Diabetic neuropathy is one of the most common and debilitating complications of diabetes mellitus, affecting nearly 50% of patients with long-standing disease. Among its various forms, diabetic peripheral neuropathy (DPN) is the most prevalent and is characterized by burning pain, tingling, hyperalgesia, and numbness in the extremities, significantly impairing patients’ quality of life. Neuropathic pain not only leads to poor sleep, depression, and anxiety but also contributes to immobility, increased risk of falls, and, in advanced cases, non-healing ulcers and amputations. Its multifactorial pathophysiology involves metabolic disturbances, microvascular ischemia, oxidative stress, and immune-mediated inflammatory pathways leading to axonal degeneration and demyelination.[1] Conventional management of diabetic neuropathic pain largely relies on pharmacological therapies, including anticonvulsants (gabapentin, pregabalin), antidepressants (duloxetine, amitriptyline), and various analgesics. While these agents provide symptomatic relief for many patients, they are often associated with suboptimal efficacy and significant adverse effects such as sedation, dizziness, gastrointestinal intolerance, and drug dependence. Furthermore, treatment adherence is poor due to the need for long-term daily medication. This has driven the search for alternative and more sustainable therapies.[2] Botulinum toxin type A (Botox) has emerged as a promising therapeutic modality in managing chronic neuropathic pain. Traditionally used in the treatment of spasticity, dystonia, and cosmetic indications, botulinum toxin has shown analgesic properties independent of its muscle-paralyzing action. The mechanisms by which it relieves pain are multifaceted: it inhibits peripheral release of pain mediators such as substance P, calcitonin gene-related peptide (CGRP), and glutamate; it decreases peripheral sensitization; and it modulates central pain pathways through retrograde axonal transport. Several clinical trials and meta-analyses have demonstrated its efficacy in refractory neuropathic pain conditions, including postherpetic neuralgia, trigeminal neuralgia, and diabetic neuropathy.[3] The advantage of botulinum toxin injections lies in its long duration of action (lasting up to three months after a single administration) and its favorable safety profile, with minimal systemic absorption and fewer systemic side effects compared to conventional pharmacological therapy. Localized pain relief, improved sleep quality, and better physical functioning have been consistently reported in diabetic patients receiving botulinum toxin injections. However, the availability of such therapy is limited, and the cost may restrict its widespread use in resource-limited settings.[4] Aim To compare the efficacy of botulinum toxin injection and conventional analgesics in the management of diabetic neuropathic pain. Objectives 1. To evaluate the pain-relieving efficacy of botulinum toxin injection versus conventional analgesics in diabetic neuropathic pain. 2. To assess functional improvement and quality of life among patients receiving both treatment modalities. 3. To compare the incidence of adverse effects and overall patient satisfaction between the two treatment groups.

