Vitamin B Complex for Inferior Alveolar Nerve Paresthesia Recovery

Detailed Description Study Design Overview This is a single-center, parallel-group, superiority, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy of vitamin B complex supplementation in promoting sensory recovery among patients with paresthesia of the inferior alveolar nerve (IAN) following mandibular third molar extraction. The study adopts an experimental, longitudinal design with repeated measures at six time points over an eight-week follow-up period. The trial will be conducted at the Faculdade de Odontologia da Universidade de São Paulo (FOUSP) and at the Fundação para o Desenvolvimento da Odontologia (FUNDECTO), both located in São Paulo, Brazil. Enrollment is expected to occur consecutively based on patient referrals and spontaneous demand from the dental surgery outpatient clinics. The total planned sample size is 50 participants, determined dynamically based on clinical availability but powered to detect clinically meaningful differences between groups based on prior literature. Study Setting and Recruitment Potential participants will be identified among patients presenting to the oral and maxillofacial surgery clinics at FOUSP/FUNDECTO with chief complaints of persistent altered sensation in the distribution of the inferior alveolar nerve following recent mandibular third molar extraction. Recruitment will be performed by trained research assistants who will screen all postoperative patients meeting the temporal inclusion window (symptom onset between 7 and 30 days prior to screening). Eligible patients will be approached, provided with a detailed explanation of the study, and given the Informed Consent Form (ICF). A minimum of 24 hours will be allowed for consideration before obtaining written informed consent. To maximize recruitment and retention, patients will receive reminder calls or text messages before each scheduled visit. Transportation reimbursement will not be provided as all visits coincide with routine postoperative follow-up appointments already scheduled as part of standard care at the institution. Randomization and Allocation Concealment After providing informed consent and completing baseline assessments (T0), eligible participants will be randomly assigned in a 1:1 ratio to either the vitamin B complex group or the placebo group. Randomization will be performed using a computer-generated random sequence with variable block sizes (block sizes 2, 4, or 6, randomly selected) to ensure allocation concealment and balance between groups over time. The randomization list will be generated by an independent statistician who will have no direct contact with participants or outcome assessors. Allocation concealment will be maintained using sequentially numbered, opaque, sealed envelopes. The envelopes will be prepared and kept by a designated researcher (the "pharmacy custodian") who is not involved in participant screening, enrollment, outcome assessments, or data analysis. After baseline assessments are completed and eligibility is reconfirmed, the enrolling investigator will contact the pharmacy custodian, who will open the next envelope and dispense the corresponding medication kit to the participant. Blinding This study employs double-blinding. The following individuals will remain blinded to group allocation until database lock: * Participants * Outcome assessors (clinicians performing sensory tests) * Primary investigator (during data collection phase) * Statistician (during interim blinded sample size re-estimation and final analysis, until database lock) Only the pharmacy custodian will be unblinded to group assignment. The custodian is responsible for preparing, storing, and dispensing the coded medication kits. To maintain blinding, the vitamin B complex and placebo capsules are identical in appearance (size, color, shape, and opaque capsule shell). Both are packaged in identical white plastic bottles labeled only with a unique participant identification number, dosage instructions ("Take one capsule daily by mouth"), and storage conditions. No other identifying information appears on the bottles. In case of a medical emergency where knowledge of the treatment assignment is required for patient safety, an emergency unblinding procedure will be available through the pharmacy custodian, who can be contacted 24/7. Any unblinding event will be documented in the participant's case report form (CRF) and reported to the ethics committee. Intervention Groups Group 1 - Vitamin B Complex (Active Intervention): Participants receive one capsule daily for eight weeks (56 days). Each capsule contains the following formulation: * Thiamine (thiamine mononitrate) - 10 mg * Riboflavin - 10 mcg * Niacin (91% niacinamide, 9% niacin) - 100 mg * Pyridoxine (pyridoxine HCl) - 10 mg * Folate (folic acid) - 400 mcg * Cyanocobalamin (vitamin B12) - 12 mcg * Biotin (as d-biotin) - 45 mcg * Pantothenic acid (calcium pantothenate) - 20 mg These doses are within the standard therapeutic range for neuropathy indications and are considered safe for daily use over eight weeks. Participants are instructed to take the capsule with food to minimize gastrointestinal discomfort. Group 2 - Placebo (Control Intervention): Participants receive one capsule daily for eight weeks. The placebo capsule is identical in appearance to the active capsule and contains only the pharmaceutical