Central Sensitization in Painful and Painless Diabetic Peripheral Neuropathy

Comparison of Central Sensitization in Painful and Painless Diabetic Peripheral Neuropathy Phenotypes: A Multidimensional Psychophysiological Assessment

This research is structured as a cross-sectional observational study. The primary objective is to compare central sensitization across painful and painless phenotypes of diabetic peripheral neuropathy. The study will be conducted among individuals diagnosed with type 2 diabetes mellitus at the Department of Geriatrics, İnönü University Turgut Özal Medical Center. All assessments will be administered in accordance with a rigorously standardized protocol.

Eligible participants will include individuals aged 18 to 80 years who have had a confirmed diagnosis of type 2 diabetes mellitus for at least one year, are capable of comprehending and following verbal instructions in Turkish required for the study procedures, and provide written informed consent.

All statistical analyses will be performed using IBM SPSS Statistics (v.29, Armonk, NY, USA) and JASP (v.0.18, Amsterdam, Netherlands).

Diabetes mellitus (DM) is a well-known metabolic disease characterized by organ dysfunction that arises directly or indirectly from the effects of chronic hyperglycemia, affecting a substantial portion of the global population. According to the International Diabetes Federation, the global prevalence of diabetes was estimated at 9.3% in 2019, with 463 million individuals living with the disease, and this prevalence is projected to rise to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045. Both Type 2 Diabetes (T2DM) and Type 1 Diabetes (T1DM) lead to elevated glucose concentrations and increased inflammatory processes, resulting in a wide range of complications including diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, cardiovascular diseases, musculoskeletal disorders, impaired fracture and wound healing, and pain. Diabetic polyneuropathy (DPN) is a clinical syndrome characterized by pain associated with lesions of the somatosensory nervous system. Between 10-20% of individuals with diabetes experience pain due to the presence of peripheral neuropathy, and there is no universally accepted gold standard for diagnosing DPN; accurately identifying painful DPN remains challenging, particularly because neuropathic pain is often difficult to distinguish from non-neuropathic pain. The mechanisms of neuropathic pain are complex. Peripheral tissue damage can trigger peripheral sensitization; however, central sensitization of the central nervous system plays the predominant role. DM may affect central nervous system processes, leading to central sensitization and dysfunction of pain modulation. Central sensitization is defined as an increased responsiveness of the central nociceptive system, which contributes to the amplification and spread of pain. Recent studies over the past five years have demonstrated that central neuropathic mechanisms may contribute to diabetes-related pain, similar to other neuropathic pain conditions. While there is extensive literature evaluating diabetic neuropathic pain, studies specifically investigating nociceptive pain remain limited. The primary aim of this study is to compare central sensitization across painful and painless diabetic peripheral neuropathy phenotypes.This research is planned as a cross-sectional observational study. It will be conducted in individuals diagnosed with Type 2 diabetes at the Department of Geriatrics, Turgut Özal Medical Center, İnönü University. All assessments will be performed according to a predetermined standardized protocol. Individuals aged 18-80 years who have had a diagnosis of Type 2 diabetes mellitus for at least one year and who can understand and follow verbal instructions in Turkish will be included. Initially, data regarding age, height, weight, smoking and alcohol use, duration of diagnosis, comorbidities, current medications and duration of use, biochemical test results, surgical history, and educational and income levels will be collected. Body mass index will be calculated for all participants. All statistical analyses will be conducted using IBM SPSS Statistics (v.29, Armonk, NY, USA) and JASP (v.0.18, Amsterdam, Netherlands). Descriptive data will be presented as mean ± SD for continuous variables and as percentages/frequencies for categorical variables. Data distribution will be assessed using the Shapiro-Wilk test. Between-group comparisons for continuous variables will be performed using one-way ANOVA or the Kruskal-Wallis test depending on distribution; when significant differences are identified, Tukey HSD or Dunn-Bonferroni post-hoc analyses will be conducted. Categorical variables will be analyzed using chi-square or Fisher's exact tests. Between-group differences will be further examined using one-way ANCOVA, with age, sex, HbA1c, diabetes duration, BMI, MNSI-clinical score, and DN4 score included as covariates. Effect sizes will be reported as partial eta-squared (η²ₚ) for interaction effects and Cohen's d for pairwise comparisons. Correlation analyses will be performed using Pearson or Spearman methods. Effect size assumptions were based on findings from a previous study investigating CPM effectiveness in individuals with diabetic polyneuropathy. That study reported mean CPM values of approximately -7.4 ± 1.0 in the painful DPN group and -2.3 ± 1.6 in the painless DPN group, yielding a mean difference of 5.1 and a pooled SD of 1.35, corresponding to Cohen's d ≈ 0.6. When adapted to a three-group phenotypic design, this effect size was converted to f ≈ 0.30 using the formula f = d / 2. Using these parameters (f = 0.30, α = 0.05, power = 0.80, number of groups = 3), a priori power analysis yielded a required sample size of 111 participants. Accounting for potential data loss, the sample size was increased by 15%, resulting in a final target of 128 participants (approximately 42-43 per group).

Inclusion Criteria:

• Being between 18 and 80 years of age
• Having a diagnosis of Type 2 diabetes mellitus for at least 1 year
• Providing written informed consent to participate in the study

Exclusion Criteria:

• Non-diabetic causes of polyneuropathy (alcohol, chemotherapy, vitamin deficiencies, renal failure, hypothyroidism, etc.)
• Active ulcer, infection, or severe vascular insufficiency in the lower extremity
• Central nervous system disorders (stroke, multiple sclerosis, spinal cord injury, etc.)
• Skin lesions, dermatitis, wounds, or infection in the test areas (foot or forearm)
• Peripheral entrapment neuropathies or related radiculopathies (e.g., carpal tunnel syndrome, C7-C8 radiculopathy)
• Chronic widespread pain syndrome (fibromyalgia, etc.) or active flaring rheumatologic disease
• Dose change within the last 2-4 weeks in medications affecting pain modulation (gabapentinoids, SNRI/TCA, opioids, hypnotics, etc.)