pregabalin and Diabetes-Mellitus--Type-1

Diabetes is a worldwide epidemic, and associated neuropathy is its most costly and disabling complication. Given the rising prevalence of painful diabetic neuropathy, it is increasingly important that we understand the best ways to diagnose and treat this condition. Diagnostic tests in this field are evolving rapidly. These include the use of skin biopsies to measure small unmyelinated fibers, as well as even newer techniques that can measure both small unmyelinated fibers and large myelinated fibers in the same biopsy. The main treatments for painful diabetic neuropathy remain management of the underlying diabetes and drugs for the relief of pain. However, emerging evidence points to major differences between type 1 and type 2 diabetes, including the ability of glycemic control to prevent neuropathy. Enhanced glucose control is much more effective at preventing neuropathy in patients with type 1 diabetes than in those with type 2 disease [corrected]. This dichotomy emphasizes the need to study the pathophysiologic differences between the two types of diabetes, because different treatments may be needed for each condition. The impact of the metabolic syndrome on neuropathy in patients with type 2 diabetes may account for the difference between the two types of diabetes and requires further study. Finally, neuropathic pain is under-recognized and undertreated despite an ever evolving list of effective drugs. Evidence exists to support several drugs, but the optimal sequence and combination of these drugs are still to be determined.

Topics: Amines; Analgesics; Analgesics, Opioid; Biopsy; Cyclohexanecarboxylic Acids; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Duloxetine Hydrochloride; Gabapentin; gamma-Aminobutyric Acid; Humans; Hypoglycemic Agents; Pregabalin; Sensory Thresholds; Skin; Thiophenes; Touch Perception

Limited information exists regarding the efficacy of pregabalin in Chinese patients with painful diabetic peripheral neuropathy (pDPN).. An 11-week double-blind placebo-controlled trial was performed in Chinese pDPN patients randomized (1 : 1) to 300 mg/day pregabalin or placebo. The primary outcome was change from baseline to endpoint in mean pain score (MPS; 0, no pain; 10, worst possible pain; using the mean of the last seven daily pain scores). Secondary outcomes included weekly MPS and responder status (MPS reduced by ≥30% or ≥50% vs baseline). Subgroup analysis assessed patients with severe (≥7) baseline MPS. Adverse events (AEs) were reported.. In all, 620 patients were randomized (pregabalin, n = 313; placebo, n = 307). Improvement in MPS with pregabalin versus placebo was not significant (P = 0.0559). Post hoc sensitivity analyses, excluding one patient/site due to Good Clinical Practice (GCP) non-compliance, showed pregabalin significantly improved MPS when excluding the patient (P = 0.0448) or site (P = 0.0142). Pregabalin significantly improved weekly MPS (P = 0.0164) and ≥50% responders at endpoint (P = 0.0384). Improvement in proportion of ≥30% responders, impression of change, pain intensity, and sleep did not differ significantly between the treatment groups. In the severe pDPN subpopulation, pregabalin significantly improved MPS versus placebo (P = 0.0040). The most commonly reported AE was dizziness (9.6% vs 3.9% with placebo).. Pregabalin did not significantly improve the primary measure of pain in the trial. Significant reductions in MPS were observed when excluding the GCP non-compliant patient/site and in the severe pDPN subpopulation. Pregabalin was well tolerated in Chinese pDPN patients.

Topics: Adolescent; Adult; Aged; Asian People; Biomarkers; Calcium Channel Blockers; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pain Measurement; Pregabalin; Safety; Treatment Outcome; Young Adult

We aimed to identify doses of mirogabalin (DS-5565) providing clinically meaningful efficacy with manageable side effects for treatment of diabetic peripheral neuropathic pain (DPNP).. Adults (≥18 years) with type 1 or 2 diabetes, HbA₁c ≤10% at screening, and DPNP for ≥6 months were eligible for study participation. Subjects (n = 452) were randomized (2:1:1:1:1:1:1 ratio) to placebo, dose-ranging mirogabalin (5, 10, 15, 20, and 30 mg/day), or pregabalin (300 mg/day) for 5 weeks. The primary end point was weekly change in average daily pain score (ADPS; 0 to 10 numeric rating scale) from baseline to week 5 (minimally meaningful effect, ≥1.0-point decrease versus placebo). ANCOVA was conducted using last observation carried forward, and treatment effect least squares (LS) means were provided for each contrast. Safety assessments included adverse events (AEs), clinical laboratory tests, and electrocardiograms.. LS mean differences in change in ADPS from baseline to week 5 versus placebo were -0.22, -0.53, -0.94, -0.88, and -1.01 for the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively, and -0.05 in the pregabalin group (P < 0.05 versus placebo for mirogabalin 15, 20, and 30 mg/day). Most frequent AEs (n = 277) were primarily mild to moderate dizziness (9.4%), somnolence (6.1%), and headache (6.1%); otherwise, mirogabalin was well tolerated.. Mirogabalin 15, 20, and 30 mg/day had statistically significant reductions in ADPS versus placebo, and mirogabalin 30 mg/day also met the criteria of minimally meaningful effect. Mirogabalin may be a promising new treatment option for patients with DPNP.

