topiramate and Diabetic-Neuropathies

Diabetic peripheral neuropathy and metabolic syndrome (MetS) are both global health challenges with well-established diagnostic criteria and significant impacts on quality of life. Clinical observations, epidemiologic evidence, and animal models of disease have strongly suggested MetS is associated with an elevated risk for cryptogenic sensory peripheral neuropathy (CSPN). MetS neuropathy preferentially affects small unmyelinated axons early in its course, and it may also affect autonomic and large fibers. CSPN risk is linked to MetS and several of its components including obesity, dyslipidemia, and prediabetes. MetS also increases neuropathy risk in patients with established type 1 and type 2 diabetes. In this review we present animal data regarding the role of inflammation and dyslipidemia in MetS neuropathy pathogenesis. Several studies suggest exercise-based lifestyle modification is a promising treatment approach for MetS neuropathy.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diet Therapy; Disease Progression; Dyslipidemias; Exercise; Humans; Hypoglycemic Agents; Metabolic Syndrome; Obesity; Peripheral Nervous System Diseases; Prediabetic State; Risk Factors; Small Fiber Neuropathy; Topiramate

Topiramate is an antiepileptic drug with multiple possible mechanisms of action. Antiepileptic drugs are widely used to treat chronic neuropathic pain (pain due to nerve damage) and fibromyalgia, and many guidelines recommend them.. To assess the analgesic efficacy and associated adverse events of topiramate for chronic neuropathic pain and fibromyalgia in adults (aged 18 years and above).. On 8 May 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, and EMBASE. We reviewed the bibliographies of all randomised trials identified and review articles, and also searched two clinical trial databases, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, to identify additional published or unpublished data.. We included randomised controlled trials (RCTs) with double-blind assessment of participant outcomes following two weeks of treatment or longer (though the emphasis of the review was on studies of eight weeks or longer) that used a placebo or active comparator.. We extracted efficacy and adverse event data, and two study authors examined issues of study quality independently. We performed analysis using two tiers of evidence. The first tier used data where studies reported the outcome of at least 50% pain reduction from baseline, lasted at least eight weeks, had a parallel group design, included 200 or more participants in the comparison, and reported an intention-to-treat analysis. First tier studies did not use last-observation-carried-forward (LOCF) or other imputation methods for dropouts. The second tier used data that failed to meet this standard; second tier results were therefore subject to potential bias.. We included four studies with 1684 participants. Three parallel-group placebo comparisons were in painful diabetic neuropathy (1643 participants), and one cross-over study with diphenhydramine as an active placebo (41 participants) was in lumbar radiculopathy. Doses of topiramate were titrated up to 200 mg/day or 400 mg/day. All studies had one or more sources of potential major bias, as they either used LOCF imputation or were of small size.No study provided first tier evidence for an efficacy outcome. There was no convincing evidence for efficacy of topiramate at 200 to 400 mg/day over placebo.Eighty-two per cent of participants taking topiramate 200 to 400 mg/day experienced at least one adverse event, as did 71% with placebo, and the number needed to treat for an additional harmful effect (NNTH) was 8.6 (95% confidence interval (CI) 4.9 to 35). There was no difference in serious adverse events recorded (6.6% versus 7.5%). Adverse event withdrawals with 400 mg daily were much more common with topiramate (27%) than with placebo (8%), with an NNTH of 5.4 (95% CI 4.3 to 7.1). Lack of efficacy withdrawal was less frequent with topiramate (12%) than placebo (18%). Weight loss was a common event in most studies. No deaths attributable to treatment were reported.. Topiramate is without evidence of efficacy in diabetic neuropathic pain, the only neuropathic condition in which it has been adequately tested. The data we have includes the likelihood of major bias due to LOCF imputation, where adverse event withdrawals are much higher with active treatment than placebo control. Despite the strong potential for bias, no difference in efficacy between topiramate and placebo was apparent.