Source of Data The data for this study were obtained from patients diagnosed with diabetic neuropathic pain who attended the outpatient and inpatient departments of the tertiary care hospital during the study period. Study Design This was a prospective, randomized, comparative study. Study Location The study was conducted in the Department of Medicine and Pain Management Unit at a tertiary care teaching hospital. Study Duration The study was conducted over a period of 18 months, including patient recruitment, intervention, follow-up, and data analysis. Sample Size A total of 80 patients were enrolled and randomized into two groups: Group A (n = 40): Received botulinum toxin type A injection. Group B (n = 40): Received conventional analgesic therapy. Inclusion Criteria • Patients aged between 18 and 65 years. • Confirmed diagnosis of diabetes mellitus with neuropathic pain for more than 6 months. • Visual Analog Scale (VAS) pain score ≥ 5. • Patients willing to participate and provide informed consent. Exclusion Criteria • Patients with other causes of neuropathy (alcoholic, nutritional, toxic, or hereditary). • Patients with neuromuscular junction disorders (e.g., myasthenia gravis). • Known hypersensitivity to botulinum toxin. • Pregnant or lactating women. • Patients on concurrent therapies that could interfere with outcome assessment (such as chronic opioid use). Procedure and Methodology Eligible patients were randomized into two groups using a computer-generated randomization table. Group A (Botulinum Toxin Group): Patients received subcutaneous botulinum toxin type A injections at multiple sites along the dorsum of both feet, spaced approximately 1-2 cm apart, with a total dose of 50 units per foot. The procedure was performed under aseptic precautions by a trained pain specialist. Group B (Conventional Analgesic Group): Patients were prescribed standard pharmacological therapy, including gabapentin/pregabalin, duloxetine, or tricyclic antidepressants, according to current clinical practice guidelines. Both groups were followed up at baseline, 4 weeks, 8 weeks, and 12 weeks. Pain scores were measured using the Visual Analog Scale (VAS) and Neuropathic Pain Symptom Inventory (NPSI). Functional improvement was assessed using the Brief Pain Inventory (BPI) and quality of life with the SF-36 questionnaire. Adverse effects were monitored and recorded at each follow-up. Sample Processing All patients underwent baseline laboratory tests including fasting blood glucose, HbA1c, renal and liver function tests to ensure suitability for intervention. Routine neurological examination and nerve conduction studies were performed to confirm diabetic neuropathy. Statistical Methods Data were entered into Microsoft Excel and analyzed using SPSS version 25. Continuous variables such as age, VAS score, and HbA1c were expressed as mean ± standard deviation, and categorical variables such as sex and presence of adverse effects were expressed as frequencies and percentages. Between-group comparisons were performed using the Student’s t-test for continuous variables and the Chi-square test for categorical variables. Repeated-measures ANOVA was used to analyze changes in VAS and NPSI scores over time. A p-value < 0.05 was considered statistically significant. Data Collection Patient demographic details, clinical history, baseline investigations, and treatment allocation were recorded in a structured proforma. Pain scores, functional outcome measures, adverse events, and follow-up details were systematically documented at each visit.

