Abstract
The use of gabapentin, a first-line drug for diabetic peripheral neuropathy (DPN), is limited by its side effects, leading to more frequent use of vitamin B as an alternative. This randomized controlled trial of 237 patients with diabetes and at least probable DPN assessed pain outcomes using the Revised Thai Short-Form McGill Pain Questionnaire, Visual Analog Scale, Present Pain Intensity, and monofilament risk score at baseline and 4 and 12 weeks. Gabapentin showed superior improvement across all measures compared with vitamin B1-6-12 and B12, supporting its role as first-line therapy. However, vitamin B1-6-12 remains a cost-effective alternative with lower side effect, warranting further economic evaluation.
The prevalence of diabetes in Thailand is ∼9.5% of the population ≥15 years of age. Of those with diabetes, 16–26% develop diabetic peripheral neuropathy (DPN), a microvascular complication that impairs quality of life and increases the risk of subsequent complications such as falling and chronic wounds (1). The underlying mechanism of DPN is oxidative stress and inflammatory stress on neurons caused by hyperglycemia. The mainstay of treatment involves pharmacological control of symptoms and management of key risk factors (2,3), including elevated BMI, smoking, longer disease duration, depressive symptoms, other diabetes-related complications, and comorbid conditions (4–7). Vitamin B12 levels should be routinely monitored in patients with diabetes using metformin, the first-line antihyperglycemic agent (1). There is evidence that prolonged use and higher doses of metformin are associated with reduced serum vitamin B12 levels and increased risk of developing DPN (8–11) from reduced cobalamin-intrinsic factor complex at the terminal ilium (12); however, serum vitamin B12 levels can be investigated only in a medical center.
Current clinical practice guidelines recommend either gabapentin or pregabalin, the presynaptic excitatory sensory nerve inhibitor, as first-line agents for symptomatic management of neuropathic pain (13–16). Dosage adjustment according to renal function is required to minimize the risk of adverse effects (17,18). However, gabapentin is listed in the Thai National Essential Drugs List as a category C drug designated for specific indications but requiring monitoring for adverse effects (19). Consequently, the role of B vitamins as either adjunctive therapy or monotherapy has garnered attention, given evidence from multiple studies suggesting their efficacy in alleviating pain and sensory disturbances with minimal adverse effects (20–23), resulting specifically from the neuroprotection and nerve regeneration effects of vitamins B1, B6, and B12 (24).
Available vitamin B formulations in Thailand include multivitamin B complexes, which lack indications for treating DPN, and vitamin B1-6-12, which is not included in the National Essential Medicines List (19) and has limited clinical evidence regarding its efficacy in DPN, despite its widespread use in general hospitals. Conversely, vitamin B12 alone, which is included in the National Essential Medicines List as a category substance (19), is not routinely available for prescription in general hospitals. Nonetheless, studies have demonstrated that vitamin B12 significantly reduces pain scores and improves sensory nerve conduction in patients with DPN (20–23), despite conflicting reports from some studies that found no such benefit (25).
Vitamin B1-6-12, particularly in its high-dose formulation (vitamin B1-6-12 forte), has been shown to significantly reduce pain and enhance sensory nerve conduction (26). However, one study reported that even the standard formulation, which contains lower doses within the recommended range (27,28), provided superior symptom control for numbness compared with vitamin B12 alone (29). It should be noted that this study was conducted in postoperative patients, whose underlying mechanisms and timelines of peripheral neuropathy differ significantly from those with diabetic neuropathy. Moreover, the age difference among study participants further limits the generalizability of the findings to populations with diabetes. Additionally, no studies to date have compared the efficacy of these vitamin regimens with standard treatment using gabapentin.
Therefore, this study aimed to evaluate the effectiveness of vitamin B1-6-12 in reducing symptoms of DPN in comparison with gabapentin, the current standard treatment, and with vitamin B12, which is listed in the National Essential Medicines List and may play a more prominent role in future treatment paradigms.