Topics: Adult; Diabetic Neuropathies; Fibromyalgia; Fructose; Humans; Neuralgia; Neuroprotective Agents; Randomized Controlled Trials as Topic; Topiramate

Topics: Amines; Anti-Asthmatic Agents; Anticonvulsants; Antidepressive Agents; Antitussive Agents; Cyclohexanecarboxylic Acids; Dextromethorphan; Diabetic Neuropathies; Fructose; Gabapentin; gamma-Aminobutyric Acid; Ganglia, Spinal; Humans; Lamotrigine; Mexiletine; Nerve Fibers; Posterior Horn Cells; Pregabalin; Selective Serotonin Reuptake Inhibitors; Sodium Channels; Topiramate; Triazines

To review the possible role of topiramate for the treatment of neuropathic pain and, specifically, the pain of diabetic peripheral neuropathy.. Clinical studies and abstracts were identified by using PubMed (January 1966--October 2003), Ovid (January 1966--December 2003), and International Pharmaceutical Abstracts (January 1970--December 2003) and by reviewing bibliographies of published studies. Key search terms included pain, peripheral neuropathy, diabetes, and topiramate. English-language studies were identified, as were pertinent references from these articles.. Published data are limited on the successful use of topiramate in the treatment of neuropathic pain syndromes, and only three prospective studies evaluated the effectiveness of topiramate in diabetic peripheral neuropathy. In addition, the use of topiramate to treat diabetic neuropathic pain syndromes successfully may be limited by patients' inability to tolerate the adverse effects associated with the agent.. Topiramate has been used successfully in relieving the pain of various neuropathies, including painful diabetic peripheral neuropathy. Randomized controlled trials that specifically focus on the use of topiramate in patients with painful diabetic peripheral neuropathy are needed to confirm the initial findings in case reports, abstracts, and small clinical trials that have focused on treating numerous neuropathic pain syndromes, including diabetic peripheral neuropathy.

Topics: Adult; Diabetic Neuropathies; Drug Administration Schedule; Fructose; Humans; Neuroprotective Agents; Randomized Controlled Trials as Topic; Severity of Illness Index; Topiramate

The Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) is a validated comprehensive questionnaire designed to capture the entire spectrum of DN related to large fiber, small fiber, and autonomic neuropathy not captured in existing instruments. We aimed to determine if the Norfolk QOL-DN could be used to capture changes in QOL that correlate with nerve fiber-specific objective measures in a placebo-controlled trial of two agents that affect different nerve fibers.. Sixty patients with DN were allocated to treatment on ruboxistaurin (RBX) (n = 18), topiramate (TPX) (n = 18), or placebo (n = 18). QOL-DN was administered and objective measures of nerve function were performed at entry and end of the study period.. Total QOL scores improved significantly in the active treatment groups (RBX -9.56 ± 4.13; TPX -12.22 ± 2.76) but not in placebo (-5.56 ± 3.49). There were differences in nerve function improvement between treatments. Neurological symptom scores (NSS) improved with TPX from 5.5 (2.3) to 4.3 (0.65) (p = .007), sensory scores improved with TPX from 15.5 (1.79) to 8.3 (1.19) (p < .001), motor scores did not change, and sensory and motor impairment scores improved with TPX from 18.8 (2.15) to 12.1 (1.71) (p = .003). Total neuropathy scores (TNS) improved with TPX from 24.35 (2.61) to 16.35 (2.02) (p = .001). Neuropathy total symptom score-6 (NTSS-6) changes were significant for both treatments: RBX 4.38 (0.75) to 1.49 (0.38) (p < .001) and TPX 7.57 (1.3) to 4.26 (0.95) (p = .036). Changes in QOL-DN large fiber subscores correlated (Spearman's rank) significantly with changes in NTSS-6 (r = 0.55; p < .0001), NSS (r = 0.31; p < .04), neuropathy impairment score (NIS) (r = 0.35; p < .02), and TNS (r = 0.48; p < .0006). Changes in QOL-DN small fiber subscores correlated significantly with changes in NTSS-6 total scores (r = 0.40; p < .005) and intraepidermal nerve fiber density (IENFD) (r = -0.29; p < .05).. Ruboxistaurin produced significant improvement in large fiber measures while TPX produced significant changes in small fiber measures. The Norfolk QOL-DN tool differentiated between these changes captured in the fiber-specific domains. Correlations were found between objective measures of neuropathy and total QOL, but those with nerve fiber domain scores were modest and reinforce the need to quantify QOL as an endpoint in neuropathy independent of other measures.