Topics: Adult; Aged; Analgesics; Bridged Bicyclo Compounds; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Dose-Response Relationship, Drug; Double-Blind Method; Female; gamma-Aminobutyric Acid; Humans; Male; Middle Aged; Neuralgia; Placebos; Pregabalin; Treatment Outcome

To evaluate the efficacy, safety and pharmacokinetics of pregabalin in treating neuropathic pain associated with diabetic peripheral neuropathy in Japanese patients.. A randomized, double-blind, placebo-controlled, multicentre 14 week clinical trial was conducted. Japanese patients with diabetic peripheral neuropathy (n = 317) were randomized to receive placebo or pregabalin at 300 or 600 mg/day. The primary efficacy measure was a change of mean pain score from baseline to end-point from patients' daily pain diaries.. Significant reductions in pain were observed in patients treated with pregabalin at 300 and 600 mg/day vs. placebo (P < 0.05). Improvements in weekly pain scores were observed as early as week 1 and were sustained throughout the study period (300 and 600 mg/day difference from placebo at study end-point, -0.63 and -0.74, respectively). Pregabalin produced significant improvements in weekly sleep interference scores, the short-form McGill Pain Questionnaire, the Medical Outcomes Study-Sleep Scale, the 36-item Short-Form Health Survey scale, and the Patient and Clinical Global Impression of Change. Patient impressions of numbness, pain and paraesthesia were also significantly improved. Regarding treatment responders, 29.1 and 35.6% of patients treated with 300 and 600 mg/day, respectively, reported ≥ 50% improvement in mean pain scores (vs. 21.5% for placebo). Pregabalin was well tolerated; somnolence (26%), dizziness (24%), peripheral oedema (13%) and weight gain (11%) were the most common adverse events and generally were reported as mild to moderate.. Pregabalin was effective in reducing pain and improving sleep disturbances due to pain, and was well tolerated in Japanese patients with painful DPN.

Topics: Analgesics; Asian People; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Drug Administration Schedule; Female; gamma-Aminobutyric Acid; Humans; Male; Middle Aged; Pain Measurement; Placebos; Pregabalin; Surveys and Questionnaires; Treatment Outcome

Anxiety Disorders and Posttraumatic Stress Disorders (PTSD) associated with type-1 diabetes mellitus (T1DM) are increasingly common comorbidities and the treatment is quite challenging. In that sense, evidence indicates that the anticonvulsant pregabalin is highly effective in treating severe cases of anxiety, as well as PTSD and diabetic neuropathic pain which is also very prevalent in T1DM. Herein, the short- and long-term effects of a single injection of pregabalin on the acquisition of a fear extinction memory and parameters of anxiety in induced-T1DM animals were investigated. For that, we used the contextual fear conditioning (CFC) and elevated plus maze paradigms, respectively. A putative antioxidant activity was also evaluated. Our findings demonstrated that induced-T1DM animals presented greater expression of fear memory, difficulty in extinguishing this fear memory, associated with a more pronounced anxiety-like response. Pregabalin was able to induce a short and long-lasting effect by facilitating the acquisition of the fear extinction memory and inducing a later anxiolytic-like effect. Also, the increased lipid peroxidation levels in the hippocampus and prefrontal cortex of induced-T1DM rats were reduced after pregabalin injection, while the decreased levels of reduced glutathione were increased in the hippocampus. Despite the need for more studies to understand the mechanism of action of pregabalin under these conditions, our data demonstrate for the first time that a single injection of pregabalin in a specific time window was able to improve behavioral parameters in addition to inducing neuroprotective effect. Thus, pregabalin has potential worth exploring for the treatment of PTSD and/or Anxiety associated with T1DM.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Diabetes Mellitus, Type 1; Extinction, Psychological; Fear; Pregabalin; Rats

Effectively treating chronic pain remains a therapeutic challenge in the clinic. Recent evidence has shown the inhibition of the soluble epoxide hydrolase (sEH) to be an effective strategy to limit chronic pain in preclinical models, horses and companion animals. Determining the safety of sEH inhibition in addition to this demonstrated efficacy is a critical step to the further development of sEH inhibitors (sEHI) as analgesics. Here we describe a comparison of the sEHI TPPU with other first in class analgesics for human chronic pain. We assess the development of tolerance to the analgesia mediated by TPPU with extended use. We also assess for CNS effects by measuring changes in motor control and functioning. The sEHI are multimodal analgesics that have demonstrated potent efficacy against chronic pain. They have previously been tested and show no reward potential using operant methods. The results of the current experiments show that they lack motor function effects and also lack the development of tolerance with extended dosing.