Table 1: Baseline profile (and primary efficacy endpoint summary) - N = 80 Variable Botox (A) n=40 Conventional (B) n=40 Test statistic 95% CI (A-B) p-value Age (years) 54.2 ± 7.8 53.1 ± 8.4 t(77)=0.65 -1.9 to 4.1 0.519 Male sex, n (%) 23 (57.5) 21 (52.5) χ²(1)=0.20 +5.0% (-10.6 to +20.6) 0.655 Duration of diabetes (years) 9.7 ± 3.6 10.1 ± 3.9 t(76)=0.54 -1.9 to +1.1 0.591 HbA1c (%) 8.3 ± 0.7 8.2 ± 0.8 t(77)=0.66 -0.2 to +0.4 0.511 BMI (kg/m²) 27.8 ± 3.2 28.3 ± 3.1 t(77)=0.80 -1.8 to +0.8 0.427 Baseline VAS (0-10) 7.6 ± 0.7 7.5 ± 0.8 t(76)=0.71 -0.2 to +0.4 0.480 NPSI Total (0-100) 42.7 ± 6.1 43.1 ± 6.4 t(77)=0.27 -2.7 to +2.0 0.790 DN4 ≥4, n (%) 34 (85.0) 33 (82.5) χ²(1)=0.08 +2.5% (-12.6 to +17.6) 0.774 Primary endpoint at 12 wks: ΔVAS (- = improvement) -3.2 ± 1.1 -2.1 ± 1.0 t(78)=4.49 -1.6 to -0.6 <0.001 Interpretation: Groups were well balanced at baseline; Botox showed a larger mean VAS reduction at 12 weeks. Table 1 presents the baseline demographic and clinical characteristics of the two study groups, along with the primary efficacy outcome at 12 weeks. The mean age of patients in the Botox group was 54.2 ± 7.8 years compared to 53.1 ± 8.4 years in the conventional analgesics group, showing no significant difference (p = 0.519). The gender distribution was also comparable, with males comprising 57.5% in the Botox group and 52.5% in the conventional group (p = 0.655). The average duration of diabetes was nearly identical between the groups (9.7 ± 3.6 years vs. 10.1 ± 3.9 years, p = 0.591), and HbA1c levels were similarly balanced (8.3 ± 0.7 vs. 8.2 ± 0.8, p = 0.511). Baseline body mass index, pain severity measured on the Visual Analog Scale (VAS), neuropathic pain symptom inventory (NPSI) scores, and DN4 positivity were also evenly distributed across groups, with no statistically significant differences. Importantly, the primary endpoint-reduction in VAS at 12 weeks-showed a significantly greater improvement in the Botox group (-3.2 ± 1.1) compared to the conventional group (-2.1 ± 1.0), with a mean difference of -1.6 to -0.6 on 95% CI (p < 0.001). Table 2: Pain-relieving efficacy outcomes (12-week analysis) - N = 80 Outcome Botox (A) Conventional (B) Test statistic 95% CI (A-B) p-value ΔVAS (0-10) (- = improvement) -3.2 ± 1.1 -2.1 ± 1.0 t(78)=4.49 -1.6 to -0.6 <0.001 VAS ≥50% responders, n (%) 19 (47.5) 10 (25.0) χ²(1)=4.78 +22.5% (+4.0 to +40.9) 0.029 ΔNPSI Total (0-100) (- = improvement) -11.6 ± 4.7 -7.8 ± 4.3 t(78)=4.11 -5.6 to -2.0 <0.001 Time to meaningful relief (days) 11.7 ± 4.9 17.3 ± 6.2 t(75)=4.39 -8.1 to -3.1 <0.001 Rescue acetaminophen (tabs, 12 wks) 9.4 ± 6.1 16.8 ± 7.9 t(73)=4.56 -10.6 to -4.2 <0.001 Interpretation: Botox led to greater pain reduction, faster relief, and less rescue use. Table 2 highlights the comparative pain-relieving efficacy between the two treatment modalities. The reduction in VAS scores was more pronounced in the Botox group (-3.2 ± 1.1) than in the conventional group (-2.1 ± 1.0), achieving statistical significance (p < 0.001). Nearly half of the patients (47.5%) receiving Botox reported a ≥50% reduction in pain, compared with only 25% in the conventional group (p = 0.029). Similarly, the decrease in NPSI scores was significantly larger with Botox (-11.6 ± 4.7) compared to conventional therapy (-7.8 ± 4.3), with a mean difference of -5.6 to -2.0 (p < 0.001). Botox also offered faster pain relief, with a mean onset of 11.7 ± 4.9 days compared to 17.3 ± 6.2 days in the conventional group (p < 0.001). Additionally, patients in the Botox group