Research Design and Methods
Study Design and Objectives
This study was a randomized controlled trial (RCT) classified as therapeutic research. Its primary objectives were to compare the mean difference in Thai Short-Form McGill Pain Questionnaire (Th-SFMPQ), Visual Analog Scale (VAS), and Present Pain Intensity (PPI) scores at weeks 0, 4, and 12 among patients with DPN receiving treatment with vitamin B1-6-12, gabapentin, or vitamin B12. A secondary objective was to evaluate the incidence of adverse effects associated with vitamin B1-6-12 compared with gabapentin and vitamin B12.
Study Population
The study included patients diagnosed with type 2 diabetes for ≥1 year who meet the inclusion criteria of having a Thai Douleur Neuropathique [Neuropathic Pain] 4 (Thai DN4) score ≥4 and a diagnostic classification of at least probable neuropathic pain (13). Participants were recruited from health-promoting hospitals under the primary care network of Srisangworn Sukhothai Hospital, located in the Si Samrong District of Thailand’s Sukhothai Province, between October 2024 and January 2025. Participating primary care units within the district included Khlong Tan, Wang Luek, Wat Ko, Ban Rai, Wang Thong, Thap Phueng, and Na Khun Krai.
Sample Size Calculation
The sample size estimation was based on data obtained from a pilot study involving 27 participants. The participants were evenly distributed across three treatment groups; group 1 received vitamin B1-6-12, group 2 received gabapentin, and group 3 received vitamin B12. Sample size was calculated using the ANCOVA method, which accounts for covariates during the computation process. Given that this was an RCT and used an explanatory sample size approach focusing primarily on the effect of the independent variable (index X), no additional covariate adjustments were deemed necessary.
The calculation was based solely on outcome scores from the Th-SFMPQ because it offered the highest level of measurement precision among the tools used. Comparisons were made between group 1 (vitamin B1-6-12) and group 2 (gabapentin) and between group 1 and group 3 (vitamin B12). The sample size was determined to achieve a statistical power of 90% and a type I error rate (α) of 5%. The estimated required sample sizes were between 71 and 163 in each intervention. Additional information about the conduct of this study can be found in the Supplementary Material.
Based on the calculation, each treatment group required 71 participants. After accounting for a 10% dropout rate, the target sample size was adjusted to 78 participants per group, resulting in a total of 234 participants. However, the actual number of participants enrolled in the study was 241, and these were distributed into three groups. Participant allocation was performed using a simple randomization method.
Inclusion, Exclusion, and Discontinuation Criteria
Participants were eligible for inclusion if they had been diagnosed with type 2 diabetes for ≥1 year, scored ≥4 out of 10 on the Thai DN4 questionnaire, and met the diagnostic criteria for probable neuropathic pain or higher, in accordance with the 2020 Clinical Guidance for Neuropathic Pain (13). The latter required fulfillment of all three of the following conditions: 1) documented history of injury or disease affecting the somatosensory nervous system with varied pain characteristic of or nonpain symptoms compatible with neuropathic pain in terms of duration, frequency, and location, with aggravating and relieving factors and no sign or symptom of compatible local tissue damage other than neuronal tissue; 2) pain localized in or extending from an area innervated by the affected nervous structure(s) in a pattern of painful polyneuropathy or a glove-and-stocking pattern; and 3) clinical examination confirming the presence of sensory nerve lesion(s), demonstrated by negative symptoms (e.g., sensory loss) or positive symptoms (e.g., hyperalgesia). To be eligible, participants also had to have no known allergy to any of the study medications and to be able to communicate effectively and demonstrate full cognitive competence.
Individuals who declined to participate were excluded. Participants were withdrawn from the study if they voluntarily withdrew from the medication or failed to comply with the medication regimen; developed serious adverse drug reactions, including seizures, drug allergy, or anaphylaxis; or experienced worsening of symptoms after medication administration, as indicated by increased Th-SFMPQ, VAS, or PPI scores. Figure 1 shows the flow of participant inclusion, exclusion, and discontinuation throughout the study period.
Figure 1.
Participant flow: inclusion, exclusion, and discontinuation throughout the study period. DM, diabetes.