vehicle (microcrystalline cellulose or similar inert excipient) with no active vitamins. Medication Supply and Adherence Monitoring All study medications will be produced in compliance with good manufacturing practices. The vitamin B complex and placebo capsules will be packaged in kits containing a 56-day supply (56 capsules per participant). At the baseline visit (T0), participants receive their assigned medication kit after randomization. They are instructed to take one capsule daily at approximately the same time each day, preferably with a meal. Adherence will be monitored through three strategies: 1. Capsule count: At each follow-up visit (T1, T2, T3, T4, T5), participants return their medication bottle. The pharmacy custodian counts remaining capsules and records the count in the CRF. Adherence is calculated as (capsules dispensed - capsules returned) / expected capsules taken over the period. Adherence ≥80% is considered acceptable. 2. Self-report diary: Participants receive a simple daily checklist to record capsule intake. Diaries are collected at each visit. 3. Direct questioning: At each visit, participants are asked about any missed doses and reasons for non-adherence. Participants with adherence below 80% will be counseled. Those who persistently miss doses (adherence \<60% over two consecutive intervals) may be withdrawn from the study but will still be included in the intention-to-treat analysis. Prohibited Concomitant Medications and Washout Participants must refrain from using any additional vitamin B complex supplements or any other neurotropic agents (e.g., methylcobalamin, alpha-lipoic acid, acetyl-L-carnitine, pregabalin, gabapentin) during the study period. Stable use (≥30 days prior to enrollment) of medications that may affect sensory function (e.g., antidepressants, anticonvulsants) is permitted provided the dose remains unchanged throughout the study. Any change in such medications will be recorded as a protocol deviation. A formal washout period is not required in this parallel-group design because each participant receives only one intervention. The low half-life of B vitamins (approximately 2-6 hours for pyridoxine, 6 days for cyanocobalamin in liver storage) does not create carryover effects that would warrant washout. Participants who have taken vitamin B complex supplements within 30 days prior to screening are excluded to prevent baseline bias. Study Procedures and Visit Schedule Participants attend six scheduled visits over 56 days: T0 - Baseline (Day 0): * Informed consent reconfirmation * Demographics and medical/dental history * Review inclusion/exclusion criteria * Baseline sensory assessment battery (detailed below) * Randomization and dispensing of medication kit (56 capsules) * Instruction on capsule intake and diary completion * Scheduling of follow-up visits T1 - Week 1 (Day 7 ± 2 days): * Medication adherence assessment (capsule count and diary) * Adverse event inquiry * Brief sensory assessment (VAS, Von Frey monofilament test) * Dispensing of remaining medication (if needed - no new supply; participants continue with original kit) T2 - Week 2 (Day 14 ± 2 days): * Complete sensory assessment battery * Medication adherence assessment * Adverse event inquiry * Diary collection and review T3 - Week 4 (Day 28 ± 3 days): * Complete sensory assessment battery * Medication adherence assessment * Adverse event inquiry * Diary review T4 - Week 6 (Day 42 ± 3 days): * Complete sensory assessment battery * Medication adherence assessment * Adverse event inquiry * Diary review T5 - Week 8 (Day 56 ± 3 days): * Final complete sensory assessment battery * Final medication adherence assessment * Final adverse event inquiry * End-of-study questionnaire (global perception of change) * Medication kit return (including any unused capsules) * Study closeout Sensory Assessment Battery All sensory tests are performed by trained, blinded outcome assessors in a quiet, temperature-controlled examination room. Tests are conducted on the affected side (ipsilateral to the IAN injury) and, for reference, on the contralateral healthy side (unless bilateral symptoms are present, in which case normative values are used). Participants are positioned supine or semi-reclined with head supported. Each test is performed three times, and the median value is recorded. 1. Visual Analog Scale (VAS) - Subjective Sensation: Participants rate their current level of altered sensation on a 100-mm horizontal line anchored by "no alteration/normal sensation" (0 mm) and "worst possible alteration/complete numbness" (100 mm). The distance from 0 to the participant's mark is measured in millimeters. 2. Semmes-Weinstein Monofilaments (Von Frey): A standardized set of 20 monofilaments (ranging from 0.008 g to 300 g) is applied perpendicularly to the skin of the affected lip/chin area until the filament bends. The test begins with the smallest filament and progresses to larger sizes until the participant reports feeling the touch. The threshold is recorded as the filament marking corresponding to the lightest touch perceived. Testing is repeated three times, alternating with "catch" trials (no application) to assess reliability. 