Topics: Adult; Aged; Anticonvulsants; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Fructose; Humans; Indoles; Male; Maleimides; Middle Aged; Placebos; Protein Kinase Inhibitors; Quality of Life; Research Design; Surveys and Questionnaires; Topiramate

To evaluate topiramate treatment on nerve function using electrophysiologic methods and a non-inferiority clinical trial design.. A double-blind, multicenter, placebo-controlled trial was conducted in patients with painful diabetic polyneuropathy (n = 67). Change in peroneal motor nerve conduction velocity (NCV) was the primary outcome. NCVs of sural sensory and ulnar nerves, and amplitude and latency changes were measured secondarily. Peripheral nerve function was also evaluated in a patient subgroup reporting treatment-emergent paresthesias.. Least squares mean decrease in NCV was greater for placebo (-0.2 m/s) than for topiramate treatment (-0.1 m/s) (95% CI: -1.30, 1.42). Secondary measures showed no decrease in nerve function for topiramate-treated patients. Neurophysiologic measures were similar in patients with and without paresthesias. The most common adverse events with topiramate were paresthesias, anorexia, weight decrease, and taste perversion.. This nerve conduction study found no evidence that topiramate is associated with deterioration of nerve function.

Topics: Aged; Anticonvulsants; Diabetic Neuropathies; Double-Blind Method; Female; Fructose; Humans; Male; Middle Aged; Neural Conduction; Peroneal Nerve; Sural Nerve; Topiramate; Ulnar Nerve

The aim of this study was to further assess the long-term safety and effectiveness of open-label topiramate therapy in subjects with moderately to severely painful diabetic peripheral neuropathy (DPN).. Adults aged 18 to 75 years received open-label topiramate (25-600 mg/d for 26 weeks) in an extension of a previously published randomized, double-blind trial comparing topiramate with placebo. Safety analyses included adverse event (AE) reports and clinical laboratory tests. Metabolic end points included body weight and glycosylated hemoglobin (HbA(1c)). Effectiveness analyses included a 100-mm pain visual analog (PVA) scale, worst and current pain severity, and sleep disruption.. Two hundred five subjects participated in this open-label extension study (118 formerly treated with topiramate and 87 who formerly received placebo). The groups did not differ in baseline demographics or disease characteristics. One hundred twenty-four (60.5%) subjects (68.6% of former topiramate recipients and 49.4% of former placebo recipients) completed the extension study; the most common reason for discontinuation was an AE (27.3% of subjects). AEs among subjects who received > or =1 dose of topiramate (n = 298) included upper respiratory tract infection (16.1%), anorexia (15.1%), diarrhea (12.8%), nausea (12.8%), paresthesia (10.7%), and headache (10.1%). Baseline pain scores were lower in those formerly treated with topiramate (n = 117) than in the former placebo group (n = 86) (PVA: 43.3 vs 52.5, P = 0.014; worst pain: 1.9 vs 2.5, P < 0.001; current pain: 1.6 vs 1.9, P = 0.026; sleep disruption: 3.6 vs 4.6, P = 0.021). At the final visit, PVA, current pain, and sleep disruption scores were not significantly different between the former topiramate and former placebo groups, but worst pain differed significantly (1.4 vs 1.8; P = 0.025). Mean weight loss from the start of topiramate therapy was 5.2 and 5.3 kg in the former topiramate and former placebo groups, respectively (P < 0.001 vs baseline). Mean HbA(1c) values before and after topiramate treatment were 7.7% and 7.4%, respectively, in the former topiramate group (P = 0.004 vs baseline), and 7.6% and 7.1%, respectively, in the former placebo group (P < 0.001 vs baseline).. Although 39.5% of subjects discontinued, most often due to AEs, the results of this 26-week, open-label extension study with topiramate (up to 600 mg/d) in subjects with moderately to severely painful DPN suggest that pain relief was effective and durable.

