits were associated with increased patient treatment satisfaction and reduced medical care utilization with regards to emergency room visits and length of hospitalization. Early addition of RSG is an effective treatment option for older T2DM patients inadequately controlled on submaximal SU monotherapy.

Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects.

BACKGROUND: Using identical methods, three simultaneous placebo-controlled trials of topiramate for painful diabetic neuropathy (PDN) did not reach significance. This independent yet concurrent placebo-controlled trial used different methods to assess topiramate efficacy and tolerability in PDN. METHODS: This 12-week, multicenter, randomized, double-blind trial included 323 subjects with PDN and pain visual analog (PVA) score of at least 40 on a scale from 0 (no pain) to 100 (worst possible pain). Topiramate (n = 214) or placebo (n = 109) was titrated to 400 mg daily or maximum tolerated dose. Short-acting rescue analgesics were permitted only during the first 6 weeks. RESULTS: Baseline characteristics were comparable between groups except for mean body weight (topiramate, 101.4 kg; placebo, 95.7 kg; p = 0.028). Twelve weeks of topiramate treatment reduced PVA scale score (from 68.0 to 46.2 mm) more effectively than placebo (from 69.1 to 54.0 mm; p = 0.038). Fifty percent of topiramate-treated subjects and 34% of placebo-treated subjects responded to treatment, defined as >30% reduction in PVA scale score (p = 0.004). Topiramate monotherapy also reduced worst pain intensity (p = 0.003 vs placebo) and sleep disruption (p = 0.020 vs placebo). Diarrhea, loss of appetite, and somnolence were the most commonly reported adverse events in the topiramate group. Topiramate reduced body weight (-2.6 vs +0.2 kg for placebo; p < 0.001) without disrupting glycemic control. CONCLUSIONS: Topiramate monotherapy reduced pain and body weight more effectively than placebo in patients with painful diabetic neuropathy.

Diabetic neuropathies.

Diabetic neuropathy (DN) is a common complication of diabetes that often is associated with considerable morbidity and mortality. The epidemiology and natural history of DN is clouded with uncertainty because of confusion regarding the definition and measurement of this disorder. The recent resurgence of interest in the vascular hypothesis, oxidative stress, the neurotrophic hypothesis,and the possibility of the role of autoimmunity has opened up new avenues of investigation for therapeutic intervention. The ability to manage successfully the many different manifestations of diabetic neuropathy depends ultimately on success in uncovering the pathogenic processes underlying this disorder.

Recognizing and treating diabetic autonomic neuropathy.

Diabetic autonomic neuropathy can cause heart disease, gastrointestinal symptoms, genitourinary disorders, and metabolic disease. Strict glycemic control can slow the onset of diabetic autonomic neuropathy and sometimes reverse it. Pharmacologic and nonpharmacologic therapies are available to treat symptoms.

Dermal neurovascular dysfunction in type 2 diabetes.

OBJECTIVE: To review evidence for a relationship between dermal neurovascular dysfunction and other components of the metabolic syndrome of type 2 diabetes. RESEARCH DESIGN AND METHODS: We review and present data supporting concepts relating dermal neurovascular function to prediabetes and the metabolic syndrome. Skin blood flow can be easily measured by laser Doppler techniques. RESULTS: Heat and gravity have been shown to have specific neural, nitrergic, and independent mediators to regulate skin blood flow. We describe data showing that this new tool identifies dermal neurovascular dysfunction in the majority of type 2 diabetic patients. The defect in skin vasodilation is detectable before the development of diabetes and is partially correctable with insulin sensitizers. This defect is associated with C-fiber dysfunction (i.e., the dermal neurovascular unit) and coexists with variables of the insulin resistance syndrome. The defect most likely results from an imbalance among the endogenous vasodilator compound nitric oxide, the vasodilator neuropeptides substance P and calcitonin gene-related peptide, and the vasoconstrictors angiotensin II and endothelin. Hypertension per se increases skin vasodilation and does not impair the responses to gravity, which is opposite to that of diabetes, suggesting that the effects of diabetes override and counteract those of hypertension. CONCLUSIONS: These observations suggest that dermal neurovascular function is largely regulated by peripheral C-fiber neurons and that dysregulation may be a component of the metabolic syndrome associated with type 2 diabetes.

Platelet dysfunction in type 2 diabetes.

Insulin resistance is a uniform finding in type 2 diabetes, as are abnormalities in the microvascular and macrovascular circulations. These complications are associated with dysfunction of platelets and the neurovascular unit. Platelets are essential for hemostasis, and knowledge of their function is basic to understanding the pathophysiology of vascular disease in diabetes. Intact healthy vascular endothelium is central to the normal functioning of smooth muscle contractility as well as its normal interaction with platelets. What is not clear is the role of hyperglycemia in the functional and organic microvascular deficiencies and platelet hyperactivity in individuals with diabetes. The entire coagulation cascade is dysfunctional in diabetes. Increased levels of fibrinogen and plasminogen activator inhibitor 1 favor both thrombosis and defective dissolution of clots once formed. Platelets in type 2 diabetic individuals adhere to vascular endothelium and aggregate more readily than those in healthy people. Loss of sensitivity to the normal restraints exercised by prostacyclin (PGI(2)) and nitric oxide (NO) generated by the vascular endothelium presents as the major defect in platelet function. Insulin is a natural antagonist of platelet hyperactivity. It sensitizes the platelet to PGI(2) and enhances endothelial generation of PGI(2) and NO. Thus, the defects in insulin action in diabetes create a milieu of disordered platelet activity conducive to macrovascular and microvascular events.