Instruments for Data Collection and Quality Assessment
Five data collection instruments were used in this study: a demographic and medical history form, an adverse drug reaction screening form, the Thai DN4 (13,30–33), the revised Th-SFMPQ (34,35), and the monofilament risk score (1,36,37).
The Thai DN4 (13,30–33), which is commonly used for DPN screening, was adopted as an inclusion criterion for this study. The sensitivity and specificity of this instrument at a cutoff score of 4 are 80% and 92%, respectively. The percentage of agreement in an interrater reliability test is 88.7% and the κ coefficient is 0.76. The intraclass correlation coefficient at the 60- to 120-day interval is 0.79 (excellent).
The revised Th-SFMPQ (34,35) was used to assess and monitor the symptoms of DPN, with a detailed severity evaluation comprising three domains: symptom descriptors, overall pain intensity (VAS), and current pain level (PPI). In an interrater reliability test, the κ coefficients in sensory score, affective score, total count, total score, VAS, and PPI are all >0.8. Intraclass correlation coefficients show nonsignificant differences in all parameters except for the affective score at the 15-day interval. An index of item-objective congruence (IOC) was performed after adaptation of the instrument for this study (Table 1).
The monofilament risk score (1,36,37) was the standard screening tool for DPN and comprised an external foot examination and a three-site monofilament test. The monofilament assessment was performed using a 10-g monofilament applied perpendicularly to the plantar surface at three sites: 1) the pulp of the hallux, 2) the first metatarsophalangeal joint, and 3) the fifth metatarsophalangeal joint, with two true applications and one sham application and with the filament maintained in position for ∼2 seconds. Tests were considered normal if participants correctly identified the site of stimulation in at least two out of three applications. If none or only one out of three responses was correct, the test was repeated another time to confirm an abnormal result. Final grading was classified into four categories: grade 0, normal external foot appearance and normal monofilament test; grade 1, normal external foot appearance and abnormal monofilament test; grade 2, foot deformity with abnormal monofilament test; and grade 3, presence of foot ulceration. The sensitivity and specificity of this instrument in patients with diabetes are 11.1 and 98.0%, respectively. The κ coefficient in patients with diabetes is 0.925 in three to four sites and 0.797 in three to 10 sites.
Table 1.
IOC for Modified Research Instrument
| Item | Expert 1 | Expert 2 | Expert 3 | Total | IOC Value | Interpretation |
|---|---|---|---|---|---|---|
| Symptom descriptors | ||||||
| Burning pain | +1 | +1 | +1 | 3 | 1.00 | Acceptable |
| Cold pain (ice-like) | +1 | +1 | +1 | 3 | 1.00 | Acceptable |
| Electric shock-like pain | +1 | +1 | +1 | 3 | 1.00 | Acceptable |
| Tingling or pins and needles | +1 | +1 | +1 | 3 | 1.00 | Acceptable |
| Stabbing pain (like being pricked by a needle) | +1 | +1 | +1 | 3 | 1.00 | Acceptable |
| Numbness (loss of sensation) | +1 | +1 | +1 | 3 | 1.00 | Acceptable |
| Itching | +1 | +1 | +1 | 3 | 1.00 | Acceptable |
| Decreased sensation to touch | +1 | 0 | +1 | 2 | 0.67 | Acceptable (revise) |
| Decreased sensation to pinprick | +1 | 0 | +1 | 2 | 0.67 | Acceptable (revise) |
| Pain evoked or increased by brushing in the painful area | 0 | +1 | +1 | 2 | 0.67 | Acceptable (revise) |
| Overall symptom severity (modified from VAS) | +1 | +1 | +1 | 3 | 1.00 | Acceptable |
| Current pain level (modified from PPI) | +1 | +1 | +1 | 3 | 1.00 | Acceptable |
Data Collection
Study participants were required to provide informed consent by signing a consent form, including statements in accordance with the Personal Data Protection Act. If participants had any questions, they were able to contact the researcher directly at any time. The researcher personally conducted interviews with the participants, completed the assessment forms, and verified the completeness of the assessments.