Topics: Analgesics; Animals; Chronic Pain; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Drug Tolerance; Enzyme Inhibitors; Epoxide Hydrolases; Gait Analysis; Male; Morphine; Phenylurea Compounds; Piperidines; Pregabalin; Rats; Rats, Sprague-Dawley; Streptozocin

We identified novel (3R, 5S)-3-aminomethyl-5-methanesulfanyl hexanoic acid (5a: DS75091588) and (3R, 5S)-3-aminomethyl-5-ethanesulfanyl hexanoic acid (6a: DS18430756) as sulfur-containing γ-amino acid derivatives that were useful for the treatment of neuropathic pain. These two compounds exhibited a potent analgesic effect in animal models of both type I diabetes and type II diabetes, and good pharmacokinetics.

Topics: Animals; Calcium Channels; Caproates; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Ligands; Mice; Molecular Structure; Neuralgia; Sulfhydryl Compounds

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).. 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.. 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.. Pregabalin significantly improved pain and sleep quality, without a clinically meaningful difference between diabetes types. ClinicalTrial.gov registration: NCT00156078, NCT00159679, NCT00143156, NCT00553475.

Topics: Analgesics; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Drug Monitoring; Dyssomnias; Female; Humans; Male; Middle Aged; Pain Measurement; Pregabalin; Randomized Controlled Trials as Topic; Treatment Outcome

Patients with diabetes often develop peripheral nerve complications, including numbness and pain in the extremities. Diabetes-induced peripheral neuropathic pain is characterized by hypersensitivity to innocuous stimuli, known as tactile allodynia. Pregabalin (PGN) is currently used to treat diabetes-induced peripheral neuropathy and alleviates allodynia. In the present study, we demonstrated that the antiallodynic effect of PGN on diabetic mice was modulated by circadian changes in its intestinal absorption. A single intraperitoneal administration of 200 mg/kg streptozotocin (STZ) to mice induced type I diabetic pathologic changes that were accompanied by tactile allodynia. The intensity of tactile allodynia in STZ-induced diabetic mice was alleviated by the oral administration of PGN; however, the antiallodynic effect varied according to its dosing time. The analgesic effect of PGN was enhanced by its administration at the times of day when its intestinal absorption was accelerated. Organic cation transporter novel type 1 (Octn1) mediated the uptake of PGN into intestinal epithelial cells. The expression of Octn1 in the small intestine of STZ-induced diabetic mice oscillated in a circadian time-dependent manner. This oscillation in Octn1 appeared to cause the time of day-dependent changes in the intestinal absorption of PGN. Similar dosing time dependencies of the antiallodynic effect of PGN and oscillation in Octn1 expression were also detected in type II diabetic db/db mice. These results suggested that the dosing time-dependent differences in the analgesic effect of PGN were attributable to circadian oscillations in the intestinal expression of Octn1 and also that optimizing its dosing schedule may assist in achieving rational pharmacotherapy for diabetes-induced peripheral neuropathic pain.

Topics: Analgesics; Animals; Calcium Channels; Carrier Proteins; Circadian Rhythm; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Epithelial Cells; gamma-Aminobutyric Acid; Humans; Hyperalgesia; Intestinal Absorption; Jejunum; Membrane Proteins; Mice, Inbred ICR; Organic Cation Transport Proteins; Pregabalin; Spinal Cord; Symporters; Time Factors; Touch

Topics: Adalimumab; Analgesics; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Antidepressive Agents; Biological Products; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Drug Interactions; Duloxetine Hydrochloride; Female; gamma-Aminobutyric Acid; Humans; Pregabalin; Psoriasis; Thiophenes; Young Adult

Topics: Adalimumab; Analgesics; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Drug Interactions; Duloxetine Hydrochloride; Female; gamma-Aminobutyric Acid; Humans; Pregabalin; Psoriasis; Selective Serotonin Reuptake Inhibitors; Thiophenes; Young Adult