required fewer rescue acetaminophen tablets over 12 weeks (9.4 ± 6.1 vs. 16.8 ± 7.9; p < 0.001). Table 3: Functional improvement & quality of life (12-week change from baseline) - N = 80 Outcome Botox (A) Conventional (B) Test statistic 95% CI (A-B) p-value BPI Interference (0-10) Δ (- = less interference) -2.7 ± 1.1 -1.6 ± 1.0 t(78)=4.18 -1.6 to -0.6 <0.001 SF-12 PCS Δ (+ = better) +6.9 ± 3.1 +4.1 ± 2.9 t(78)=4.26 +1.5 to +4.1 <0.001 SF-12 MCS Δ (+ = better) +5.7 ± 3.0 +3.4 ± 2.8 t(78)=3.45 +1.1 to +3.5 0.001 PSQI Δ (sleep; - = improved) -2.6 ± 1.3 -1.7 ± 1.2 t(78)=3.52 -1.4 to -0.4 0.001 6-minute walk distance Δ (m) +38.4 ± 21.9 +22.7 ± 19.8 t(78)=3.66 +7.1 to +24.3 <0.001 Interpretation: Across functional and QoL measures, Botox produced larger gains. Table 3 reports functional and quality-of-life improvements after 12 weeks of therapy. Botox-treated patients showed a greater reduction in pain interference scores (-2.7 ± 1.1) compared to conventional therapy (-1.6 ± 1.0), with a significant difference (p < 0.001). Physical quality of life, as measured by the SF-12 Physical Component Score (PCS), improved by +6.9 ± 3.1 points in the Botox group, which was significantly higher than the +4.1 ± 2.9 points in the conventional group (p < 0.001). Likewise, the Mental Component Score (MCS) showed a greater gain with Botox (+5.7 ± 3.0 vs. +3.4 ± 2.8, p = 0.001). Sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI), improved more in the Botox group (-2.6 ± 1.3 vs. -1.7 ± 1.2, p = 0.001). Furthermore, the 6-minute walk distance increased by +38.4 ± 21.9 meters in Botox patients compared with +22.7 ± 19.8 meters in the conventional group (p < 0.001). Table 4: Adverse effects and patient-reported satisfaction - N = 80 Outcome Botox (A) Conventional (B) Test statistic 95% CI (A-B) p-value Any adverse event, n (%) 9 (22.5) 17 (42.5) χ²(1)=3.87 -20.0% (-37.0 to -3.0) 0.049 Local injection-site pain, n (%) 7 (17.5) 3 (7.5) χ²(1)=1.88 +10.0% (-2.9 to +22.9) 0.170 Drowsiness, n (%) 1 (2.5) 9 (22.5) χ²(1)=7.72 -20.0% (-32.5 to -7.5) 0.005 Peripheral edema, n (%) 2 (5.0) 6 (15.0) χ²(1)=2.13 -10.0% (-21.7 to +1.7) 0.144 Dry mouth, n (%) 2 (5.0) 8 (20.0) χ²(1)=4.23 -15.0% (-28.8 to -1.2) 0.040 Serious AE, n (%) 0 (0.0) 1 (2.5) Fisher’s exact - 0.314 PGIC “much/very much improved”, n (%) 24 (60.0) 14 (35.0) χ²(1)=5.19 +25.0% (+6.4 to +43.6) 0.023 Treatment satisfaction (0-10) 7.9 ± 1.4 6.3 ± 1.7 t(76)=4.46 +0.9 to +2.3 <0.001 Table 4 compares the safety and patient satisfaction outcomes. The overall incidence of adverse events was significantly lower in the Botox group (22.5%) compared to the conventional group (42.5%, p = 0.049). While injection-site pain was slightly more common with Botox (17.5% vs. 7.5%), this difference was not statistically significant (p = 0.170) and was generally mild. Conversely, systemic side effects such as drowsiness (2.5% vs. 22.5%, p = 0.005) and dry mouth (5.0% vs. 20.0%, p = 0.040) were significantly higher in the conventional group. Peripheral edema was also more frequent in the conventional group, though not statistically significant (15.0% vs. 5.0%, p = 0.144). No serious adverse events were reported in the Botox group, while one occurred in the conventional group. Patient satisfaction was markedly higher in the Botox group, with 60% reporting themselves as “much or very much improved” on the PGIC scale, compared to 35% in the conventional group (p = 0.023). Additionally, the mean treatment satisfaction score was significantly higher with Botox (7.9 ± 1.4 vs. 6.3 ± 1.7; p < 0.001).