Protection of Participant Rights
This study was approved by the Human Research Ethics Committee of Srisangworn Sukhothai Hospital, Sukhothai, Thailand. The certificate of approval (no. 26/2567) was valid from 28 October 2024 to 27 October 2025.
Data Analysis and Statistical Methods
Data were analyzed using STATA/MP, v. 16.1, statistical software. Basic data and preliminary outcomes were analyzed using descriptive statistics such as frequency and percentage and mean ± SD. Statistical significance was assessed using a P value threshold of 0.05. Clinical outcomes were further analyzed using mean differences, with statistical significance also determined at a P value of 0.05.
Expected Benefits
Health care providers may use the findings of this research to adjust medication practices for managing neuropathic pain more appropriately, especially in primary care setting. Additionally, interested individuals may use the results as a basis for further research.
Results
Study Participants
Of the 241 participants who met the inclusion criteria and agreed to participate, a simple random sampling method was used to assign them to one of three groups. Group 1 included 80 participants who received gabapentin, group 2 included 80 participants who received vitamin B12, and group 3 included 81 participants who received vitamin B1-6-12.
After the 4-week treatment and follow-up period, a few participants were withdrawn from the study based on specific criteria. One participant in the gabapentin group discontinued the medication because of myoclonus and chose not to continue treatment. Two participants in the vitamin B12 group did not return for follow-up appointments. One participant in the vitamin B1-6-12 group experienced worsened symptoms and was withdrawn from the study. Consequently, 237 participants completed the study and were included in the analyses per protocol. Seventy-nine participants (33.33%) were in group 1 (gabapentin), 78 (32.91%) were in group 2 (vitamin B12), and 80 (33.76%) were in group 3 (vitamin B1-6-12).
Demographic and baseline characteristics of the participants, by group, are shown in Table 2.
Table 2.
Demographic and Baseline Characteristics
| Characteristic | Gabapentin (n = 79) | Vitamin B12 (n = 78) | Vitamin B1-6-12 (n = 80) | P |
|---|---|---|---|---|
| Sex Male Female |
11 (13.9) 68 (86.1) |
20 (25.6) 58 (74.4) |
12 (15.0) 68 (85.0) |
0.122 |
| Age, years | 64.1 ± 10.5 | 65.4 ± 9.5 | 63.4 ± 10.1 | 0.439 |
| BMI, kg/m2 | 24.8 ± 4.6 | 24.9 ± 4.5 | 26.4 ± 5.4 | 0.069 |
| BMI range, kg/m2 <18.5 18.5–22.9 23.0–24.9 25.0–29.9 ≥30.0 |
5 (6.3) 23 (29.1) 16 (20.3) 25 (31.6) 10 (12.7) |
6 (7.7) 18 (23.1) 16 (20.5) 29 (37.2) 9 (11.5) |
2 (2.5) 23 (28.7) 9 (11.3) 27 (33.7) 19 (23.7) |
0.257 |