3. Two-Point Discrimination (2PD): A two-point discriminator (disk-criminator or caliper) is applied along the longitudinal axis of the lower lip on the affected side. Starting with a 15-mm separation, the distance is decreased until the participant can no longer distinguish two points as separate. The smallest distance at which two points are correctly identified in at least 3 out of 4 applications is recorded as the static 2PD threshold. Normal value for the lower lip is typically 2-5 mm. 4. Pinprick Sensation (Sharp Touch): A disposable 27-gauge needle or a standardized pinprick device is lightly applied to the skin of the affected area until the participant perceives a sharp sensation. The stimulus is applied five times, interspersed with blunt touch (cotton swab) controls. Responses are graded as: normal (sharp perceived as sharp on all applications), hypesthesia (sharp perceived as dull on ≥50% of applications), or anesthesia (no sharp sensation perceived). 5. Thermal Sensation (Cold/Warm): Two glass test tubes (one filled with cold water at 10°C ± 2°C, one with warm water at 40°C ± 2°C) are alternately applied to the skin of the affected area for 2 seconds each. The participant reports whether the sensation is cold, warm, or cannot differentiate. Testing is repeated three times for each temperature. 6. Photographic Mapping: Digital photographs of the affected area (lower lip, chin, and vestibular mucosa) are taken at each visit. A marking grid may be used to map the boundaries of altered sensation. Photographs are stored in a secured, password-protected database with participant identifiers removed. 7. Global Perception of Change (T5 only): At study completion, participants answer: "Compared to before you started the study medication, how would you rate your sensation now?" Responses are on a 7-point Likert scale: (1) very much worse, (2) much worse, (3) slightly worse, (4) unchanged, (5) slightly improved, (6) much improved, (7) very much improved. Outcome Measures Primary Outcome Measure: Change in static two-point discrimination (2PD) threshold from baseline (T0) to 8 weeks (T5) on the affected side, measured in millimeters. A reduction in 2PD threshold (i.e., ability to distinguish smaller distances) indicates sensory recovery. Secondary Outcome Measures: * Change in Semmes-Weinstein monofilament threshold from T0 to each follow-up time point (T1-T5) * Change in Visual Analog Scale (VAS) score from T0 to T5 * Change in pinprick sensation category (normal/hypesthesia/anesthesia) from T0 to T5 * Change in thermal sensation accuracy from T0 to T5 * Proportion of participants achieving "clinically meaningful improvement" defined as ≥50% reduction in VAS score OR normalization of 2PD (≤5 mm) at T5 * Global perception of change at T5 (dichotomized as improved vs. not improved) Exploratory Outcomes: * Trajectory of sensory recovery over time (group × time interaction effect) * Correlation between objective (2PD, monofilaments) and subjective (VAS) measures * Impact of baseline severity on treatment response (subgroup analysis) Data Collection and Management All data will be collected using paper Case Report Forms (CRFs) during each visit. CRFs are designed with checkboxes, numerical fields, and standardized response options to minimize data entry errors. After each visit, CRFs are reviewed by the study coordinator for completeness and logical consistency. Data will be double-entered into a secure, password-protected electronic database (REDCap or similar platform) by two independent data entry personnel. Discrepancies will be resolved by referring to the original CRFs. Participants are identified only by a unique study ID number. A separate linkage file (name, medical record number, study ID) is stored in an encrypted, access-restricted folder accessible only to the primary investigator and study coordinator. All paper documents are stored in locked cabinets in a locked research office. Sample Size Considerations The target sample size is 50 participants (25 per group). This sample size was determined based on a combination of clinical feasibility and statistical considerations. Prior studies on sensory recovery following IAN injury report an effect size (Cohen's d) of approximately 0.6-0.8 for neurotropic interventions compared to placebo. Assuming a conservative effect size of 0.7, alpha = 0.05 (two-sided), and power = 80%, the required sample size is approximately 34 participants (17 per group). Accounting for an anticipated 20-25% dropout rate over 8 weeks, the target was adjusted to 50 participants (25 per group). A blinded sample size re-estimation will be performed after the pilot phase (20-30 participants) to refine the sample size calculation based on observed variability in the primary outcome. Statistical Analysis Plan All analyses will follow the intention-to-treat (ITT) principle, including all randomized participants in their original assigned groups regardless of adherence or protocol deviations. A per-protocol analysis will be conducted as a sensitivity analysis including only participants with ≥80% adherence and no major protocol violations. Baseline comparisons: Demographic and clinical characteristics will be compared between groups using independent t-tests or Mann-Whitney U tests for continuous variables (depending on normality assessed by Shapiro-Wilk test) and chi-square or Fisher's exact tests for categorical variables. Primary analysis: Change in 2PD threshold from T0 to T5 will be compared between groups using an independent t-test (if normally distributed) or Mann-Whitney U test (if non-normal). The mean difference between groups will be reported