Small fiber neuropathy and neurovascular disturbances in diabetes mellitus.

Functional and organic abnormalities in small unmyelinated C fibers are the hallmark of type 2 diabetes. These may be silent clinically or present with burning feet, neurovascular abnormalities, wherein warm, cold, and heat pain thresholds are disturbed in association with impairment in skin blood flow and loss of PGP 9.5 immunostaining nerves in the skin. There is a dysfunctional phase preceding organic structural damage to the neurovascular unit. It coexists with elements of the metabolic syndrome, particularly insulin resistance (IR), elevated systolic blood pressure, and diabetic dyslipidemia i.e. dysfunction of the neurovascular unit may contribute to IR due to compromised blood flow with decreased delivery of fuels to their target tissues. If this proves to be the case, it will become important to re-focus energies on the defective neuropeptidergic regulation of blood flow as an approach to ameliorating diabetes. Because there is a functional phase that precedes structural damage, reversibility of the defect is achievable.

Methods for evaluation of peripheral neurovascular dysfunction.

Measurement of skin blood flow is a sensitive marker of C-fiber neurovascular dysfunction. It precedes development of abnormalities in diabetes mellitus, correlates with in vivo indices of the metabolic syndrome, and may be a "benchmark" for future studies on agents to improve microvascular dysfunction in diabetes mellitus. Skin blood flow can be measured under basal and stimulated conditions. There are different methods of evaluation. Iontophoresis and microdialysis are novel methods of drug delivery and the latter may be used as a means of extracting analytes in the skin. Theses methods are not invasive (iontophoresis) or minimally invasive (microdialysis). They can be performed repeatedly and safely in most patients. The use of microdialysis may be limited by sampling only water-soluble molecules. An alternative to microdialysis is iontophoresis, which works better with polar molecules. A combination of microdialysis and iontophoresis techniques can be useful in assessment of the pharmacokinetics of polar and nonpolar agents and the physiology and pathophysiology of the skin neurovascular system.

Age 85+ years accelerates large-fiber peripheral nerve dysfunction and diabetes contributes even in the oldest-old: the Women's Health and Aging Study.

BACKGROUND: Both diabetes mellitus and advancing age are associated with peripheral nerve dysfunction (PND). However, the independent and potentially synergistic effects of these factors in old age are poorly described, especially among the oldest-old and among people with an existing disability. METHODS: A total of 894 women aged 65+ years participating in the Women's Health and Aging Study received a baseline home interview and clinical examination during which PND was evaluated by the Vibratron II. Age and diabetes were examined in relation to the level of PND (normal, mild, moderate, or severe). Height, alcohol consumption, smoking, report of neurologic symptoms, and diabetes duration were examined as potential confounders. RESULTS: Eighteen percent of the sample reported diabetes, 42% had normal nerve function, and 23.9%, 14.5%, and 19.5% had mild, moderate, and severe PND, respectively. Women aged 85+ years had 6.5, 7.5, and 13.3 times the odds of mild, moderate, and severe PND relative to women aged 65-74 years, adjusted for diabetes and height. Women who reported diabetes had 1.8, 2.4, and 1.6 times the risk of mild, moderate, and severe PND relative to those who did not, adjusted for age and height. No interaction between age and diabetes was observed. CONCLUSIONS: Age is strongly associated with decrements in large-fiber peripheral nerve function in disabled women aged 65+ years, with greatly accelerated risk among those aged 85+ years. Despite the overwhelmingly strong effects of advancing age on PND in this cohort, diabetes remains a significant correlate of PND. Future studies may determine whether prevention or control of diabetes is effective in reducing the occurrence of PND in old age and whether a reduction in PND will translate into reduced disability in this age group.

Independent effects of peripheral nerve dysfunction on lower-extremity physical function in old age: the Women's Health and Aging Study.

OBJECTIVE: To determine the role of peripheral nerve dysfunction (PND) in the disablement pathway. RESEARCH DESIGN AND METHODS: Vibration perception threshold (VPT) was measured in 894 women aged > or = 65 years, and those with normal peripheral nerve function and with mild, moderate, and severe PND were identified. Lower-extremity impairments included quadriceps strength (kilograms) and three progressively difficult balance tasks (able/unable). Functional limitations included rising from a chair (able/unable) and usual pace and fast-paced walking speeds (meters/second). Level of PND was related to impairments and functional limitations in linear and logistic regression models that controlled for potentially confounding factors, including reported diabetes. RESULTS: Level of PND was associated with impaired balance (adjusted odds ratios: 2.21, 1.95, and 3.02 for mild, moderate, and severe PND, respectively, relative to normal, P < 0.05). PND was also associated with decrements in both usual and fast-paced walking speeds (-0.08, -0.08, and -0.15 m/s for usual pace and -0.13, -0.12, and -0.24 m/s for fast-paced walking speed for women with mild, moderate, and severe PND, respectively; P < 0.01 for all). Reported diabetes was not associated with these outcomes in the presence of PND. Some, but not all, of the association between PND and functional limitations was explained by the relationship between PND and impairments. CONCLUSIONS: PND is significantly associated with both lower-extremity impairments and functional limitations in older women, and PND appears to have independent effects on functional limitations. The independent effect of diabetes on these outcomes may be limited when PND is considered. Further research is needed to determine if PND is causally related to disability in old age.