| Comorbidities Hypertension Dyslipidemia Chronic kidney disease Cardiovascular disease Peripheral arterial disease Depressive symptoms Other |
75 (94.9) 69 (87.3) 67 (84.8) 9 (11.4) 0 (0.0) 0 (0.0) 1 (1.3) 4 (5.1) |
74 (96.1) 64 (82.1) 61 (78.2) 16 (20.5) 1 (1.3) 0 (0.0) 1 (1.3) 5 (6.4) |
78 (97.5) 69 (86.3) 71 (88.7) 10 (12.5) 1 (1.3) 0 (0.0) 1 (1.3) 5 (6.3) |
0.709 0.646 0.197 0.238 0.774 NA 1.000 0.944 |
| Chronic smoking | 4 (5.1) | 2 (2.6) | 4 (5.0) | 0.778 |
| Chronic alcohol drinking | 3 (3.8) | 3 (3.9) | 1 (1.3) | 0.573 |
| A1C, % | 7.5 ± 1.8 | 7.4 ± 1.6 | 7.6 ± 1.9 | 0.654 |
| A1C range, % <7.0 7.0–10.9 ≥11.0 |
38 (48.1) 37 (46.8) 4 (5.1) |
39 (50.0) 36 (46.1) 3 (3.6) |
38 (47.5) 37 (46.3) 5 (6.3) |
0.985 |
| Complications Diabetic retinopathy Diabetic ulcer |
2 (2.5) 2 (2.5) 0 (0.0) |
4 (5.1) 4 (5.1) 0 (0.0) |
4 (5.0) 4 (5.0) 0 (0.0) |
0.722 0.722 NA |
| Metformin dose, mg/day 0 500 1,000 1,500 2,000 2,500 3,000 |
8 (10.1) 5 (6.3) 31 (39.2) 8 (10.1) 25 (31.7) 1 (1.3) 1 (1.3) |
13 (16.7) 9 (11.5) 25 (32.1) 7 (9.0) 21 (26.9) 1 (1.3) 2 (2.7) |
17 (21.3) 8 (10.0) 25 (31.3) 6 (7.5) 20 (25.0) 4 (5.0) 0 (0.0) |
0.152 0.546 0.516 0.848 0.651 0.373 0.217 |
| Thai DN4 score at week 0 | 5.1 ± 1.4 | 5.0 ± 1.5 | 5.1 ± 1.5 | 0.805 |
Data are n (%) or mean ± SD. NA, not applicable.
Outcomes
Study outcomes at weeks 0, 4, and 12 are described below and summarized in Table 3 and depicted in Figures 2–5.
Table 3.
Outcomes
| Parameter | Gabapentin (n = 79) | Vitamin B12 (n = 78) | Vitamin B1-6-12 (n = 80) | P | |||||
|---|---|---|---|---|---|---|---|---|---|
| Th-SFMPQ at week 0 | 10.6 ± 4.0 | 10.4 ± 5.0 | 10.9 ± 4.1 | 0.772 | |||||
| Th-SFMPQ at week 4 | 6.1 ± 3.7 | 7.2 ± 4.7 | 7.2 ± 4.0 | 0.157 | |||||
| Th-SFMPQ at week 12 | 4.0 ± 3.3 | 5.1 ± 4.0 | 5.1 ± 3.8 | 0.105 | |||||
| VAS at week 0 | 5.8 ± 2.1 | 5.7 ± 2.1 | 6.1 ± 2.1 | 0.550 | |||||
| VAS at week 4 | 3.5 ± 2.1 | 3.7 ± 1.9 | 3.9 ± 2.1 | 0.380 | |||||
| VAS at week 12 | 2.3 ± 2.0 | 2.7 ± 1.8 | 2.7 ± 2.1 | 0.396 | |||||
| PPI at week 0 | 2.6 ± 1.1 | 2.3 ± 1.0 | 2.8 ± 1.1 | 0.013 | |||||
| PPI at week 4 | 1.8 ± 1.1 | 1.7 ± 0.8 | 1.8 ± 0.8 | 0.908 | |||||
| PPI at week 12 | 1.2 ± 0.9 | 1.3 ± 0.7 | 1.3 ± 0.9 | 0.834 | |||||
| Monofilament risk score at week 0 | 0.5 ± 0.7 | 0.6 ± 0.7 | 0.4 ± 0.6 | 0.327 | |||||
| Monofilament risk score at week 12 | 0.2 ± 0.5 | 0.3 ± 0.6 | 0.2 ± 0.4 | 0.213 | |||||
| Mean Differences in Scores on Key Symptom Measures | |||||||||
| Week 0 to Week 4 | Week 0 to Week 12 | P | P Compared With Gabapentin | P Compared With Vitamin B12 | |||||
| Th-SFMPQ | |||||||||
| Gabapentin | −4.5 (−5.1 to −3.9) | −6.6 (−7.3 to −5.9) | 0.010 | — | — | ||||
| Vitamin B12 | −3.2 (−3.9 to −2.6) | −5.3 (−6.1 to −4.6) | 0.003 | — | |||||
| Vitamin B1-6-12 | −3.7 (−4.3 to −3.1) | −5.9 (−6.6 to −5.1) | 0.066 | 0.241 | |||||
| VAS | |||||||||