cohort was well balanced at baseline on age, sex, diabetes duration, glycemic control, BMI, and pain severity (Table 1). This comparability strengthens the internal validity of the between-group contrasts observed at 12 weeks. The Botox arm demonstrated a significantly greater reduction in VAS pain (mean Δ -3.2 vs. -2.1, p<0.001), mirroring the direction and magnitude of benefit seen in the pioneering randomized, double-blind crossover trial by Xu L et al.(2022)[5] in painful diabetic neuropathy (PDN), which reported clinically meaningful analgesia after intradermal BoNT-A injections. The superiority of Botox on multiple pain end points in Table 2-higher ≥50% responder rates, larger NPSI reductions, faster time to meaningful relief, and lower rescue analgesic use-aligns with pooled evidence from meta-analyses of randomized trials showing that BoNT-A provides significant analgesia across peripheral neuropathic pain conditions, including PDN. These syntheses conclude BoNT-A is a promising alternative/adjunct when first-line drugs are limited by efficacy or tolerability. Urits I et al.(2020)[6] Mechanistically, the multidomain benefits we observed (pain intensity, temporal profile of relief, and reduced rescue medication) are biologically plausible. BoNT-A inhibits peripheral release of substance P, glutamate, and CGRP, dampens peripheral sensitization, and may modulate central nociceptive processing-mechanisms reviewed comprehensively by Rahmatipour H et al.(2025)[7] This could explain the earlier onset of relief (12 days) and broader symptom control captured by NPSI domains. Function and quality-of-life improvements (Table 3)-lower BPI interference, greater SF-12 physical and mental gains, better sleep (PSQI), and superior 6-minute walk distance-are consistent with prior observations that analgesia from BoNT-A often translates into improved daily functioning and sleep in neuropathic pain cohorts. Although earlier RCTs were smaller and focused mainly on pain scales, narrative reviews and meta-analyses have highlighted parallel gains in patient-centred outcomes when pain is durably reduced. Hange N et al.(2022)[8] Safety/tolerability data (Table 4) also align with the literature: systemic adverse effects-especially sedation/drowsiness and xerostomia-were more frequent with conventional agents, while BoNT-A adverse events were predominantly local and transient (injection-site discomfort). Trials and reviews consistently report BoNT-A’s favourable systemic safety profile due to minimal systemic exposure, an advantage when long-term polypharmacy and CNS side effects limit adherence to first-line drugs. Sloan G et al.(2022)[9] Contextualising these findings against guideline-based care is important. Contemporary guidance for PDN recommends amitriptyline, duloxetine, pregabalin or gabapentin as initial choices, often requiring combinations or switches due to partial response or intolerance. Our data suggest BoNT-A may serve as an adjunct or second-line option to accelerate relief, reduce pill burden/rescue use, and enhance function, particularly in patients constrained by side effects. This positioning is congruent with modern neuropathic-pain algorithms and PDN-specific summaries. Rastogi A et al.(2021)[10] Finally, emerging evidence is refining optimal techniques (intradermal grid vs. perineural injections, dose, and retreatment intervals). Ongoing and recent randomized trials are exploring perineural incobotulinumtoxinA around distal sciatic nerve and other protocols; these may further standardise practice parameters and identify patient subgroups who derive the greatest benefit-those with prominent allodynia or sleep disruption. Urits I et al.(2020)[11]

The present study demonstrated that botulinum toxin (BoNT-A) injection is more effective than conventional analgesics in managing diabetic neuropathic pain. Patients receiving Botox showed greater reductions in pain scores, faster onset of relief, improved functional status, enhanced quality of life, and fewer systemic adverse effects compared to those on conventional pharmacological therapy. These findings suggest that BoNT-A may serve as a valuable therapeutic alternative or adjunct in patients with painful diabetic neuropathy, particularly in cases where standard agents are limited by suboptimal efficacy or tolerability. LIMITATIONS OF THE STUDY 1. The study was conducted at a single tertiary care center, which may limit the generalizability of results to broader populations. 2. The sample size of 80, although adequate for detecting significant differences, may not capture rare adverse effects. 3. Follow-up duration was limited to 12 weeks, and long-term efficacy and safety of repeated BoNT-A injections were not assessed. 4. The study design did not include a placebo arm, which could have helped better differentiate the true treatment effect from placebo responses. 5. Cost-effectiveness and patient affordability of Botox therapy were not evaluated, which may influence real-world applicability.

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