with 95% confidence intervals. Cohen's d will be calculated as a measure of effect size. Longitudinal analysis: Repeated measures (2PD, VAS, monofilament thresholds at T0, T2, T3, T4, T5) will be analyzed using a Linear Mixed Model for Repeated Measures (MMRM) with fixed effects for group, time, and group × time interaction, and random intercepts for participants. This approach handles missing data under the missing at random (MAR) assumption without requiring imputation. Contrast statements will compare groups at each time point with Bonferroni adjustment for multiple comparisons. Secondary analyses: Proportions of participants achieving clinically meaningful improvement will be compared using chi-square test. Number needed to treat (NNT) will be calculated as 1 / (absolute risk reduction). Correlation between objective and subjective measures will be assessed using Pearson or Spearman correlation coefficients. Subgroup analyses: Exploratory subgroup analyses will be performed stratified by baseline severity (mild, moderate, severe based on 2PD threshold or monofilament score), age (\<40 vs. ≥40 years), and time from injury to treatment initiation (7-14 days vs. 15-30 days). These analyses are hypothesis-generating only. Missing data: The MMRM approach handles missing outcomes without formal imputation. Sensitivity analyses will be conducted using multiple imputation by chained equations (MICE) with 20 imputed datasets to assess robustness of findings to different missing data assumptions. Adverse Event Monitoring All adverse events (AEs) will be collected from the time of informed consent until the final study visit (T5). At each visit, participants are asked a non-leading question: "Have you experienced any health problems or unusual symptoms since your last visit?" All AEs are recorded in the CRF with details on onset, duration, severity (mild, moderate, severe), seriousness (meeting criteria for serious adverse event \[SAE\]), relationship to study intervention (unrelated, unlikely, possible, probable, definite), and outcome. Serious Adverse Events (SAEs): Any AE resulting in death, hospitalization prolongation, persistent or significant disability, or life-threatening event will be reported to the principal investigator within 24 hours. The PI will notify the ethics committee (CEP) within 24 hours for deaths or life-threatening events, and within 7 days for other SAEs. Expected AEs: Mild gastrointestinal symptoms (nausea, abdominal discomfort) related to vitamin B complex occur in \<5% of users. Skin rash or urticaria (allergic reaction) occurs in \<1%. Localized discomfort during sensory testing (momentary sharp or cold sensation) is expected but resolves immediately. Unexpected AEs: Any AE not listed in the protocol or ICF as expected will be considered unexpected. The Data and Safety Monitoring Committee (DSMC) - composed of two independent clinicians not involved in the study - will review unexpected AEs monthly. If the frequency or severity of AEs exceeds pre-specified stopping boundaries (e.g., grade 3 or 4 toxicity in \>10% of participants), the DSMC may recommend study suspension. Ethical Considerations This study will be conducted in accordance with the Declaration of Helsinki (2013 revision), Resolution 466/12 of the Brazilian National Health Council (CNS), and Good Clinical Practice (GCP) guidelines. The protocol, informed consent form, and all participant-facing materials will be approved by the Research Ethics Committee of the Faculdade de Odontologia da Universidade de São Paulo (FOUSP CEP) before any study activities begin. Any protocol amendments will be submitted for ethical approval prior to implementation. All participants will provide written informed consent. The ICF explains the study purpose, procedures, risks, benefits, voluntary nature of participation, right to withdraw without penalty, and data confidentiality protections. For participants with limited literacy, the ICF will be read aloud in the presence of an impartial witness. Data Safety and Monitoring Given the low-risk nature of the intervention and the small sample size, an external Data Safety and Monitoring Board (DSMB) is not required. Instead, a Data and Safety Monitoring Committee (DSMC) consisting of two faculty members from the FOUSP Department of Surgery, Prosthesis and Maxillofacial Trauma will review: * Recruitment and retention metrics monthly * Adverse event reports monthly * Protocol deviations quarterly * Blinding integrity after the pilot phase (without unblinding group assignments) The DSMC has the authority to recommend study modification, suspension, or termination if safety concerns arise. Dissemination Policy Results of this study, regardless of whether findings are positive, negative, or inconclusive, will be submitted for publication in a peer-reviewed scientific journal. Authorship will follow International Committee of Medical Journal Editors (ICMJE) guidelines. The study will also be registered in a publicly accessible clinical trials registry (ClinicalTrials.gov) before participant enrollment begins. No publication restrictions will be imposed. Trial Status The study is currently in the preparatory phase. Recruitment is expected to begin within 3 months following ethics committee approval. The estimated primary completion date (final data collection for primary outcome measure) is 12 months after the first participant enrollment.