| Gabapentin | −2.3 (−2.6 to −2.0) | −3.4 (−3.8 to −3.1) | 0.290 | — | — | ||||
| Vitamin B12 | −2.0 (−2.3 to −1.7) | −3.1 (−3.4 to −2.7) | 0.117 | — | |||||
| Vitamin B1-6-12 | −2.1 (−2.4 to −1.8) | −3.3 (−3.7 to −2.9) | 0.512 | 0.359 | |||||
| PPI | |||||||||
| Gabapentin | −0.8 (−1.0 to −0.6) | −1.3 (−1.5 to −1.1) | <0.001 | — | — | ||||
| Vitamin B12 | −0.5 (−0.7 to −0.4) | −0.9 (−1.1 to −0.8) | 0.003 | — | |||||
| Vitamin B1-6-12 | −1.0 (−1.1 to −0.8) | −1.5 (−1.7 to −1.3) | 0.125 | <0.001 | |||||
| Monofilament risk score | |||||||||
| Gabapentin | — | −0.3 (−0.4 to −0.1) | 0.822 | — | — | ||||
| Vitamin B12 | — | −0.3 (−0.4 to −0.1) | 0.801 | — | |||||
| Vitamin B1-6-12 | — | −0.2 (−0.1 to −0.3) | 0.534 | 0.714 | |||||
Data are mean ± SD or mean difference (95% CI).
Figure 2.
Th-SFMPQ scores at weeks 0, 4, and 12.
Figure 5.
Monofilament risk scores at weeks 0 and 12.
Figure 3.
VAS scores at weeks 0, 4, and 12.
Figure 4.
PPI scores at weeks 0, 4, and 12.
At Baseline (Week 0)
Mean scores on the Th-SFMPQ were 10.6 ± 4.0 in the gabapentin group, 10.4 ± 5.0 in the vitamin B12 group, and 10.9 ± 4.1 in the vitamin B1-6-12 group. These differences were not statistically significant. Mean VAS scores were 5.8 ± 2.1, 5.7 ± 2.1, and 6.1 ± 2.1 in the gabapentin, vitamin B12, and vitamin B1-6-12 groups, respectively. These differences were not statistically significant. Mean PPI scores were 2.6 ± 1.1, 2.3 ± 1.0, and 2.8 ± 1.1, respectively, with a statistically significant difference between groups (P = 0.013). Mean monofilament risk scores were 0.5 ± 0.7 in the gabapentin group, 0.6 ± 0.7 in the vitamin B12 group, and 0.4 ± 0.6 in the vitamin B1-6-12 group. These differences were not statistically significant.
At Week 4
Mean scores on the Th-SFMPQ were 6.1 ± 3.7 in the gabapentin group, 7.2 ± 4.7 in the vitamin B12 group, and 7.2 ± 4.0 in the vitamin B1-6-12 group. These differences were not statistically significant. Mean VAS scores were 3.5 ± 2.1, 3.7 ± 1.9, and 3.9 ± 2.1, respectively, with no statistically significant differences. Mean PPI scores were 1.8 ± 1.1, 1.7 ± 0.8, and 1.8 ± 0.8, respectively, with no statistically significant differences.
At Week 12
Mean scores on the Th-SFMPQ were 4.0 ± 3.3 in the gabapentin group, 5.1 ± 4.0 in the vitamin B12 group, and 5.1 ± 3.8 in the vitamin B1-6-12 group. These differences were not statistically significant. Mean VAS scores were 2.3 ± 2.0, 2.7 ± 1.8, and 2.7 ± 2.1, respectively, with no statistically significant differences. Mean PPI scores were 1.2 ± 0.9, 1.3 ± 0.7, and 1.3 ± 0.9, respectively, with no statistically significant differences. Mean monofilament risk scores were 0.2 ± 0.5 in the gabapentin group, 0.3 ± 0.6 in the vitamin B12 group, and 0.2 ± 0.4 in the vitamin B1-6-12 group. These differences were not statistically significant.