Topics: Adolescent; Adult; Aged; Anorexia; Anticonvulsants; Body Weight; Diabetic Neuropathies; Diarrhea; Double-Blind Method; Female; Fructose; Humans; Male; Middle Aged; Pain; Pain Measurement; Respiratory Tract Infections; Sleep Deprivation; Time Factors; Topiramate

To evaluate the efficacy and tolerability of topiramate in patients with painful diabetic polyneuropathy.. Patients with moderate to extreme pain (0-4 Categorical Pain Scale score > or = 2) were randomized to placebo or topiramate (100, 200, or 400 mg/day) in three similar double-blind trials. The primary efficacy analysis was pain reduction from final visit to baseline in the 100-mm Visual Analog Scale (VAS) for the intent-to-treat populations.. After 18-22 weeks of double-blind treatment, pain reductions were numerically greater with topiramate in two studies but differences between topiramate and placebo in VAS scores or in the secondary efficacy endpoints did not reach statistical significance in any of the three studies. Across all studies, 24% of topiramate-treated patients and 8% of placebo-treated patients discontinued due to adverse events; groups did not differ in the occurrence of serious adverse events.. These studies did not find topiramate to be significantly more effective than placebo in reducing pain scores in patients with painful diabetic polyneuropathy. Several design features may have precluded the studies from having sufficient sensitivity to differentiate effective and ineffective treatments. The study design and results are instructive for other investigators designing future clinical studies in neuropathic pain.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Diabetic Neuropathies; Dose-Response Relationship, Drug; Double-Blind Method; Fructose; Humans; Male; Middle Aged; Neuralgia; Neuroprotective Agents; Pain Measurement; Topiramate

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.. 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.. 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.. Topiramate monotherapy reduced pain and body weight more effectively than placebo in patients with painful diabetic neuropathy.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Appetite; Appetite Depressants; Body Weight; Diabetic Neuropathies; Double-Blind Method; Female; Fructose; Humans; Leg; Male; Middle Aged; Neuralgia; Patient Dropouts; Sleep Disorders, Intrinsic; Topiramate; Treatment Outcome

The current study aimed to test the neuroprotective action of topiramate in mouse peripheral diabetic neuropathy (DN) and explored some mechanisms underlying this action. Mice were assigned as vehicle group, DN group, DN + topiramate 10-mg/kg and DN + topiramate 30-mg/kg. Mice were tested for allodynia and hyperalgesia and then spinal cord and sciatic nerves specimens were examined microscopically and neurofilament heavy chain (NEFH) immunostaining was performed. Results indicated that DN mice had lower the hotplate latency time (0.46-fold of latency to licking) and lower von-Frey test pain threshold (0.6-fold of filament size) while treatment with topiramate increased these values significantly. Sciatic nerves from DN control mice showed axonal degeneration while spinal cords showed elevated GFAP (5.6-fold) and inflammatory cytokines (∼3- to 4-fold) but lower plasticity as indicated by GAP-43 (0.25-fold). Topiramate produced neuroprotection and suppressed spinal cord GFAP/inflammation but enhanced GAP-43. This study reinforces topiramate as neuroprotection and explained some mechanisms included in alleviating neuropathy.