Analysis of Results
Data pertaining to the analysis of results is summarized in Table 3. When considering how mean scores on the Th-SFMPQ changed between week 0 and week 12, the gabapentin group had a mean difference of −6.6 (95% CI −7.3 to −5.9), the vitamin B12 group had a mean difference of −5.3 (95% CI −6.1 to −4.6), and the vitamin B1-6-12 group had a mean difference of −5.9 (95% CI −6.6 to −5.1) The overall comparison among the three groups showed a statistically significant difference (P = 0.010). Pairwise comparisons were also made. The gabapentin group compared with the vitamin B12 group showed a statistically significant difference (P = 0.003), whereas the gabapentin group compared with the vitamin B1-6-12 group did not show a statistically significant difference (P = 0.066). Likewise, the vitamin B12 group compared with the vitamin B1-6-12 group did not show a statistically significant difference (P = 0.241).
For the VAS between week 0 and week 12, the gabapentin group had a mean difference of −3.4 (95% CI −3.8 to −3.1), the vitamin B12 had a mean difference of −3.1 (95% CI −3.4 to −2.7), and the vitamin B1-6-12 group had a mean difference of −3.3 (95% CI −3.7 to −2.9). No statistically significant difference was found among the three groups (P = 0.290). In pairwise comparisons, the gabapentin group compared with the vitamin B12 group did not show a statistically significant difference (P = 0.117), the gabapentin group compared with the vitamin B1-6-12 group did not show a statistically significant difference (P = 0.512), and the vitamin B12 group compared with the vitamin B1-6-12 group likewise did not show a statistically significant difference (P = 0.359).
For the PPI between week 0 and week 12, the gabapentin group had a mean difference of −1.3 (95% CI −1.5 to −1.1), the vitamin B12 group had a mean difference of −0.9 (95% CI −1.1 to −0.8), and the vitamin B1-6-12 group had a mean difference of −1.5 (95% CI −1.7 to −1.3). The overall comparison revealed a statistically significant difference (P <0.001). In pairwise comparisons, the gabapentin group compared with the vitamin B12 group showed a statistically significant difference (P = 0.003), the gabapentin group compared with the vitamin B1-6-12 group did not show a statistically significant difference (P = 0.125), and the vitamin B12 group compared with the vitamin B1-6-12 group did show a statistically significant difference (P <0.001).
For monofilament risk score between week 0 and week 12, the gabapentin group had a mean difference of −0.3 (95% CI −0.4 to −0.1), the vitamin B12 group had a mean difference of −0.3 (95% CI −0.4 to −0.1), and the vitamin B1-6-12 group had a mean difference of −0.2 (95% CI −0.1 to −0.3). No statistically significant difference was found among the three groups (P = 0.822). In pairwise comparisons, the gabapentin group compared with the vitamin B12 group did not show a statistically significant difference (P = 0.801), the gabapentin group compared with the vitamin B1-6-12 group did not show a statistically significant difference (P = 0.534), and the vitamin B12 group compared with the vitamin B1-6-12 group did not show a statistically significant difference (P <0.714).
Discussion
This study was conducted among participants with comparable baseline characteristics. It was found that the group receiving gabapentin experienced greater reductions in scores on the Th-SFMPQ, VAS, PPI, and monofilament risk score instruments compared with both the vitamin B12 and the vitamin B1-6-12 groups. Notably, the reductions in Th-SFMPQ and PPI scores were statistically significantly greater than those observed in the vitamin B12 group (P = 0.003 for both). This finding supports the use of gabapentin as a first-line option, in line with the American Diabetes Association’s guidelines on DPN (2,3), as well as the Royal College of Physicians of Thailand’s recommendations on screening, prevention, and management of diabetic foot ulcers (1), and the Thai Association for the Study of Pain’s clinical practice guidelines for neuropathic pain (13). However, gabapentin was associated with a higher incidence of daytime sleepiness as a side effect. When comparing vitamin B1-6-12 and vitamin B12, the vitamin B1-6-12 group showed greater reductions in Th-SFMPQ, VAS, and PPI scores than the vitamin B12 group, although only the PPI score difference reached statistical significance, and the monofilament risk score had a greater decrease in the vitamin B12 group. This finding is consistent with an earlier study by Traising (29).
Strengths and Limitations
A key strength of this study is that each treatment option was selected based on real-world clinical practice and aligned with the National Essential Medicines List. This strategy enhanced the applicability and relevance of the findings to routine clinical settings. Additionally, the RCT design provides a high level of evidence within the hierarchy of clinical research methodologies. Although the primary analysis followed a per-protocol approach, minimal loss to follow-up limited the risk of allocation bias and helped preserve the benefits of randomization.
The main limitation of this study lies in the subjective nature of most pain-assessment tools used. Only three items were based on objective clinical examination by a physician. As a result, the study may be affected by recall bias, through which participants may not have accurately remembered or reported the severity of their symptoms. Moreover, having the prescribing physician conduct the interviews may have introduced courtesy bias, causing participants to underreport their symptoms at follow-up. Nonetheless, the use of the Th-SFMPQ, which includes various dimensions of pain and sensory contents, likely improved the accuracy of pain assessment. Still, modifying the questionnaire items may introduce information bias. To minimize this issue, the researcher conducted an IOC evaluation to ensure content validity (Table 1). Another limitation is the lack of blinding for both participants and the researcher, which may have contributed to performance and detection bias.
Future Directions
Recommendations for further research include studying the added value of combining gabapentin with vitamin B1-6-12 compared with using either treatment alone, given their different mechanisms of action and common combined use in practice. Additionally, further studies on the cost-effectiveness of gabapentin versus vitamin B1-6-12 are warranted, especially because both showed similar efficacy, but vitamin B1-6-12 is less expensive than both gabapentin and vitamin B12. Further investigation into the predictors of daytime sleepiness caused by gabapentin in Asian or Thai populations is also suggested, as this side effect was frequently observed even when doses were adjusted according to renal function (17,18).
Conclusion
Gabapentin was found to be more effective in controlling symptoms of DPN compared with both vitamin B1-6-12 and vitamin B12. Although gabapentin was associated with mild side effects such as daytime sleepiness, its superior efficacy supports its consideration as a first-line treatment option. However, further research into the economic value of vitamin B1-6-12 is recommended, given its comparable effectiveness and lower cost compared with both gabapentin and vitamin B12.
This article contains supplementary material online at https://doi.org/10.2337/figshare.30229558.
Acknowledgments
Acknowledgments
The author acknowledges Wipawan Kaewmanee, MD, the author’s supervisor in Buddhachinaraj Phitsanulok Hospital, and Natcha Kanjanachom, MD, the author’s supervisor in Srisangworn Sukhothai Hospital, for help preparing the manuscript. Prof. Dr. Jayanton Patumanond, MD, PhD, Center for Clinical Epidemiology and Clinical Statistics, Chiang Mai University, contributed to the study format and the statistical analysis. Tanakarn Sarakam, MD, and Sasitorn Sriphothong, MD, the author’s co-supervisor in Buddhachinaraj Phitsanulok Hospital, contributed to the discussion and integrity of the study. These individuals did not meet the criteria authorship as defined by the American Diabetes Association’s Journal Policies and are therefore acknowledged but not listed as authors.
During the course of preparing this work, the author used ChatGPT-4o for the purpose of grammar correction and sentence arrangement. Following the use of this tool/service, the author formally reviewed the content for its accuracy and edited it as necessary. The author takes full responsibility for all of the content.
Duality of Interest
No potential conflicts of interest relevant to this article were reported.
Author Contributions
As the sole author, N.P. researched data, wrote the manuscript, reviewed/edited the manuscript, contributed to discussion, and is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding Statement
This study was supported by a research grant from Srisangworn Sukhothai Hospital in Sukhothai, Thailand.
Supporting information
References
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