Topics: Animals; Diabetes Mellitus; Diabetic Neuropathies; Disease Models, Animal; GAP-43 Protein; Hyperalgesia; Intermediate Filaments; Mice; Neuroprotection; Topiramate

This study assesses the antinociceptive effect induced by different dosages of topiramate (TP), an anticonvulsant drug that is orally administered in models of neuropathic pain and acute pain in rats and mice, respectively. Orally administered TP (80 mg/Kg) in mice causes antinociception in the first and second phases of a formalin test, while in doses of 20 and 40 mg/Kg it was only effective in the second phase. TP (80 mg/Kg, p.o) also exhibited antinociceptive action in the hot plate test, however, it did not have an effect in the capsaicin test in mice, nor in the model of neuropathic pain in diabetic rats. The antinociceptive effect caused by TP (80 mg/Kg, p.o) in the formalin test was reversed by prior treatment with naloxone (opioid antagonist), but not with glibenclamide (antagonist of the potassium channel), ondansetron (antagonist of the serotonin 5HT3 receptor) or cyproheptadine (antagonist of the serotonin 5HT2A receptor).The data show that TP has an important antinociceptive effect in the models of nociception induced by chemical (formalin) or thermal (hot plate) stimuli, and that the opioid system plays a part in the antinociceptive effect, as shown by formalin.

Topics: Acute Disease; Analgesics; Animals; Diabetic Neuropathies; Disease Models, Animal; Fructose; Male; Mice; Pain; Pain Measurement; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin, 5-HT3; Topiramate

Topics: Diabetic Neuropathies; Fructose; Humans; Neuroprotective Agents; Topiramate

Diabetic peripheral neuropathy affects 5 to 50% of people with diabetes in the United States. It is a progressive disorder that results in a gradual decrease in peripheral sensation and eventually complete loss of sensation. Patients with diabetic peripheral neuropathy are challenging to treat because of intolerable adverse medication effects and the development of tolerance to medical treatment. We present the case of a patient with peripheral neuropathy that was unresponsive to usual therapies. She experienced significant relief with the administration of topiramate. Topiramate is an anticonvulsant that is gaining recognition in the treatment of patients with neuropathic pain syndromes.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Fructose; Humans; Middle Aged; Neuroprotective Agents; Pain; Topiramate

Topics: Administration, Oral; Amyloid; Diabetes Mellitus; Diabetic Neuropathies; Drug Combinations; Drug Delivery Systems; Fructose; Humans; Hypoglycemic Agents; Indoles; Insulin; Insulin Lispro; Islet Amyloid Polypeptide; Maleimides; Neuroprotective Agents; Topiramate

We describe a case of bilateral acute angle closure glaucoma associated with oral topiramate therapy. A 64 year old woman developed bilateral acute angle closure glaucoma two weeks after beginning topiramate therapy for peripheral diabetic neuropathy. A topical and systemic anti-glaucomatous treatment were given and laser peripheral iridotomies were performed and, the intraocular pressure were stabilized. However, the anterior chambers remained very shallow and peripheral ciliochoroidal detachment was observed and confirmed echographically. Assuming that the mechanism of acute bilateral simultaneous angle closure glaucoma differs from the common pupillary block, and is related to external cause, the topiramate therapy was discontinued, and the patient was treated with cycloplegic agent and steroids. A gradual deepening of the anterior chamber and resolution of the choroidal edema were accompanied by improvement of visual acuity and corneal clarity. The presumed mechanism of drug related acute bilateral angle closure glaucoma is choroidal effusion and detachment associated with forward budging of the iris-lens diaphragm. This, in turn, causes a shallow anterior chamber and blockage of the ocular draining system.

Topics: Cornea; Diabetic Neuropathies; Female; Fructose; Functional Laterality; Glaucoma, Angle-Closure; Humans; Middle Aged; Mydriatics; Neuroprotective Agents; Steroids; Topiramate; Ultrasonography; Visual Acuity